Module KB
Reusable biological module sketches rendered from YAML. Columns with numeric counts are derived by recursively walking each module document. Click a column header to sort; counts and concepts come straight from the YAML.
Some modules can also be run: see the executable models (Boolean networks you can run in the browser, and associated kinetic models), or use the model filter below.
| Module | Type | Status | Taxon | PTNs | Concepts | Nodes | Annotons | Parts | Variant sets | Variants | Connections | Genes rev. | Leaf gaps | Module DR | Models | Source |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
2-methylcitrate cycleMODULE:methylcitrate_cycleCONCRETE A propionate-assimilation pathway that activates propionate to propionyl-CoA, condenses propionyl-CoA with oxaloacetate to form 2-methylcitrate,... [more...][less]A propionate-assimilation pathway that activates propionate to propionyl-CoA, condenses propionyl-CoA with oxaloacetate to form 2-methylcitrate, converts 2-methylcitrate to 2-methylisocitrate through alternative dehydration/isomerization implementations, and cleaves 2-methylisocitrate to succinate and pyruvate. The direct PrpD route is distinguished from the two-component AcnD/PrpF route, and the common aconitase-family hydration step is represented separately, with AcnB- and AcnA-family implementations. The pathway is widespread in proteobacteria and actinobacteria and is also present in fungal mitochondria. |
Metabolic Pathway | COMPLETE | 5 | propionate catabolic process |
12 | 8 | 7 | 2 | 4 | 5 | 15/15 | 0 | ✓ | modules/methylcitrate_cycle.yaml | ||
26S proteasome in Drosophila melanogasterMODULE:dmel_proteasomeCONCRETE The 26S proteasome degrades proteins tagged with polyubiquitin chains. Its 20S core particle is a barrel of four stacked heptameric rings, two... [more...][less]The 26S proteasome degrades proteins tagged with polyubiquitin chains. Its 20S core particle is a barrel of four stacked heptameric rings, two outer rings of alpha subunits that gate substrate entry and two inner rings of beta subunits, three of which (beta1, beta2 and beta5) are N-terminal threonine proteases with caspase-like, trypsin-like and chymotrypsin-like specificities. The 19S regulatory particle caps the core. Its base contains six AAA+ ATPases (Rpt1-Rpt6) that unfold substrates and open the core gate, together with the scaffolds Rpn1 and Rpn2. Ubiquitin receptors (Rpn10 and Rpn13) bind ubiquitylated substrates, the lid metalloprotease Rpn11 removes ubiquitin chains before degradation, and Uch-L5 bound to Rpn13 trims chains. Drosophila has a testis-specific 26S proteasome in which paralogs replace several alpha, beta, Rpt, Rpn and Uch-L5 subunits. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | proteasome complex |
18 | 14 | 7 | 5 | 10 | 1 | 0/50 | 0 | ✗ | modules/dmel_proteasome.yaml | |
3-Hydroxypropionate/4-hydroxybutyrate CO2 fixation cycle (Sulfolobales)MODULE:hydroxypropionate_hydroxybutyrate_cycleCONCRETE The autotrophic CO2 fixation cycle of the Sulfolobales. Acetyl-CoA is carboxylated to malonyl-CoA and reduced through malonate semialdehyde and... [more...][less]The autotrophic CO2 fixation cycle of the Sulfolobales. Acetyl-CoA is carboxylated to malonyl-CoA and reduced through malonate semialdehyde and 3-hydroxypropionate to propionyl-CoA, which is carboxylated a second time and rearranged to succinyl-CoA. Succinyl-CoA is reduced through succinate semialdehyde to 4-hydroxybutyrate, which is activated, dehydrated to crotonyl-CoA and converted through acetoacetyl-CoA into two molecules of acetyl-CoA. One acetyl-CoA restarts the cycle, so each turn fixes two bicarbonate molecules into one acetyl-CoA. Several enzymes act twice: one carboxylase acts on acetyl-CoA and propionyl-CoA, one reductase on malonyl-CoA and succinyl-CoA, and one crotonase-family enzyme dehydrates 3-hydroxypropionyl-CoA and hydrates crotonyl-CoA. |
Metabolic Pathway | DRAFT | Sulfolobales |
0 | carbon fixation |
19 | 16 | 18 | 0 | 0 | 16 | 17/17 | 0 | ✗ | modules/hydroxypropionate_hydroxybutyrate_cycle.yaml | |
3-hydroxypropionate bicycleMODULE:hydroxypropionate_bicycleABSTRACT The 3-hydroxypropionate bicycle of Chloroflexus aurantiacus, which fixes two bicarbonate molecules per turn using two biotin-dependent carboxylases... [more...][less]The 3-hydroxypropionate bicycle of Chloroflexus aurantiacus, which fixes two bicarbonate molecules per turn using two biotin-dependent carboxylases and no oxygen-sensitive ferredoxin chemistry at all. The first cycle carboxylates acetyl-CoA to malonyl-CoA, reduces that to 3-hydroxypropionate, reactivates and reduces it to propionyl-CoA, carboxylates again to methylmalonyl-CoA, and rearranges that to succinyl-CoA, which is converted through to (S)-malyl-CoA and cleaved to release glyoxylate and regenerate acetyl-CoA. The second cycle exists because glyoxylate is not directly usable: it is condensed with propionyl-CoA and processed to citramalyl-CoA, whose cleavage yields pyruvate for biosynthesis and returns acetyl-CoA to the first cycle. Hence "bicycle" - two cycles sharing the propionyl-CoA node. Being oxygen-insensitive, it works in the aerobic and microaerophilic conditions that exclude MODULE:reductive_tca_cycle and MODULE:wood_ljungdahl_pathway, with which it is a sibling, as it is of MODULE:calvin_benson_bassham_cycle. The distinct archaeal 3-hydroxypropionate/4-hydroxybutyrate cycle of the Sulfolobales is a different pathway and is not modelled here. |
Metabolic Pathway | DRAFT | 0 | carbon fixation by 3-hydroxypropionate cycle carbon fixation |
8 | 8 | 7 | 0 | 0 | 9 | 0/2 | 0 | ✗ | modules/hydroxypropionate_bicycle.yaml | ||
ABCE model of floral organ identity (MADS floral quartets)MODULE:floral_organ_identity_abceCONCRETE In the eudicot flower, four concentric whorls of organs (sepals, petals, stamens and carpels) get their identities from overlapping homeotic gene... [more...][less]In the eudicot flower, four concentric whorls of organs (sepals, petals, stamens and carpels) get their identities from overlapping homeotic gene activities, as described by the ABC model and its later ABCE extension. In Arabidopsis thaliana the A function is supplied by APETALA1 (AP1, a MIKC-type MADS-domain transcription factor) and APETALA2 (AP2, an AP2/ERF-domain transcriptional repressor). The B function is supplied by the obligate MADS heterodimer APETALA3/PISTILLATA (AP3/PI) and the C function by AGAMOUS (AG). The E function is supplied redundantly by the four SEPALLATA MADS proteins (SEP1-SEP4). A alone specifies sepals (whorl 1), A+B petals (whorl 2), B+C stamens (whorl 3) and C carpels (whorl 4). E activity is required for B and C function: sep1 sep2 sep3 flowers make only sepals, and sep1 sep2 sep3 sep4 flowers make only leaf-like organs. At the molecular level, the floral quartet model proposes that each organ identity is set by a distinct tetrameric MADS complex. Two MADS dimers bind two CArG boxes and loop the DNA between them, with SEP proteins (above all SEP3) acting as the tetramerization hub. Expressing A or C together with B and E genes is enough to turn leaves into petal-like or stamen-like organs. A and C are mutually antagonistic. AP2 confines AG to the inner two whorls by recruiting the TOPLESS/HDA19 co-repressor, while AG excludes AP1 from the inner whorls. The SEP3-AG tetramer also terminates the floral meristem after carpel initiation. Floral meristem identity (LEAFY, AP1 meristem function, CAULIFLOWER, FRUITFULL, TERMINAL FLOWER1) is a separate, upstream module. LEAFY is cited here only as an activator of the B and C genes. The D-class ovule identity genes (STK/SHP) and the downstream organ differentiation programs are also outside this boundary. |
Developmental Process | DRAFT | Arabidopsis thaliana |
0 | specification of floral organ identity |
11 | 13 | 6 | 1 | 4 | 4 | 9/9 | 0 | ✗ | modules/floral_organ_identity_abce.yaml | |
ADP-heptose precursor biosynthesisMODULE:adp_heptose_biosynthesisCONCRETE ADP-manno-heptose precursor synthesis converts sedoheptulose 7-phosphate into ADP-D-glycero-beta-D-manno-heptose through isomerization, C-1... [more...][less]ADP-manno-heptose precursor synthesis converts sedoheptulose 7-phosphate into ADP-D-glycero-beta-D-manno-heptose through isomerization, C-1 phosphorylation, C-7 dephosphorylation and adenylylation. A further C-6 epimerization supplies the L,D stereoisomer where required. The same reaction sequence is implemented by separate, bifunctional or trifunctional enzymes and supplies Gram-negative lipopolysaccharide and selected Gram-positive secondary metabolites. An archaeal enzyme set also produces ADP-heptose in an engineered archaeal host; native biological uses outside bacteria remain unresolved. |
Metabolic Pathway | COMPLETE | Archaeal lineages with a complete ADP-heptose enzyme complement Bacterial lineages retaining ADP-manno-heptose synthesis |
0 | phosphoheptose biosynthetic process ADP-L,D-heptose biosynthetic process |
6 | 5 | 5 | 0 | 0 | 4 | 16/16 | 0 | ✗ | modules/adp_heptose_biosynthesis.yaml | |
AMP-activated protein kinase complex in Drosophila melanogasterMODULE:dmel_ampk_complexCONCRETE AMP-activated protein kinase is a heterotrimeric energy sensor made of a catalytic alpha subunit, a scaffolding beta subunit with a... [more...][less]AMP-activated protein kinase is a heterotrimeric energy sensor made of a catalytic alpha subunit, a scaffolding beta subunit with a glycogen-binding domain, and a gamma subunit whose CBS repeats bind AMP, ADP and ATP. Drosophila has a single gene for each subunit (AMPKalpha, alicorn and SNF4Agamma). When cellular energy falls, nucleotide binding to the gamma subunit promotes phosphorylation of the alpha activation loop by LKB1 and protects it from dephosphorylation. Active AMPK restores energy balance by inhibiting anabolic pathways, including TORC1 signaling and lipid synthesis, and promoting catabolism; in Drosophila it is also needed for epithelial polarity under energy stress and for normal lifespan and lipid storage. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | nucleotide-activated protein kinase complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_ampk_complex.yaml | |
AMPK energy sensing — LKB1-STRAD-MO25 or Ca2+/calmodulin-CAMKK2 Thr172 activation of the AMPK alpha/beta/gamma heterotrimer, PP2A/PPM1E/PPM1F/PP1-R6 inactivation, and TSC2-mTORC1, ACC and CPT1 outputs; PRKAA1/2, PRKAB1/2, PRKAG1/2/3, STK11, STRADA, CAB39, CALM1-3, CAMKK1/2, PPP2CA, PPM1E, PPM1F, PPP1CA/B, PPP1R3D, TSC1, TSC2MODULE:ampk_energy_sensingCONCRETE AMP-activated protein kinase (AMPK) is the principal cellular energy sensor of mammals. It is a heterotrimer of a catalytic alpha subunit (PRKAA1... [more...][less]AMP-activated protein kinase (AMPK) is the principal cellular energy sensor of mammals. It is a heterotrimer of a catalytic alpha subunit (PRKAA1 or PRKAA2), a scaffolding beta subunit (PRKAB1 or PRKAB2) that carries a glycogen-binding domain and bridges alpha and gamma, and a regulatory gamma subunit (PRKAG1, PRKAG2 or PRKAG3) whose four tandem cystathionine-beta-synthase (CBS) repeats form the adenine nucleotide-binding sites. The kinase is active only when Thr172 in the alpha-subunit activation loop is phosphorylated. Two upstream kinases do this. The LKB1 complex, in which the kinase STK11 (LKB1) is held in an active conformation by the pseudokinase STRADA and the scaffold CAB39 (MO25alpha), is constitutively active, so its output is set by the AMPK side: when ATP production falls or consumption rises, AMP and ADP displace ATP from the gamma-subunit sites, which promotes Thr172 phosphorylation, protects the phosphate from phosphatases and (for AMP) allosterically activates the kinase. Alternatively, a rise in cytosolic calcium activates calmodulin, which activates the calmodulin-dependent protein kinase kinases, chiefly CAMKK2, and these phosphorylate Thr172 without any change in adenine nucleotides. The signal is terminated by dephosphorylation of Thr172 by protein phosphatase 2A, by the PPM-family phosphatases PPM1E and PPM1F, and, in pancreatic beta cells, by a protein phosphatase 1 holoenzyme targeted to AMPK by its regulatory subunit PPP1R3D (R6). Active AMPK switches off ATP-consuming processes and switches on ATP-producing ones. It phosphorylates TSC2, increasing the GTPase-activating activity of the TSC1-TSC2 complex towards RHEB, and it phosphorylates the mTORC1 subunit raptor; both inhibit mTORC1 and so protein synthesis and cell growth. It phosphorylates and inhibits acetyl-CoA carboxylase, lowering malonyl-CoA, which both reduces fatty acid synthesis and relieves malonyl-CoA inhibition of carnitine palmitoyltransferase 1, so that long-chain fatty acids enter mitochondria for beta-oxidation. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cellular response to glucose starvation |
13 | 10 | 7 | 2 | 5 | 9 | 5/23 | 0 | ✗ | modules/ampk_energy_sensing.yaml | |
ATM signaling at DNA double-strand breaks — MRN sensing and ATM activation, gammaH2AX-MDC1 amplification, the RNF8-UBE2N-RNF168 ubiquitin cascade, 53BP1-RIF1 versus BRCA1-A recruitment, and phosphatase/deubiquitinase/HECT-ligase attenuation; ATM/MRE11/RAD50/NBN/KAT5/H2AX/MDC1/RNF8/UBE2N/RNF168/TP53BP1/RIF1/BRCA1MODULE:atm_dsb_signalingCONCRETE A DNA double-strand break (DSB) in chromatin is detected by the MRE11-RAD50-NBN (MRN) complex, which binds and tethers the broken DNA ends and... [more...][less]A DNA double-strand break (DSB) in chromatin is detected by the MRE11-RAD50-NBN (MRN) complex, which binds and tethers the broken DNA ends and recruits the serine/threonine kinase ATM through a conserved C-terminal motif of NBN. Inactive ATM dimers dissociate into active monomers that autophosphorylate on Ser1981, and acetylation of ATM by the histone acetyltransferase KAT5 (TIP60), which is held in a constitutive complex with ATM, is needed for full kinase activity. Active ATM phosphorylates hundreds of substrates. At the break it phosphorylates the histone variant H2AX on Ser139 over megabase domains of flanking chromatin, producing gammaH2AX. The tandem BRCT domain of MDC1 binds the phosphorylated H2AX C-terminus, and MDC1 in turn binds ATM and NBN, concentrating more MRN-ATM on the flanking chromatin and so spreading H2AX phosphorylation in a positive feedback loop. ATM-phosphorylated MDC1 recruits the RING E3 ubiquitin ligase RNF8 through its FHA domain. RNF8, working with the E2 enzyme UBE2N (UBC13), initiates K63-linked ubiquitin chains on chromatin proteins, which recruit a second RING ligase, RNF168. RNF168 monoubiquitylates nucleosomal H2A and H2AX on Lys13/Lys15 and extends K63-linked chains, amplifying the ubiquitin signal. These marks recruit two antagonistic readers. 53BP1 (TP53BP1) binds nucleosomes that carry both H4K20me2 and H2AK15ub; the H4K20me2 sites are first unmasked by VCP/p97-driven extraction of L3MBTL1 and by RNF8/RNF168-dependent degradation of KDM4A. ATM-phosphorylated 53BP1 recruits RIF1, and together they block DNA end resection and favour non-homologous end joining, chiefly in G1. The BRCA1-A complex, recruited by the RAP80 (UIMC1) ubiquitin-interaction motifs to K63 chains, carries BRCA1-BARD1 and the K63-specific deubiquitinase BRCC3 (BRCC36); BRCA1 and its partner CtIP displace 53BP1-RIF1 from S phase onward, and KAT5 acetylation of H2AK15, which blocks its ubiquitylation, further limits 53BP1 binding, so that resection and homologous recombination are favoured. SUMO conjugation by PIAS1 and PIAS4 is needed for productive accumulation of 53BP1, BRCA1 and RNF168, and the SUMO-targeted ubiquitin ligase RNF4 turns over SUMOylated MDC1. In parallel, ATM-phosphorylated RNF20-RNF40 monoubiquitylates H2B to relax chromatin for repair. The phosphorylation state of H2AX Tyr142, set by the WSTF (BAZ1B) tyrosine kinase and removed by EYA phosphatases, gates MDC1 binding and the choice between repair and apoptosis. The signal is confined and switched off by phosphatases that dephosphorylate ATM and gammaH2AX (PP2A, PP4, PP6 and WIP1/PPM1D), by deubiquitinases that remove the chromatin ubiquitin marks (USP3, USP16, USP44) or inhibit UBE2N without catalysis (OTUB1), and by the HECT ligases TRIP12 and UBR5, which keep RNF168 levels limiting. ATM output then drives checkpoint arrest through CHK2 and p53, apoptosis or senescence, and the repair reactions themselves; those downstream programs are outside this module. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | signal transduction in response to DNA damage protein localization to site of double-strand break |
16 | 34 | 13 | 1 | 2 | 13 | 11/41 | 0 | ✗ | modules/atm_dsb_signaling.yaml | |
ATR-ATRIP checkpoint kinase complex in Drosophila melanogasterMODULE:dmel_atr_atrip_complexCONCRETE ATR is a phosphatidylinositol 3-kinase-related protein kinase that responds to single-stranded DNA at stalled replication forks and processed DNA... [more...][less]ATR is a phosphatidylinositol 3-kinase-related protein kinase that responds to single-stranded DNA at stalled replication forks and processed DNA breaks. Its partner ATRIP binds RPA-coated single-stranded DNA and recruits ATR, which then phosphorylates checkpoint targets such as Chk1 to arrest the cell cycle and stabilize replication forks. In Drosophila ATR is encoded by mei-41 and ATRIP by mus304; mutants are sensitive to DNA damage and are defective in DNA damage checkpoints. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ATR-ATRIP complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_atr_atrip_complex.yaml | |
Abscisic acid signaling across land plants: PYR/PYL–PP2C–Raf–SnRK2 relay and transcriptional or stomatal outputsMODULE:abscisic_acid_signalingCONCRETE Land plants share an abscisic acid (ABA) signaling toolkit comprising PYR/PYL/RCAR receptors, clade A PP2C phosphatases, Raf-like kinases,... [more...][less]Land plants share an abscisic acid (ABA) signaling toolkit comprising PYR/PYL/RCAR receptors, clade A PP2C phosphatases, Raf-like kinases, ABA-responsive SnRK2 kinases and ABRE-binding bZIP transcription factors. In the established angiosperm relay, ABA-stimulated receptors inhibit PP2Cs and relieve their inhibition of SnRK2; Raf-mediated phosphorylation initiates SnRK2 activity, followed by amplification through intermolecular SnRK2 phosphorylation. Constitutively active Arabidopsis B2 RAFs and stress-responsive B3 RAFs have distinct regulatory roles. Moss ARK also activates SnRK2, but moss evidence instead places PP2CAs mainly downstream of SnRK2 and do not impose the same upstream ABA-dependent release switch. Some receptors, including liverwort MpPYL1 and monomeric rice RCAR5/PYL5, retain basal phosphatase inhibition without hormone. Activated SnRK2s support bZIP-dependent protective transcription in both moss and angiosperm experiments. A guard-cell branch directly established in Arabidopsis and rice couples SnRK2 phosphorylation to SLAC1 anion efflux and stomatal closure. That branch is optional within this land-plant module; liverworts lack stomata. ABA biosynthesis, transport, catabolism, calcium-dependent branches and protein turnover lie outside the boundary. |
Signaling Pathway | COMPLETE | angiosperms land plants |
0 | abscisic acid-activated signaling pathway |
7 | 8 | 6 | 0 | 0 | 6 | 19/19 | 0 | ✗ | modules/abscisic_acid_signaling.yaml | |
Activin signaling pathway in Drosophila melanogasterMODULE:dmel_activin_signalingCONCRETE The Drosophila activin branch of TGF-beta signaling is triggered by the activin-like ligands Activin-beta, Dawdle and Myoglianin. These ligands... [more...][less]The Drosophila activin branch of TGF-beta signaling is triggered by the activin-like ligands Activin-beta, Dawdle and Myoglianin. These ligands bind a receptor complex of the type I serine/threonine kinase Baboon and a type II receptor kinase (Punt, or Wishful thinking). The activated type I receptor phosphorylates the receptor-regulated SMAD Smox (dSmad2), which partners with the co-SMAD Medea and enters the nucleus to regulate target genes. The pathway acts in neuronal remodeling, cell and tissue growth, and metabolic homeostasis. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | activin receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 5/8 | 0 | ✗ | modules/dmel_activin_signaling.yaml | |
Adrenal and interrenal steroidogenesisMODULE:adrenal_steroidogenesisCONCRETE Adrenal and interrenal steroidogenic cells convert cholesterol to pregnenolone and route it into corticosteroid or androgen branches.... [more...][less]Adrenal and interrenal steroidogenic cells convert cholesterol to pregnenolone and route it into corticosteroid or androgen branches. StAR-dependent cholesterol delivery and mitochondrial CYP11A cleavage supply the common entry. HSD3B and microsomal CYP17/CYP21 activities determine intermediate routes; mitochondrial CYP11 activities produce cortisol, corticosterone or aldosterone according to enzyme specificity and tissue expression. Human, mouse and zebrafish implementations share reactions but differ in paralog use, expression and terminal products. |
Metabolic Pathway | COMPLETE | Vertebrata |
0 | 15 | 17 | 14 | 0 | 0 | 17 | 11/11 | 0 | ✗ | modules/adrenal_steroidogenesis.yaml | ||
Aerobic nicotinate degradation through 2,5-dihydroxypyridineMODULE:aerobic_nicotinate_degradationCONCRETE A six-reaction aerobic nicotinate degradation route in Pseudomonadota, converting nicotinate to fumarate through 6-hydroxynicotinate,... [more...][less]A six-reaction aerobic nicotinate degradation route in Pseudomonadota, converting nicotinate to fumarate through 6-hydroxynicotinate, 2,5-dihydroxypyridine, N-formylmaleamate, maleamate and maleate. The characterized two-component NicAB enzyme initiates hydroxylation, followed by NicC oxidative decarboxylation, NicX ring cleavage, NicD deformylation, NicF deamidation and MaiA isomerization. Related bacteria share downstream chemistry while differing in pathway distribution and entry-enzyme architecture. |
Metabolic Pathway | COMPLETE | Pseudomonadota with the aerobic maleamate route |
0 | nicotinate catabolic process |
7 | 6 | 6 | 0 | 0 | 5 | 9/9 | 0 | ✗ | modules/aerobic_nicotinate_degradation.yaml | |
Aerobic phenylacetate catabolismMODULE:phenylacetate_catabolismCONCRETE A bacterial aerobic phenylacetyl-CoA ("box") pathway that activates phenylacetate, epoxidizes the aromatic ring with the multicomponent PaaABCE... [more...][less]A bacterial aerobic phenylacetyl-CoA ("box") pathway that activates phenylacetate, epoxidizes the aromatic ring with the multicomponent PaaABCE system, isomerizes and hydrolytically opens the ring, oxidizes the resulting semialdehyde, and processes the open-chain CoA ester through two thiolytic cleavages separated by a beta-oxidation-like hydration and oxidation sequence, yielding acetyl-CoA and succinyl-CoA. Regulatory and detoxification proteins are outside the required reaction chain. |
Metabolic Pathway | COMPLETE | bacteria |
0 | phenylacetate catabolic process |
11 | 9 | 10 | 0 | 0 | 8 | 20/20 | 0 | ✓ | modules/phenylacetate_catabolism.yaml | |
Alcoholic fermentation of pyruvate to ethanolMODULE:alcoholic_fermentationABSTRACT Alcoholic fermentation converts pyruvate to acetaldehyde and carbon dioxide, then reduces acetaldehyde to ethanol while oxidizing NADH to NAD+. The... [more...][less]Alcoholic fermentation converts pyruvate to acetaldehyde and carbon dioxide, then reduces acetaldehyde to ethanol while oxidizing NADH to NAD+. The terminal branch regenerates reducing-cofactor balance without itself producing ATP; upstream ATP yield depends on the glycolytic route. Canonical thiamine-dependent pyruvate decarboxylases operate in fungi, plants and selected bacteria, while Carassius fish possess a separately evolved mitochondrial E1-derived implementation. Zinc-dependent medium-chain and group III alcohol dehydrogenases provide distinct reduction catalysts, with metal activation and physiological deployment varying among members. An optional acetoin/butanediol branch diverts carbon through PDC carboligation or the bacterial catabolic acetolactate route. |
Metabolic Pathway | COMPLETE | Bacteria Carassius Embryophyta Eukaryota Fungi |
0 | pyruvate fermentation to ethanol |
18 | 11 | 7 | 4 | 10 | 4 | 23/23 | 0 | ✗ | modules/alcoholic_fermentation.yaml | |
Alginate O-acetylationMODULE:alginate_o_acetylationABSTRACT Bacterial alginate O-acetylation modifies mannuronate residues as the polymer traverses the cell envelope. In characterized pseudomonads, the... [more...][less]Bacterial alginate O-acetylation modifies mannuronate residues as the polymer traverses the cell envelope. In characterized pseudomonads, the membrane MBOAT component AlgI and periplasm-facing SGNH protein AlgJ act with the interaction mediator AlgF and polymer-modifying enzyme AlgX. Azotobacter uses homologous proteins, with AlgV corresponding to Pseudomonas AlgJ. AlgX directly transfers acetyl groups to polymannuronate in vitro, while the physiological donor and complete AlgI-to-AlgJ-to-AlgX relay remain unresolved. Polymer precursor synthesis, polymerization, export and mannuronate epimerization are separate but physically coupled processes. |
Biological Process | COMPLETE | Pseudomonas and Azotobacter alginate-acetylating lineages |
0 | alginic acid acetylation |
5 | 4 | 4 | 0 | 0 | 4 | 12/12 | 0 | ✗ | modules/alginate_o_acetylation.yaml | |
Alginate polymerization and exportMODULE:alginate_polymerization_exportABSTRACT A bacterial synthase-dependent alginate-production module: Alg8 polymerizes mannuronate with the c-di-GMP-responsive Alg44 partner, periplasmic... [more...][less]A bacterial synthase-dependent alginate-production module: Alg8 polymerizes mannuronate with the c-di-GMP-responsive Alg44 partner, periplasmic AlgG and AlgKX support polymer handling, and the AlgE outer-membrane channel mediates export. AlgG epimerization changes polymer composition, while AlgL removes misplaced periplasmic polymer in a background-dependent homeostasis role. AlgX acetyltransferase chemistry, precursor synthesis, extracellular epimerases and upstream regulation are separate processes. |
Metabolic Pathway | COMPLETE | Pseudomonas aeruginosa Reviewed Pseudomonas and Azotobacter alginate-producing lineages |
0 | alginic acid biosynthetic process |
7 | 8 | 6 | 0 | 0 | 5 | 21/21 | 0 | ✗ | modules/alginate_polymerization_export.yaml | |
Aliphatic glucosinolate biosynthesis and myrosinase activation (glucosinolate-myrosinase defense system)MODULE:aliphatic_glucosinolate_myrosinase_defenseABSTRACT This module describes the chain-elongated methionine glucosinolate pathway and classical myrosinase activation in characterized Brassicaceae. It is... [more...][less]This module describes the chain-elongated methionine glucosinolate pathway and classical myrosinase activation in characterized Brassicaceae. It is not a universal pathway for all glucosinolate-producing plants. Methionine-derived (aliphatic) glucosinolates are made in three phases: (1) side-chain elongation, a cycle recruited from leucine biosynthesis that runs partly in the cytosol and partly in the chloroplast: methionine is deaminated to its 2-oxo acid in the cytosol (BCAT4), and after import into the chloroplast the 2-oxo acid is condensed with acetyl-CoA (MAM), isomerized (IPMI), oxidatively decarboxylated (IPMDH1) and transaminated back to a chain-elongated methionine homolog (BCAT3), each turn adding one methylene group; (2) formation of the core glucosinolate structure, in which CYP79F converts the chain-elongated amino acid to an aldoxime, CYP83A1 activates the aldoxime for glutathione conjugation, the conjugate is trimmed by gamma-glutamyl peptidase (GGP1) and cleaved by the C-S lyase SUR1 to a thiohydroximate, which is S-glucosylated (UGT74C1/UGT74B1) and finally sulfated from PAPS by desulfoglucosinolate sulfotransferases (SOT16-18); and (3) side-chain modification, in which flavin monooxygenases (FMO GS-OX) S-oxygenate methylthioalkyl to methylsulfinylalkyl glucosinolates and the 2-oxoglutarate-dependent dioxygenase AOP2 converts these to alkenyl glucosinolates such as allylglucosinolate (sinigrin). The classical damage-activated defense chemistry depends on hydrolysis of the stored glucosinolate. On tissue damage, thioglucosidases (myrosinases, TGG1/TGG2) hydrolyze it to an unstable aglucone that rearranges by default to an isothiocyanate; Fe(II)-dependent specifier proteins (ESP, NSPs, TFP) instead redirect the aglucone to epithionitriles, simple nitriles or organic thiocyanates. Natural variation at MAM, AOP and ESP loci accounts for much of the glucosinolate and breakdown-product diversity between accessions and species. Transcriptional regulation (MYB28/MYB29 with MYC2-4), glucosinolate transport (GTR1/GTR2), indole and aromatic glucosinolates, and sulfate activation to PAPS are outside this module's boundary. BCAT3 is a characterized short-chain exit route rather than the sole exit enzyme for all chain lengths. Native transport between compartments is required; transport proteins are outside this module. Decoration and specifier branches vary among species, accessions and tissues. |
Metabolic Pathway | DRAFT | Brassicaceae |
0 | glucosinolate biosynthetic process glucosinolate catabolic process |
25 | 20 | 19 | 2 | 5 | 18 | 35/35 | 0 | ✓ | modules/aliphatic_glucosinolate_myrosinase_defense.yaml | |
All-trans-retinoic acid metabolism — RBP4/STRA6 retinol delivery, CRBP1 binding, RDH10/DHRS3 retinol-retinal interconversion, ALDH1A1-3 retinal oxidation, CRABP1/2 binding and CYP26A1/B1/C1 catabolismMODULE:retinoic_acid_metabolismCONCRETE All-trans-retinoic acid (atRA), the most potent vitamin A metabolite, is made on demand inside target cells from circulating retinol and is cleared... [more...][less]All-trans-retinoic acid (atRA), the most potent vitamin A metabolite, is made on demand inside target cells from circulating retinol and is cleared by oxidative catabolism, so that its tissue level is set by the balance of local synthesis and local destruction. Retinol travels in plasma bound to retinol-binding protein 4 (RBP4), which circulates as a complex with the transthyretin (TTR) tetramer. The multi-pass membrane receptor STRA6 binds holo-RBP4 and moves retinol into the cell, where it is bound by cellular retinol-binding protein 1 (CRBP1, RBP1). The first and rate-limiting step of synthesis is the reversible, membrane-associated oxidation of all-trans-retinol to all-trans-retinal by the short-chain dehydrogenase/reductase RDH10. RDH10 works together with the retinaldehyde reductase DHRS3: the two proteins activate each other, and DHRS3 reduces retinal back to retinol, so the pair sets the flux of retinal toward acid. Cytosolic medium-chain alcohol dehydrogenases can also oxidise retinol. The second step, the oxidation of retinal to atRA, is irreversible and is catalysed by the NAD+-dependent retinaldehyde dehydrogenases ALDH1A1, ALDH1A2 and ALDH1A3, whose distinct tissue patterns define where atRA is produced in the embryo. Cellular retinoic acid-binding proteins bind atRA in the cytosol: CRABP2 delivers it to the nuclear retinoic acid receptors, and CRABP1 sequesters it and favours its catabolism. atRA is inactivated by the cytochrome P450 retinoic acid hydroxylases CYP26A1, CYP26B1 and CYP26C1, which form 4-hydroxy-, 4-oxo- and 18-hydroxy-atRA in the endoplasmic reticulum; CYP26A1 and DHRS3 are induced by atRA, giving negative feedback on its own level. Retinol not used for synthesis can be stored as retinyl esters, made by LRAT and hydrolysed back to retinol by retinyl ester hydrolases such as the carboxylesterase CES1. Loss of RDH10 or ALDH1A2 in mouse abolishes embryonic atRA synthesis, CYP26B1 deficiency causes craniosynostosis and skeletal anomalies, and STRA6 and RBP4 defects cause microphthalmia and coloboma. |
Metabolic Pathway | DRAFT | Homo sapiens |
0 | retinoic acid metabolic process |
18 | 15 | 9 | 3 | 8 | 7 | 1/15 | 0 | ✗ | modules/retinoic_acid_metabolism.yaml | |
Anaphase-promoting complex/cyclosome in Drosophila melanogasterMODULE:dmel_anaphase_promoting_complexCONCRETE The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit RING E3 ubiquitin ligase that drives mitotic exit by targeting securin and... [more...][less]The anaphase-promoting complex/cyclosome (APC/C) is a large multisubunit RING E3 ubiquitin ligase that drives mitotic exit by targeting securin and mitotic cyclins for proteasomal degradation, and that keeps APC/C substrate levels low in G1. Its catalytic core is formed by the cullin-like subunit Apc2 (Morula) and the RING subunit Apc11 (Lemming A). A platform of Apc1 (Shattered), Apc4 and Apc5 (Ida) supports the core and an arc of tetratricopeptide-repeat subunits (Cdc27/Apc3, Cdc16/Apc6, Apc7 and Cdc23/Apc8). Substrates are recognized by Apc10 together with a WD40 coactivator, Fizzy (Cdc20) in mitosis or Fizzy-related (Cdh1) at mitotic exit and during endocycles. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | anaphase-promoting complex |
8 | 6 | 5 | 1 | 2 | 0 | 0/12 | 0 | ✗ | modules/dmel_anaphase_promoting_complex.yaml | |
Angiotensin II receptor signaling — Ang II activation of AT1 (AGTR1) via Gq/11-PLC, JAK2/TYK2 and GRK/beta-arrestin desensitisation with AGTRAP/ARAP1 trafficking, versus AT2 (AGTR2) via Gi-linked SHP-1/MKP-1 phosphatases and MTUS1/ZBTB16MODULE:angiotensin_ii_receptor_signalingCONCRETE Angiotensin II (Ang II), the octapeptide released from angiotensinogen by the renin-angiotensin cascade, is the agonist of two seven-transmembrane... [more...][less]Angiotensin II (Ang II), the octapeptide released from angiotensinogen by the renin-angiotensin cascade, is the agonist of two seven-transmembrane G protein-coupled receptors with largely opposing actions: the type 1 receptor AT1 (AGTR1) and the type 2 receptor AT2 (AGTR2). The two receptors share only ~34% sequence identity and couple to different signalling machinery, so this module treats them as a variant set of receptor branches off a common ligand. AT1 is the dominant and best-understood receptor, expressed in most tissues and mediating vasoconstriction, aldosterone release, fluid homeostasis and cell proliferation. Agonist-occupied AT1 acts as a guanine-nucleotide exchange factor for the Gq/11 family (GNAQ, GNA11), whose GTP-bound alpha subunit activates phospholipase C beta to cleave PIP2 into IP3 and diacylglycerol, raising intracellular calcium and activating protein kinase C — the shared Gq-PLC-calcium-PKC effector cassette modelled elsewhere. AT1 also drives G protein-independent arms: it binds and activates the Janus kinases JAK2 and TYK2 to engage STAT transcription factors, and it is phosphorylated by G protein-coupled receptor kinases (GRK2, GRK3, GRK5, GRK6) so that the beta-arrestins ARRB1 and ARRB2 uncouple it from G proteins, carry it into clathrin-coated pits and scaffold an arrestin-dependent ERK signal. Receptor fate is tuned by two C-terminal-tail-binding proteins: AGTRAP (ATRAP), which promotes internalisation and dampens signalling, and ARAP1, which recycles the receptor back to the plasma membrane. The AT2 receptor couples instead to the inhibitory Gi alpha subunits (GNAI2, GNAI3) and, in both G protein-dependent and -independent ways, activates protein tyrosine phosphatases — SHP-1 (PTPN6) and the MAP-kinase phosphatase MKP-1 (DUSP1) — that inactivate the ERK MAP-kinase cascade, giving AT2 its antiproliferative, pro-apoptotic and vasodilatory character that counterbalances AT1. AT2 also signals through C-terminal-tail partners, best characterised being MTUS1 (ATIP) and the transcription factor ZBTB16 (PLZF). The upstream proteolytic generation of Ang II by renin, ACE and chymase is a separate pathway and is not modelled here. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | angiotensin-activated signaling pathway |
16 | 21 | 10 | 2 | 5 | 9 | 11/21 | 0 | ✗ | modules/angiotensin_ii_receptor_signaling.yaml | |
Anti-CRISPR suppression of host CRISPR-Cas immunityMODULE:anti_crispr_suppressionCONCRETE Proteins encoded by bacteriophages, archaeal viruses, prophages and other mobile genetic elements suppress host CRISPR-Cas immunity through... [more...][less]Proteins encoded by bacteriophages, archaeal viruses, prophages and other mobile genetic elements suppress host CRISPR-Cas immunity through alternative mechanisms. These include blocking effector assembly or target recognition, sequestering an effector subunit or disabling its nuclease, modifying Cas proteins, cleaving guide RNA, and degrading an immune second messenger. A mobile element may combine several inhibitors, but these are not compulsory sequential steps. Optional anti-CRISPR-associated regulators control inhibitor expression. The examples span bacterial and archaeal hosts; plasmid and conjugative-element inhibitors need not have a viral origin. |
Biological Process | DRAFT | Bacteria Viruses |
0 | symbiont-mediated suppression of host CRISPR-cas system |
15 | 14 | 2 | 1 | 12 | 0 | 13/13 | 0 | ✗ | modules/anti_crispr_suppression.yaml | |
Apical-basal polarity complexes (Par, Crumbs, Scribble) in Drosophila melanogasterMODULE:dmel_epithelial_polarity_complexesCONCRETE Epithelial cells divide their plasma membrane into apical and basolateral domains using three conserved groups of polarity proteins that act on... [more...][less]Epithelial cells divide their plasma membrane into apical and basolateral domains using three conserved groups of polarity proteins that act on each other. The Par complex, Bazooka (Par-3), Par-6 and atypical protein kinase C (aPKC), marks the apical side and the adherens junction; aPKC phosphorylates basolateral proteins to exclude them from the apical membrane. The Crumbs complex, the transmembrane protein Crumbs with Stardust (PALS1) and Patj, defines the apical membrane above the adherens junction. The Scribble module, Scribble, Discs large (Dlg1) and Lethal (2) giant larvae (Lgl), acts basolaterally and restricts apical determinants. Mutual antagonism between apical and basolateral proteins sets the boundary, and loss of the Scribble module causes neoplastic overgrowth. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | establishment or maintenance of epithelial cell apical/basal polarity |
4 | 5 | 3 | 0 | 0 | 3 | 2/9 | 0 | ✗ | modules/dmel_epithelial_polarity_complexes.yaml | |
Arabidopsis autonomous flowering contributions to FLC repressionMODULE:autonomous_flowering_pathwayCONCRETE Arabidopsis autonomous flowering regulators promote floral transition through overlapping mechanisms that reduce FLOWERING LOCUS C (FLC)... [more...][less]Arabidopsis autonomous flowering regulators promote floral transition through overlapping mechanisms that reduce FLOWERING LOCUS C (FLC) expression. FCA and FY couple processing of COOLAIR antisense RNA to chromatin-associated and termination machinery involving FLD, LD, SDG26/ASHH1, APRF1 and TOPP4. FPA contributes through a distinct RNA-processing route; FLK recognizes modified FLC sense mRNA; FVE/MSI4 supports chromatin-regulatory associations. These relationships vary with genetic background, dosage and locus. Reduced FLC can release repression of FT and SOC1, while FVE also has a distinct direct regulatory effect at FT. Conserved proteins in other plants share biochemical features without necessarily sharing this native RNA-target and chromatin circuit. |
Biological Process | COMPLETE | Arabidopsis thaliana |
0 | 12 | 13 | 7 | 1 | 4 | 10 | 13/13 | 0 | ✗ | modules/autonomous_flowering_pathway.yaml | ||
Arabidopsis core circadian oscillator (CCA1/LHY - PRR - evening complex - ZTL)MODULE:plant_circadian_clock_oscillatorCONCRETE The core circadian oscillator of Arabidopsis thaliana is a network of interlocked transcriptional repressor loops that generates a roughly 24 h... [more...][less]The core circadian oscillator of Arabidopsis thaliana is a network of interlocked transcriptional repressor loops that generates a roughly 24 h rhythm in the nucleus. It is reinforced by timed, light-gated proteolysis. At dawn, the single-MYB transcription factors CCA1 and LHY peak and repress evening-phased clock genes (TOC1, ELF4, LUX, ELF3) through evening elements in their promoters. Through the day, the pseudo-response regulators PRR9, PRR7, PRR5 and finally TOC1 (PRR1) accumulate in sequential waves. Each binds target promoters through its C-terminal CCT domain and represses CCA1 and LHY, recruiting TOPLESS/TPR corepressors with histone deacetylase, so that CCA1/LHY expression stays low until the end of the night. At dusk the evening complex (EC) assembles: the scaffold ELF3 bridges the DNA-binding MYB protein LUX and the small protein ELF4. The EC represses PRR9, PRR7, GI and LUX itself through the LUX binding site, closing the evening-to-morning connection and gating growth genes (PIF4/PIF5) to the end of the night. Post-translational control sets the pace. The LOV-domain F-box photoreceptor ZEITLUPE (ZTL), as the substrate adaptor of an SCF E3 ligase, targets phosphorylated TOC1 and PRR5 for proteasomal degradation, mainly in the dark. GIGANTEA binds ZTL in a blue-light-enhanced manner and stabilizes it during the day, so ZTL activity rises at dusk. Light input through phytochromes and cryptochromes, temperature input (sensed partly by the ELF3 prion-like domain), and output pathways such as photoperiodic flowering (GI-CO-FT, CDFs) are outside this module's boundary except where a component acts directly within the oscillator loops. |
Biological Process | DRAFT | Arabidopsis thaliana |
0 | circadian rhythm |
6 | 12 | 5 | 0 | 0 | 7 | 11/11 | 0 | ✗ | modules/plant_circadian_clock_oscillator.yaml | |
Arf1-dependent COPI coat assembly at the GolgiMODULE:golgi_copi_vesicle_coatCONCRETE COPI-coated vesicles carry escaped ER-resident proteins back from the Golgi to the ER and move cargo between Golgi cisternae. A Sec7-domain... [more...][less]COPI-coated vesicles carry escaped ER-resident proteins back from the Golgi to the ER and move cargo between Golgi cisternae. A Sec7-domain exchange factor of the GBF1/Gea class activates the small GTPase Arf1 on cis-Golgi membranes, and Arf1-GTP recruits the heptameric coatomer complex as a preassembled unit. Coatomer's outer B-subcomplex (alpha, beta', epsilon) binds dilysine retrieval signals and forms the cage, and its inner F-subcomplex (beta, gamma, delta, zeta), related to the clathrin adaptor complexes, contacts Arf1 and the membrane. This module is the eukaryote-wide protein core of COPI coat assembly, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
8 | retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum intra-Golgi vesicle-mediated transport COPI vesicle coat |
3 | 9 | 2 | 0 | 0 | 1 | 4/14 | 0 | ✗ | modules/golgi_copi_vesicle_coat.yaml | |
Arginine catabolism via arginase and ornithine aminotransferaseMODULE:arginine_catabolism_arginase_pathwayCONCRETE Arginase and ornithine aminotransferase route arginine through ornithine to glutamate 5-semialdehyde, which equilibrates spontaneously with... [more...][less]Arginase and ornithine aminotransferase route arginine through ornithine to glutamate 5-semialdehyde, which equilibrates spontaneously with pyrroline-5-carboxylate (P5C). This comparative module covers demonstrated budding- and fission-yeast, Arabidopsis and human enzymes, without asserting identical flux or compartmentation throughout Eukaryota. In budding yeast, cytosolic P5C reduction makes proline, which can enter mitochondrial proline oxidation and semialdehyde oxidation; anaerobic cultures instead retain proline as an endpoint. Mitochondrial ornithine aminotransferase and P5C dehydrogenase permit direct semialdehyde oxidation in the plant and animal implementations. The aminotransferase is reversible, and its intestinal biosynthetic direction is outside this catabolic boundary. Plant arginases belong to a distinct arginase/agmatinase family. Urea disposal, transmembrane substrate supply, arginine re-synthesis, polyamine synthesis and regulation remain adjoining pathways. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | L-arginine catabolic process L-ornithine catabolic process |
14 | 9 | 6 | 3 | 7 | 4 | 18/18 | 0 | ✗ | modules/arginine_catabolism_arginase_pathway.yaml | |
ArnE/ArnF lipid A L-Ara4N donor flippingMODULE:lipid_a_l_arabinose_modificationCONCRETE A focused inner-membrane submodule of polymyxin-resistance lipid A modification in which ArnF acts with ArnE to move... [more...][less]A focused inner-membrane submodule of polymyxin-resistance lipid A modification in which ArnF acts with ArnE to move undecaprenyl-phosphate-alpha-L-Ara4N from the cytoplasmic leaflet to the periplasmic leaflet, positioning the lipid-linked aminoarabinose donor for ArnT-dependent transfer to lipid A. BasS/BasR-PmrA/PmrB induction, upstream ArnBCAD synthesis of the donor, and the ArnT transfer reaction are outside this reviewed ArnF-anchored module. |
Transport Step | DRAFT | bacteria |
0 | intramembrane lipid transporter activity lipopolysaccharide biosynthetic process |
1 | 1 | 0 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/lipid_a_l_arabinose_modification.yaml | |
Arp2/3 complex in Drosophila melanogasterMODULE:dmel_arp2_3_complexCONCRETE The Arp2/3 complex is a seven-subunit actin nucleator that binds the side of an existing actin filament and starts a new filament at a 70 degree... [more...][less]The Arp2/3 complex is a seven-subunit actin nucleator that binds the side of an existing actin filament and starts a new filament at a 70 degree angle, producing branched actin networks. Two actin-related proteins, Arp2 and Arp3, form the template for the daughter filament, while the five ARPC subunits (ARPC1-ARPC5) hold them in place and contact the mother filament. The complex is intrinsically inactive and is switched on by nucleation-promoting factors such as SCAR/WAVE and WASp. In Drosophila, Arp2/3-driven branched actin is needed for lamellipodia, ring canal growth, myoblast fusion and many other processes. Drosophila has two ARPC3 paralogs, Arpc3A and Arpc3B, so two forms of the complex are possible. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Arp2/3 protein complex |
6 | 4 | 3 | 1 | 2 | 0 | 0/8 | 0 | ✗ | modules/dmel_arp2_3_complex.yaml | |
Assimilatory sulfate reduction to sulfide (APS and PAPS routes)MODULE:aps_dependent_assimilatory_sulfate_reductionCONCRETE Assimilatory sulfate reduction supplies sulfide for sulfur-containing metabolites in characterized bacterial, fungal and plant systems. ATP... [more...][less]Assimilatory sulfate reduction supplies sulfide for sulfur-containing metabolites in characterized bacterial, fungal and plant systems. ATP sulfurylase first forms APS. Activated sulfate is then reduced either directly by an APS reductase or after APS kinase forms PAPS. The plant APS reductase exemplar uses glutathione through a fused redox domain; bacterial APS and fungal PAPS reductases have distinct external redox-partner requirements. Siroheme/iron-sulfur sulfite reductases complete the six-electron reduction, using characterized NADPH-linked complexes or ferredoxin-linked enzymes; the immediate carrier in the Pseudomonas Fpr-linked system remains unresolved. Sulfate import, cofactor biosynthesis, reductant regeneration and downstream sulfide incorporation are boundary processes. |
Metabolic Pathway | COMPLETE | Arabidopsis thaliana Bacteria Fungi Viridiplantae |
3 | sulfate assimilation |
15 | 12 | 5 | 3 | 9 | 5 | 29/29 | 0 | ✓ | modules/aps_dependent_assimilatory_sulfate_reduction.yaml | |
Augmin (HAUS) complex in Drosophila melanogasterMODULE:dmel_augmin_complexCONCRETE Augmin is an eight-subunit complex that recruits the gamma-tubulin ring complex to the sides of existing microtubules, so that new microtubules... [more...][less]Augmin is an eight-subunit complex that recruits the gamma-tubulin ring complex to the sides of existing microtubules, so that new microtubules branch from old ones. This microtubule-dependent nucleation amplifies microtubule number within the mitotic and meiotic spindle. In Drosophila the complex was first identified in S2 cells, where loss of augmin subunits reduces spindle microtubule density. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | HAUS complex |
9 | 8 | 8 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_augmin_complex.yaml | |
Autographiviridae host defense evasion, RNA polymerase shutoff, single-subunit transcription, and minimal T7 replisomeMODULE:phage_t7_replisome_transcriptionCONCRETE An integrated host-takeover, transcription, and genome-replication module characteristic of T7-like lytic podoviruses (Autographiviridae).... [more...][less]An integrated host-takeover, transcription, and genome-replication module characteristic of T7-like lytic podoviruses (Autographiviridae). Immediately upon entry of the leading left end of the linear genome, host Escherichia coli RNA polymerase transcribes the Class I early operon from promoters A1, A2, and A3, producing: (1) the B-form DNA mimic Ocr (gp0.3), which blocks Type I restriction-modification and BREX complexes; (2) the serine/threonine protein kinase gp0.7, which phosphorylates the beta-prime subunit of host RNA polymerase, RNase E, and translation factors to attenuate host gene expression; (3) the single-subunit phage RNA polymerase (gp1); and (4) the ATP-dependent DNA ligase (gp1.3). T7 RNA polymerase then drives high-velocity transcription of Class II replication and host-shutoff genes and Class III structural genes from phage-specific 23-bp promoters. Class II gene 2 protein (gp2) binds the beta-prime jaw domain of host sigma-70-RNA polymerase holoenzyme to completely shut off residual host transcription, while endonuclease I (gp3) and the 5'-3' exonuclease/RNase H (gp6) degrade the host chromosome to supply deoxynucleoside monophosphates for phage DNA synthesis. Genome replication is executed by a minimal four-protein replisome comprising the gp5 DNA polymerase complexed 1:1 with host Escherichia coli thioredoxin as its processivity factor, the hexameric ring bifunctional primase-helicase (gp4), and the C-terminally acidic single-stranded DNA-binding protein (gp2.5), followed by concatemer maturation and Holliday junction resolution assisted by gp6, gp1.3, and gp3. |
Biological Process | COMPLETE | Caudoviricetes Escherichia phage T7 |
0 | symbiont-mediated evasion of host restriction-modification system symbiont-mediated suppression of host transcription DNA-templated viral transcription viral DNA genome replication degradation of host chromosome by virus |
5 | 10 | 4 | 0 | 0 | 4 | 10/10 | 0 | ✗ | modules/phage_t7_replisome_transcription.yaml | |
Autophagosome biogenesis by the core Atg machinery in Drosophila melanogasterMODULE:dmel_autophagosome_biogenesisCONCRETE Macroautophagy begins with formation of a cup-shaped phagophore that expands and closes to form the double-membrane autophagosome. The core Atg... [more...][less]Macroautophagy begins with formation of a cup-shaped phagophore that expands and closes to form the double-membrane autophagosome. The core Atg proteins act in conserved functional units. The Atg1 kinase complex (Atg1, Atg13, Atg17/FIP200 and Atg101) initiates phagophore formation in response to nutrient starvation and TOR inhibition. The class III phosphatidylinositol 3-kinase complex (Vps34/Pi3K59F, Vps15, Atg6/Beclin 1 and Atg14) produces phosphatidylinositol 3-phosphate at the phagophore. Atg9 vesicles supply membrane and Atg9 has phospholipid scramblase activity, while Atg2, recruited with the PI3P-binding Atg18 proteins, transfers lipids to the expanding phagophore. Two ubiquitin-like conjugation systems act downstream: Atg7 and Atg10 conjugate Atg12 to Atg5, and the Atg12-Atg5-Atg16 complex promotes lipidation of Atg8 proteins with phosphatidylethanolamine by Atg7 and Atg3 after processing of Atg8 by the Atg4 proteases. In Drosophila, the fat body of starved larvae is the classic setting for studying this pathway. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | autophagosome assembly |
8 | 16 | 7 | 0 | 0 | 5 | 0/22 | 0 | ✗ | modules/dmel_autophagosome_biogenesis.yaml | |
Autophagosome lifecycleMODULE:autophagosome_lifecycleCONCRETE The autophagosome is a transient organelle. It is assembled from a phagophore that nucleates at a phagophore assembly site, expands around... [more...][less]The autophagosome is a transient organelle. It is assembled from a phagophore that nucleates at a phagophore assembly site, expands around cytoplasmic cargo with membrane supplied by Atg9 vesicles and lipid transfer from the ER, closes into a double-membrane vesicle, and then fuses with a lysosome or vacuole, where its inner membrane and cargo are degraded. This umbrella module composes the modules for those stages by reference. The core autophagy machinery is required in every eukaryote; the lineage-specific descriptions of assembly are optional. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | macroautophagy autophagosome |
4 | 0 | 3 | 0 | 0 | 0 | 0/0 | 0 | ✗ | modules/autophagosome_lifecycle.yaml | |
Axonemal outer and inner dynein arms in Drosophila melanogasterMODULE:dmel_axonemal_dynein_armsCONCRETE Axonemal dyneins are the motors that bend motile cilia and flagella. They are attached in rows along the doublet microtubules of the 9+2 axoneme as... [more...][less]Axonemal dyneins are the motors that bend motile cilia and flagella. They are attached in rows along the doublet microtubules of the 9+2 axoneme as outer dynein arms, which mainly set beat frequency, and inner dynein arms, which mainly shape the waveform. Each arm contains one or more dynein heavy chains, the ATP-driven motor subunits, together with intermediate and light chains that anchor the arm and regulate it. In Drosophila, motile axonemes are found only in sperm flagella and in the cilia of chordotonal mechanosensory neurons, so axonemal dyneins act in male fertility and hearing. Several sperm-specific heavy chains are encoded by the Y-chromosome fertility factors kl-2, kl-3 and kl-5. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | axonemal dynein complex |
9 | 20 | 8 | 0 | 0 | 0 | 0/17 | 0 | ✗ | modules/dmel_axonemal_dynein_arms.yaml | |
B-family DNA polymerase complexes and DNA polymerase gamma in Drosophila melanogasterMODULE:dmel_dna_polymerase_complexesCONCRETE Eukaryotic genome replication uses three multisubunit B-family DNA polymerases. DNA polymerase alpha-primase synthesizes the RNA-DNA primers that... [more...][less]Eukaryotic genome replication uses three multisubunit B-family DNA polymerases. DNA polymerase alpha-primase synthesizes the RNA-DNA primers that start leading and lagging strands. DNA polymerase epsilon extends the leading strand and DNA polymerase delta extends the lagging strand and matures Okazaki fragments; both have 3'-5' proofreading exonuclease activity. DNA polymerase zeta, made of the catalytic subunit Rev3 (PolZ1), Rev7 (PolZ2) and the two Pol delta accessory subunits, performs translesion synthesis past DNA damage. DNA polymerase gamma, a family A enzyme made of a catalytic subunit and an accessory subunit, replicates mitochondrial DNA. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | DNA polymerase complex |
6 | 5 | 5 | 0 | 0 | 0 | 2/15 | 0 | ✗ | modules/dmel_dna_polymerase_complexes.yaml | |
BBSome ciliary trafficking complex moduleMODULE:bbsome The BBSome is a conserved octameric protein complex that acts as a coat-like adaptor for ciliary membrane-protein trafficking. It is built from... [more...][less]The BBSome is a conserved octameric protein complex that acts as a coat-like adaptor for ciliary membrane-protein trafficking. It is built from eight core subunits (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8/TTC8, BBS9, and BBIP1/BBS18), assembled with the help of a dedicated chaperonin-like module (BBS6/MKKS, BBS10, BBS12 acting with the CCT/TRiC chaperonin). Once assembled, the BBSome is recruited to the ciliary membrane by the GTP-bound Arf-like GTPase ARL6/BBS3, where it polymerizes into a coat that recognizes signaling-receptor cargo (ciliary GPCRs and Hedgehog-pathway components) and couples them to the intraflagellar transport (IFT) machinery, mediating ciliary import and export of receptors out of the cilium. LZTFL1/BBS17 regulates BBSome ciliary trafficking, and CCDC28B is a BBSome-associated accessory factor. Loss of BBSome function causes Bardet-Biedl syndrome. This module models the BBSome as a cellular component / protein complex grounded in GO:0034464, capturing its composition, assembly, membrane recruitment, cargo trafficking, and regulation. |
Protein Complex | COMPLETE | ciliated eukaryotes |
0 | BBSome intraciliary transport |
7 | 6 | 6 | 0 | 0 | 4 | 14/14 | 1 | ✗ | modules/bbsome.yaml | |
BCL2-family mitochondrial outer membrane permeabilization control moduleMODULE:bcl2_family_momp_control Mammalian BCL2-family proteins control mitochondrial outer membrane permeabilization during intrinsic apoptosis. BH3-only proteins activate or... [more...][less]Mammalian BCL2-family proteins control mitochondrial outer membrane permeabilization during intrinsic apoptosis. BH3-only proteins activate or derepress the pore-forming effectors BAX and BAK, while pro-survival BCL2-like proteins bind BH3 helices to sequester activators and effectors. When BH3-only activity overwhelms the pro-survival buffer, BAX and BAK oligomerize at the mitochondrial outer membrane to release cytochrome c and other intermembrane-space proteins into the apoptotic execution pathway. |
Regulatory Step | DRAFT | Mammalia |
0 | mitochondrial outer membrane permeabilization |
4 | 11 | 3 | 0 | 0 | 3 | 9/9 | 0 | ✗ | modules/bcl2_family_momp_control.yaml | |
BLOC and BORC complexes in Drosophila melanogasterMODULE:dmel_bloc_borc_complexesCONCRETE The biogenesis of lysosome-related organelles complexes BLOC-1, BLOC-2 and BLOC-3 are needed to form lysosome-related organelles such as... [more...][less]The biogenesis of lysosome-related organelles complexes BLOC-1, BLOC-2 and BLOC-3 are needed to form lysosome-related organelles such as melanosomes in mammals and pigment granules in Drosophila eyes. BLOC-1 is an eight-subunit complex of small coiled-coil proteins (including dysbindin, pallidin, muted and snapin) that cooperates with endosomal sorting to deliver cargo to these organelles. BLOC-2 contains the HPS3, HPS5 and HPS6 subunits in mammals; the Drosophila HPS5 homolog is pink (p). BLOC-3, a heterodimer of HPS1 and HPS4, is a guanine nucleotide exchange factor for Rab32 and Rab38 in mammals. BORC is a related complex that shares Blos1, Blos2 and Snapin with BLOC-1 and adds BORCS5, BORCS6, BORCS7, BORCS8 and KXD1 subunits; it recruits Arl8 to lysosomes and controls their positioning. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | BLOC-1 complex BLOC-2 complex BLOC-3 complex BORC complex |
5 | 4 | 4 | 0 | 0 | 0 | 0/17 | 0 | ✗ | modules/dmel_bloc_borc_complexes.yaml | |
BMP signaling pathway in Drosophila melanogasterMODULE:dmel_bmp_signalingCONCRETE Bone morphogenetic protein (BMP) signaling in Drosophila is triggered by the ligands Decapentaplegic (Dpp), Glass bottom boat (Gbb) and Screw... [more...][less]Bone morphogenetic protein (BMP) signaling in Drosophila is triggered by the ligands Decapentaplegic (Dpp), Glass bottom boat (Gbb) and Screw (Scw), which act as homo- or heterodimers. Ligands bind heteromeric complexes of type I receptor kinases (Thickveins, Saxophone) and type II receptor kinases (Punt, Wishful thinking). The activated type I receptor phosphorylates the receptor-regulated SMAD Mad, which forms a complex with the co-SMAD Medea and accumulates in the nucleus. With the zinc-finger protein Schnurri, the Mad-Medea complex represses brinker and activates other targets. The pathway patterns the dorsal-ventral axis of the embryo and the wing imaginal disc, maintains germline stem cells, and regulates synaptic growth at the neuromuscular junction, where Gbb and Wishful thinking act. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | BMP signaling pathway |
6 | 10 | 5 | 0 | 0 | 4 | 3/11 | 0 | ✗ | modules/dmel_bmp_signaling.yaml | |
BMP signaling pathway moduleMODULE:bmp_signaling BMP ligands activate type I and type II serine/threonine kinase receptor complexes that phosphorylate SMAD1/5-family effectors and regulate... [more...][less]BMP ligands activate type I and type II serine/threonine kinase receptor complexes that phosphorylate SMAD1/5-family effectors and regulate developmental patterning and differentiation. |
Signaling Pathway | DRAFT | metazoa |
4 | BMP signaling pathway |
7 | 8 | 6 | 0 | 0 | 4 | 4/6 | 0 | ✓ | modules/bmp_signaling.yaml | |
Bacterial 23S rRNA U747/U1939 C5 methylationMODULE:bacterial_23s_rrna_m5u747_methylationCONCRETE A paired rRNA modification program producing 5-methyluridine at positions corresponding to Escherichia coli 23S rRNA U747 and U1939. In E. coli,... [more...][less]A paired rRNA modification program producing 5-methyluridine at positions corresponding to Escherichia coli 23S rRNA U747 and U1939. In E. coli, RlmC and RlmD divide these two activities; in the characterized Bacillus subtilis and Streptococcus pneumoniae implementations, RlmCD modifies both sites. The reactions share SAM-dependent C5 chemistry but act on distinct RNA regions. Their coexistence does not establish a required order or dependence between the two reactions. This comparison covers the named bacterial examples rather than universal bacterial conservation. |
Biological Process | DRAFT | Bacillus subtilis subsp. subtilis str. 168 Bacteria Escherichia coli K-12 Streptococcus pneumoniae TIGR4 |
0 | rRNA base methylation |
10 | 6 | 6 | 1 | 3 | 0 | 4/4 | 0 | ✗ | modules/bacterial_23s_rrna_m5u747_methylation.yaml | |
Bacterial 3-mercaptopropionate and 3-sulfinopropionate desulfination pathwayMODULE:bacterial_3sp_thioether_desulfination Three-step aerobic catabolic pathway by which Variovorax paradoxus strain TBEA6 and related betaproteobacteria degrade the organosulfur compounds... [more...][less]Three-step aerobic catabolic pathway by which Variovorax paradoxus strain TBEA6 and related betaproteobacteria degrade the organosulfur compounds 3-mercaptopropionate (3MP, generated by cleavage of the thioether 3,3'-thiodipropionate, TDP) and 3-sulfinopropionate (3SP) into propanoyl-CoA and inorganic sulfite. First, the cysteine dioxygenase homolog Mdo (3-mercaptopropionate dioxygenase) catalyzes the O2-dependent dioxygenation of 3-mercaptopropionate to 3-sulfinopropionate (PMID:19001372). Second, the homodimeric class III CoA-transferase Act (succinyl-CoA:3-sulfinopropionate CoA-transferase, UniProtKB:B9U6P4, VPARA_05450) transfers CoA from succinyl-CoA (or itaconyl-CoA/glutaryl-CoA) to 3-sulfinopropionate to form 3-sulfinopropanoyl-CoA (3SP-CoA) and succinate (PMID:23772073); in V. paradoxus TBEA6, an unmarked delta-act deletion mutant retains growth on TDP and 3SP, indicating that at least one additional uncharacterized CoA-activating enzyme can partially substitute for Act in vivo (PMID:23772073). Third, the homotetrameric FAD-containing 3-sulfinopropanoyl-CoA desulfinase Acd (EC 3.13.1.4; Variovorax paradoxus TBEA6 UniProtKB:B9U6P5, VPARA_05440, encoded immediately downstream of act; orthologous to Advenella mimigardefordensis DPN7 Acd UniProtKB:Q705F0) catalyzes the non-oxidative C-S bond cleavage (desulfination) of 3-sulfinopropanoyl-CoA into propanoyl-CoA and sulfite (PMID:24317404). |
Metabolic Pathway | COMPLETE | Variovorax paradoxus |
0 | sulfur compound catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 2/2 | 0 | ✗ | modules/bacterial_3sp_thioether_desulfination.yaml | |
Bacterial AhpC peroxide reduction and regeneration systemsMODULE:bacterial_alkyl_hydroperoxide_reductaseCONCRETE Bacterial AhpC peroxiredoxins reduce hydroperoxides and are recycled by distinct electron-donor systems. Sampled implementations couple AhpC to... [more...][less]Bacterial AhpC peroxiredoxins reduce hydroperoxides and are recycled by distinct electron-donor systems. Sampled implementations couple AhpC to AhpF in E. coli, Salmonella and Bacillus, to a thioredoxin/reductase pair in H. pylori and M. tuberculosis, or to the mycobacterial Lpd–lipoyl-DlaT–AhpD relay. Pairing, donor preference, substrate range and oligomeric state are bounded by their native or reconstituted experimental contexts. |
Molecular Function | COMPLETE | Bacillus subtilis subsp. subtilis str. 168 Bacteria Escherichia coli K-12 Helicobacter pylori 26695 Mycobacterium tuberculosis H37Rv Salmonella enterica subsp. enterica serovar Typhimurium str. LT2 |
0 | peroxiredoxin activity |
7 | 16 | 0 | 1 | 6 | 10 | 15/15 | 0 | ✗ | modules/bacterial_alkyl_hydroperoxide_reductase.yaml | |
Bacterial D-ribose uptake and entryMODULE:bacterial_ribose_uptake_and_entryCONCRETE A reusable bacterial route in which an RbsABC complex imports D-ribose, RbsD accelerates interconversion of the beta-pyranose and beta-furanose... [more...][less]A reusable bacterial route in which an RbsABC complex imports D-ribose, RbsD accelerates interconversion of the beta-pyranose and beta-furanose forms, and RbsK phosphorylates ribose to D-ribose 5-phosphate for entry into central carbon and nucleotide metabolism. Transcriptional regulation and downstream pentose-phosphate reactions are outside the module boundary. |
Biological Process | DRAFT | bacteria |
0 | D-ribose catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 6/6 | 0 | ✓ | modules/bacterial_ribose_uptake_and_entry.yaml | |
Bacterial DNA-directed RNA polymerase core enzymeMODULE:bacterial_rna_polymerase_coreCONCRETE Species-neutral bacterial module for the DNA-directed RNA polymerase core enzyme that carries out DNA-templated RNA synthesis. The conserved... [more...][less]Species-neutral bacterial module for the DNA-directed RNA polymerase core enzyme that carries out DNA-templated RNA synthesis. The conserved bacterial canonical core enzyme is built from an alpha dimer, beta and beta-prime catalytic cleft subunits, and the omega assembly/stability subunit. This module deliberately stops at the core enzyme and excludes sigma factors, transcription elongation factors, and promoter-specific regulatory proteins. |
Protein Complex | DRAFT | bacteria |
0 | DNA-directed RNA polymerase complex DNA-templated transcription |
4 | 4 | 3 | 0 | 0 | 2 | 4/8 | 0 | ✓ | modules/bacterial_rna_polymerase_core.yaml | |
Bacterial DnaK/DnaJ/GrpE protein refolding cycleMODULE:bacterial_dnak_dnaj_refolding_cycleCONCRETE A bacterial cytosolic Hsp70 refolding module in which the Hsp40 co-chaperone DnaJ captures unfolded or misfolded clients, stimulates DnaK ATP... [more...][less]A bacterial cytosolic Hsp70 refolding module in which the Hsp40 co-chaperone DnaJ captures unfolded or misfolded clients, stimulates DnaK ATP hydrolysis through its J domain, and promotes substrate locking onto DnaK; GrpE then drives nucleotide exchange to reset the DnaK cycle and release clients for folding. The sigma32/RpoH feedback branch, ClpB-dependent disaggregation, and DnaK's ATP-independent holdase side activity are outside this focused DnaK/DnaJ/GrpE folding cycle. |
Biological Process | DRAFT | bacteria |
0 | protein refolding ATP-dependent protein folding chaperone ATPase activator activity adenyl-nucleotide exchange factor activity |
4 | 3 | 3 | 0 | 0 | 3 | 3/3 | 0 | ✗ | modules/bacterial_dnak_dnaj_refolding_cycle.yaml | |
Bacterial DsbA/DsbB oxidative protein foldingMODULE:bacterial_dsbab_oxidative_foldingCONCRETE A bacterial envelope mechanism in which a membrane DsbB-family relay regenerates oxidized DsbA-family proteins, which introduce disulfides into... [more...][less]A bacterial envelope mechanism in which a membrane DsbB-family relay regenerates oxidized DsbA-family proteins, which introduce disulfides into exported substrate proteins. Quinone-coupled recycling is directly established in selected systems; native acceptor identity and isolated kinetics remain unresolved for the Bacillus and Campylobacter comparisons. Catalytic domains act in the Gram-negative periplasm or outside the Bacillus cytoplasmic membrane. Initial disulfide insertion does not guarantee the native disulfide pattern. DsbC/DsbD repair and DsbA/VKOR oxidation are distinct mechanisms. |
Biological Process | COMPLETE | Bacteria |
0 | protein folding |
13 | 10 | 3 | 2 | 9 | 2 | 14/14 | 0 | ✗ | modules/bacterial_dsbab_oxidative_folding.yaml | |
Bacterial FabA/FabB unsaturated-fatty-acid biosynthesisMODULE:bacterial_unsaturated_fatty_acid_biosynthesis A reusable oxygen-independent branch of bacterial type-II fatty-acid synthesis in which FabA dehydrates 3-hydroxydecanoyl-ACP and isomerizes the... [more...][less]A reusable oxygen-independent branch of bacterial type-II fatty-acid synthesis in which FabA dehydrates 3-hydroxydecanoyl-ACP and isomerizes the resulting trans-2-decenoyl-ACP to cis-3-decenoyl-ACP, FabB commits that intermediate to elongation, and FabF can extend palmitoleoyl-ACP toward cis-vaccenoyl-ACP. General FAS-II reduction and dehydration reactions are shared with saturated-fatty-acid synthesis and are outside this focused branch. |
Metabolic Pathway | DRAFT | 1 | unsaturated fatty acid biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 3/6 | 0 | ✓ | modules/bacterial_unsaturated_fatty_acid_biosynthesis.yaml | ||
Bacterial Fdx-supported, HscBA-assisted Isc iron-sulfur cluster assemblyMODULE:bacterial_isc_iron_sulfur_cluster_assemblyCONCRETE A bacterial Isc mechanism for iron-sulfur cluster assembly and transfer supported by Isc ferredoxin and the dedicated HscBA cycle. IscS mobilizes... [more...][less]A bacterial Isc mechanism for iron-sulfur cluster assembly and transfer supported by Isc ferredoxin and the dedicated HscBA cycle. IscS mobilizes cysteine sulfur as a persulfide and supplies IscU, the transient cluster scaffold. Reduced Isc ferredoxin supplies reducing equivalents; HscB recruits IscU to the HscA ATPase, coupling ATP hydrolysis to cluster release and delivery. An optional IscA carrier branch supports condition- and client-dependent iron or cluster handling. Reduced anaerobic ISC implementations and scaffold-suppressor bypasses are comparative boundary cases outside the encoded Fdx-supported, HscBA-assisted profile; their altered requirements are not additional modeled variants here. IscR regulation, CyaY and IscX modulation, upstream iron and reductant supply, mitochondrial ISC, and the separate Suf and Nif systems lie outside this mechanism. |
Biological Process | COMPLETE | bacteria |
0 | iron-sulfur cluster assembly |
9 | 7 | 6 | 1 | 2 | 4 | 17/17 | 0 | ✗ | modules/bacterial_isc_iron_sulfur_cluster_assembly.yaml | |
Bacterial GroEL/GroES chaperonin foldingMODULE:bacterial_groel_groes_chaperonin_foldingCONCRETE A bacterial cytosolic chaperonin module in which GroEL double rings, capped by GroES, use cycles of ATP binding and hydrolysis to encapsulate... [more...][less]A bacterial cytosolic chaperonin module in which GroEL double rings, capped by GroES, use cycles of ATP binding and hydrolysis to encapsulate non-native polypeptides and release folded clients. The HOCl-activated chaperedoxin CnoX can plug into this system by protecting oxidizing GroEL clients through holdase binding and reversible mixed-disulfide formation, then dissociating when GroES binds. |
Biological Process | DRAFT | bacteria |
0 | ATP-dependent protein folding chaperone protein refolding |
3 | 3 | 2 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/bacterial_groel_groes_chaperonin_folding.yaml | |
Bacterial ImuABC damage-induced mutagenesisMODULE:bacterial_imuabc_damage_induced_mutagenesisCONCRETE A bacterial ImuA-type accessory protein, ImuB adaptor and DnaE2/ImuC polymerase cooperate in damage-tolerant DNA synthesis. This family-grounded... [more...][less]A bacterial ImuA-type accessory protein, ImuB adaptor and DnaE2/ImuC polymerase cooperate in damage-tolerant DNA synthesis. This family-grounded realization spans experimentally characterized bacterial lineages without asserting that every bacterium carries the cassette. ImuB couples the accessory protein and polymerase to the replication clamp; DnaE2 supplies DNA synthesis. RecA signaling and LexA-family repression are optional, regulon-specific induction context. Mutational output depends on the organism, damage and growth state: induced mutagenesis and stationary-phase antimutator effects need not conflict. Nucleotide excision repair, homologous recombination and bulk chromosome replication are outside the module boundary, although translesion synthesis itself participates in the broader GO process DNA replication. |
Biological Process | COMPLETE | bacteria |
0 | translesion synthesis |
9 | 7 | 5 | 1 | 3 | 4 | 12/12 | 0 | ✓ | modules/bacterial_imuabc_damage_induced_mutagenesis.yaml | |
Bacterial Kdp potassium-homeostasis systemMODULE:bacterial_kdp_potassium_homeostasisCONCRETE A reusable bacterial module coupling KdpD/KdpE phosphorelay control to the high-affinity KdpFABC potassium pump. KdpD senses conditions associated... [more...][less]A reusable bacterial module coupling KdpD/KdpE phosphorelay control to the high-affinity KdpFABC potassium pump. KdpD senses conditions associated with potassium limitation and phosphorylates KdpE, activated KdpE promotes kdpFABC transcription, and the membrane KdpFABC complex couples ATP hydrolysis to potassium uptake. Constitutive potassium channels and lower-affinity uptake systems are outside this module. |
Biological Process | COMPLETE | bacteria |
0 | potassium ion homeostasis |
6 | 4 | 5 | 0 | 0 | 3 | 13/13 | 0 | ✗ | modules/bacterial_kdp_potassium_homeostasis.yaml | |
Bacterial L-carnitine catabolism through 3-dehydrocarnitineMODULE:bacterial_l_carnitine_catabolismCONCRETE An aerobic bacterial pathway that converts L-carnitine to glycine betaine through 3-dehydrocarnitine. An NAD-dependent L-carnitine dehydrogenase... [more...][less]An aerobic bacterial pathway that converts L-carnitine to glycine betaine through 3-dehydrocarnitine. An NAD-dependent L-carnitine dehydrogenase forms 3-dehydrocarnitine; a beta-keto acid cleavage enzyme (CdhC/BcoG) transfers the trimethylammonio-acetyl (betainyl) group to acetyl-CoA, releasing acetoacetate and forming betainyl-CoA; and a betainyl-CoA thioesterase releases glycine betaine and free CoA. The thioesterase is either a separate hotdog-fold protein (CdhB) or the C-terminal region of a bifunctional dehydrogenase-thioesterase (CdhAB/BcoE-BcoF). Where carnitine is taken up through an ABC importer, the CaiX substrate-binding protein confers carnitine selectivity on the shared CbcWV choline/betaine/carnitine core. The oxygenolytic CntAB route to trimethylamine, anaerobic Cai reduction to gamma-butyrobetaine, compatible-solute retention, acetoacetate activation, and downstream glycine-betaine demethylation are outside this boundary. |
Metabolic Pathway | COMPLETE | Pseudomonadota |
0 | carnitine catabolic process |
7 | 5 | 4 | 1 | 2 | 3 | 11/11 | 0 | ✓ | modules/bacterial_l_carnitine_catabolism.yaml | |
Bacterial L-cysteine biosynthesis via O-acetyl-L-serineMODULE:bacterial_cysteine_biosynthesis_via_o_acetylserineABSTRACT A reusable two-step bacterial pathway in which serine O-acetyltransferase (CysE) converts L-serine and acetyl-CoA to O-acetyl-L-serine, followed by... [more...][less]A reusable two-step bacterial pathway in which serine O-acetyltransferase (CysE) converts L-serine and acetyl-CoA to O-acetyl-L-serine, followed by a pyridoxal-phosphate-dependent O-acetylserine sulfhydrylase that incorporates sulfide to produce L-cysteine. OAS-active CysK or CysM proteins can implement the terminal reaction. The route is distributed across bacterial lineages, but neither the gene names nor broad family membership establish substrate choice. Thiosulfate incorporation produces S-sulfocysteine and requires a further reduction; it is adjacent chemistry rather than the direct sulfide route. A regulatory cysteine synthase complex forms in some lineages but is not a required pathway assembly. Upstream sulfide generation and distinct O-phosphoserine/sulfur-carrier pathways lie outside this module. |
Metabolic Pathway | COMPLETE | bacteria that implement the O-acetylserine plus sulfide route |
3 | cysteine biosynthesis from serine |
6 | 4 | 2 | 1 | 3 | 1 | 15/15 | 0 | ✗ | modules/bacterial_cysteine_biosynthesis_via_o_acetylserine.yaml | |
Bacterial L-threonine biosynthesis from L-aspartateMODULE:bacterial_aspartate_to_threonine_biosynthesisCONCRETE Three species-native examples of the five-reaction aspartate-to-threonine pathway distinguish Pseudomonas standalone enzymes, E. coli bifunctional... [more...][less]Three species-native examples of the five-reaction aspartate-to-threonine pathway distinguish Pseudomonas standalone enzymes, E. coli bifunctional AK/HDH isozymes, and the Corynebacterium alpha2beta2 aspartokinase. Every complete route requires the intervening aspartate-semialdehyde dehydrogenase. Shared upstream steps also supply other amino-acid branches. The boundary begins at intracellular aspartate and ends at threonine; cofactors and reductant are supplied. A separate P. aeruginosa ThrH comparison uses phosphoserine instead of ATP for homoserine phosphorylation. |
Metabolic Pathway | COMPLETE | Bacteria Corynebacterium glutamicum ATCC 13032 Escherichia coli K-12 Pseudomonas aeruginosa PAO1 Pseudomonas putida KT2440 |
0 | L-threonine biosynthetic process |
25 | 19 | 16 | 3 | 8 | 12 | 17/17 | 0 | ✗ | modules/bacterial_aspartate_to_threonine_biosynthesis.yaml | |
Bacterial Lol-dependent outer-membrane lipoprotein traffickingMODULE:bacterial_lol_lipoprotein_traffickingCONCRETE A diderm-bacterial module for delivery of mature lipoproteins from the inner membrane to the outer membrane. The inner-membrane ABC-superfamily... [more...][less]A diderm-bacterial module for delivery of mature lipoproteins from the inner membrane to the outer membrane. The inner-membrane ABC-superfamily complex LolCDE uses ATP hydrolysis by LolD to extract an outer-membrane-destined lipoprotein from the outer leaflet of the inner membrane, without moving it across the bilayer, and hands it to the periplasmic carrier LolA. LolA shields the lipid anchor while crossing the periplasm and passes the lipoprotein mouth-to-mouth to the outer-membrane lipoprotein LolB, which incorporates it into the outer membrane. Lipoproteins with an inner-membrane retention signal are not released. Lipoprotein maturation and the functions of individual lipoproteins lie outside the module. Escherichia coli K-12, in which the pathway was defined, and Pseudomonas putida KT2440 supply exact exemplars for all five components. |
Biological Process | COMPLETE | diderm bacteria |
3 | lipoprotein localization to outer membrane |
4 | 3 | 3 | 0 | 0 | 2 | 10/10 | 0 | ✓ | modules/bacterial_lol_lipoprotein_trafficking.yaml | |
Bacterial Mla intermembrane phospholipid transportMODULE:bacterial_mla_intermembrane_phospholipid_transportCONCRETE Phospholipid exchange between the outer and inner membranes of diderm (Gram-negative-type) bacteria by the Mla (maintenance of lipid asymmetry)... [more...][less]Phospholipid exchange between the outer and inner membranes of diderm (Gram-negative-type) bacteria by the Mla (maintenance of lipid asymmetry) system. Three interfaces are required: an outer-membrane MlaA/VacJ lipoprotein, which in characterized enterobacteria sits in a complex with trimeric porins and accesses phospholipid in the outer leaflet; a soluble periplasmic MlaC carrier that binds phospholipid in a hydrophobic pocket and shuttles it between the membranes; and the inner-membrane MlaFEDB ABC complex, in which the MlaE permease and the hexameric MCE-domain MlaD ring form a continuous lipid pathway energized by MlaF ATP hydrolysis, with the STAS-domain MlaB bound to MlaF on the cytoplasmic side. The system keeps phospholipid out of the lipopolysaccharide-rich outer leaflet; the module represents the conserved transport architecture without forcing a single retrograde or anterograde net direction. |
Biological Process | COMPLETE | diderm bacteria |
0 | intermembrane phospholipid transfer |
4 | 3 | 3 | 0 | 0 | 0 | 12/12 | 0 | ✓ | modules/bacterial_mla_intermembrane_phospholipid_transport.yaml | |
Bacterial NADPH-dependent GS–GOGAT ammonia assimilationMODULE:bacterial_ammonia_assimilationCONCRETE Glutamine synthetase and a two-chain NADPH-dependent glutamate synthase couple ammonium incorporation to net L-glutamate synthesis. GS uses ATP to... [more...][less]Glutamine synthetase and a two-chain NADPH-dependent glutamate synthase couple ammonium incorporation to net L-glutamate synthesis. GS uses ATP to amidate L-glutamate; GOGAT transfers the glutamine amide nitrogen to 2-oxoglutarate using NADPH, yielding two glutamates. One glutamate replenishes the GS substrate pool, giving one net glutamate per turn. This chemistry occurs in Pseudomonas putida, Escherichia coli, Bacillus subtilis and Azospirillum brasilense, with differences in enzyme families, regulation, assembly and physiological dependence. |
Metabolic Pathway | COMPLETE | Azospirillum brasilense Bacillus subtilis subsp. subtilis str. 168 Bacteria Escherichia coli K-12 Pseudomonas putida KT2440 |
0 | ammonia assimilation cycle |
13 | 8 | 8 | 1 | 4 | 8 | 12/12 | 0 | ✓ | modules/bacterial_ammonia_assimilation.yaml | |
Bacterial Ntr nitrogen-regulatory cascade and assimilation outputMODULE:bacterial_ntr_nitrogen_regulationCONCRETE The bacterial nitrogen-regulatory (Ntr) system, which couples intracellular nitrogen status to the sigma-54-dependent nitrogen-scavenging regulon.... [more...][less]The bacterial nitrogen-regulatory (Ntr) system, which couples intracellular nitrogen status to the sigma-54-dependent nitrogen-scavenging regulon. The bifunctional uridylyltransferase/uridylyl-removing enzyme GlnD senses glutamine and sets the uridylylation state of the PII signal transduction proteins (GlnB, GlnK). PII proteins also bind 2-oxoglutarate, ATP and ADP, and in their unmodified state stimulate the phosphatase and inhibit the kinase activity of the sensor histidine kinase NtrB. NtrB phosphorylates the conserved receiver aspartate of NtrC, and phosphorylated NtrC uses its AAA+ enhancer-binding module with the sigma-54 holoenzyme to open -24/-12 promoters, inducing ammonium scavenging and ammonia assimilation. The module covers glutamine sensing, PII signal integration, His->Asp phosphotransfer, sigma-54-dependent activation, and the immediate assimilatory output. |
Signaling Pathway | COMPLETE | bacteria |
0 | regulation of nitrogen utilization |
8 | 10 | 7 | 0 | 0 | 5 | 12/12 | 0 | ✗ | modules/bacterial_ntr_nitrogen_regulation.yaml | |
Bacterial PAMP perception by LRR receptor kinases (FLS2/EFR with BAK1)MODULE:bacterial_pamp_lrr_receptor_signalingCONCRETE Arabidopsis detects conserved epitopes of bacterial proteins at the plasma membrane with leucine-rich-repeat receptor kinases (LRR-RKs) that act as... [more...][less]Arabidopsis detects conserved epitopes of bacterial proteins at the plasma membrane with leucine-rich-repeat receptor kinases (LRR-RKs) that act as pattern recognition receptors (PRRs). FLS2 binds flg22, the conserved N-terminal epitope of flagellin, and EFR binds elf18, the N-terminal epitope of elongation factor Tu. Ligand binding recruits the SERK-family co-receptor kinase BAK1 (SERK3): in the FLS2 complex BAK1 contacts the C terminus of FLS2-bound flg22 and the two kinases activate each other by transphosphorylation. The activated receptor complex phosphorylates receptor-like cytoplasmic kinases (RLCKs) of subfamily VII. BIK1 is phosphorylated by BAK1 within minutes, then directly phosphorylates the plasma membrane NADPH oxidase RBOHD, which together with calcium binding to its EF-hands produces the apoplastic burst of superoxide; BIK1 also promotes the flg22-induced rise in cytosolic calcium. In a second branch, RLCK VII kinases phosphorylate the MAP kinase kinase kinases MAPKKK3 and MAPKKK5, which activate the MAP kinase kinases MKK4 and MKK5 and, through them, the MAP kinases MPK3 and MPK6, which drive defence gene expression. These early events together initiate pattern-triggered immunity against bacteria. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | detection of bacterium pathogen-associated molecular pattern receptor signaling pathway |
13 | 9 | 10 | 1 | 2 | 6 | 10/10 | 0 | ✗ | modules/bacterial_pamp_lrr_receptor_signaling.yaml | |
Bacterial Pst phosphate uptakeMODULE:bacterial_pst_phosphate_uptakeCONCRETE A reusable bacterial high-affinity phosphate-uptake module in which PstS captures inorganic phosphate, the PstA/PstC membrane subunits form the... [more...][less]A reusable bacterial high-affinity phosphate-uptake module in which PstS captures inorganic phosphate, the PstA/PstC membrane subunits form the translocation pathway, and a PstB dimer supplies ATP-dependent energy coupling. The module represents uptake by the PstSACB transporter and ends with cytoplasmic phosphate delivery. PhoU-mediated homeostasis and PhoR/PhoB starvation signaling regulate this system but are not transport steps. |
Biological Process | COMPLETE | bacteria |
3 | phosphate ion transmembrane transport |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✓ | modules/bacterial_pst_phosphate_uptake.yaml | |
Bacterial RecBCD double-strand-end resectionMODULE:bacterial_recbcd_end_resectionCONCRETE A reusable bacterial homologous-recombination initiation module in which the RecBCD complex engages a double-strand DNA end, the oppositely... [more...][less]A reusable bacterial homologous-recombination initiation module in which the RecBCD complex engages a double-strand DNA end, the oppositely directed RecB and RecD motors unwind the duplex, RecC participates in a taxon-dependent recombinogenic switch, the RecB nuclease produces a 3-prime single-stranded tail, and RecB promotes RecA loading. The identity and even sequence dependence of the switch vary among bacteria. RecFOR single-strand-gap repair, RecA strand exchange, RuvABC branch migration and resolution, replication restart, and bacterial nonhomologous end joining are separate modules. |
Biological Process | COMPLETE | 2 | double-strand break repair via homologous recombination |
6 | 7 | 5 | 0 | 0 | 4 | 8/8 | 0 | ✗ | modules/bacterial_recbcd_end_resection.yaml | ||
Bacterial Rod complex peptidoglycan polymerization and crosslinkingMODULE:bacterial_rod_complex_peptidoglycan_transpeptidationCONCRETE A lateral cell-wall synthesis module for the bacterial Rod complex in which the SEDS glycosyltransferase RodA polymerizes lipid II-derived glycan... [more...][less]A lateral cell-wall synthesis module for the bacterial Rod complex in which the SEDS glycosyltransferase RodA polymerizes lipid II-derived glycan strands and the class B penicillin-binding protein MrdA/PBP2 forms 4-3 peptide crosslinks. The RodA-MrdA synthase pair is the elongasome counterpart of the septal FtsW-FtsI pair and supports rod-shape maintenance. Precursor lipid II synthesis, MreB-guided spatial control, class A PBP backup polymerases, and turnover/remodeling reactions are outside this focused module. |
Biological Process | DRAFT | bacteria |
0 | peptidoglycan biosynthetic process regulation of cell shape |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/bacterial_rod_complex_peptidoglycan_transpeptidation.yaml | |
Bacterial RuvABC Holliday-junction processingMODULE:bacterial_ruvabc_holliday_junction_processingCONCRETE A reusable bacterial homologous-recombination module in which RuvA recognizes and opens a four-way Holliday junction, RuvB uses ATP to drive branch... [more...][less]A reusable bacterial homologous-recombination module in which RuvA recognizes and opens a four-way Holliday junction, RuvB uses ATP to drive branch migration, and RuvC cleaves the migrated junction to produce duplex recombination products. RecG supplies a mechanistically parallel branch-migration route in bacteria that encode it. Presynaptic RecFOR and RecBCD processing, RecA strand exchange, replication restart, and DNA ligation are neighboring modules. |
Biological Process | COMPLETE | 1 | recombinational repair |
5 | 4 | 4 | 0 | 0 | 3 | 8/8 | 0 | ✗ | modules/bacterial_ruvabc_holliday_junction_processing.yaml | ||
Bacterial SRP-dependent cotranslational membrane targetingMODULE:bacterial_srp_cotranslational_targetingCONCRETE A reusable bacterial module for cotranslational targeting of hydrophobic nascent membrane proteins to the cytoplasmic membrane. A signal... [more...][less]A reusable bacterial module for cotranslational targeting of hydrophobic nascent membrane proteins to the cytoplasmic membrane. A signal recognition particle made of the Ffh GTPase and a small SRP RNA (4.5S RNA in E. coli and Pseudomonas) binds the signal sequence of a ribosome-nascent-chain complex, the peripheral membrane SRP receptor FtsY captures that complex at the membrane, and reciprocal GTPase activation in the Ffh-FtsY NG-domain heterodimer promotes handoff to the SecYEG insertion machinery and dissociation of Ffh and FtsY. The boundary ends at this handoff; SecYEG-mediated translocation and insertion are downstream modules. |
Biological Process | COMPLETE | bacteria |
1 | SRP-dependent cotranslational protein targeting to membrane |
4 | 6 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/bacterial_srp_cotranslational_targeting.yaml | |
Bacterial TonB-energized outer-membrane ferric-siderophore importMODULE:bacterial_tonb_siderophore_import A conserved Gram-negative bacterial transport module mediating active import of ferric-siderophore complexes across the outer membrane into the... [more...][less]A conserved Gram-negative bacterial transport module mediating active import of ferric-siderophore complexes across the outer membrane into the periplasm. Because the outer membrane lacks an electrochemical proton gradient, outer-membrane TonB-dependent ferric-siderophore receptors (such as BfrD1) rely on the inner-membrane TonB-ExbB-ExbD complex — comprising the pentameric ExbB proton-channel stator (ExbB4), the dimeric ExbD proton-coupling subunit (ExbD5), and the inner-membrane-anchored, periplasm-spanning energy transducer TonB — to harvest and transduce the cytoplasmic-membrane proton-motive force across the periplasmic space. Physical contact between the C-terminal domain of TonB and the N-terminal TonB box of the receptor plug domain drives conformational opening of the 22-stranded outer-membrane beta-barrel channel and translocation of the ferric-siderophore complex into the periplasm. Siderophore biosynthesis, extracellular siderophore secretion, and subsequent periplasmic-to-cytoplasmic ABC transport are outside this module boundary. |
Biological Process | DRAFT | Bacteria |
0 | siderophore-iron import into cell |
4 | 4 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/bacterial_tonb_siderophore_import.yaml | |
Bacterial alkanesulfonate uptake and FMN-dependent desulfonationMODULE:bacterial_alkanesulfonate_uptake_desulfonationCONCRETE SsuABC-mediated alkanesulfonate uptake can supply an aerobic two-component desulfonation system in which a flavin reductase provides reduced FMN... [more...][less]SsuABC-mediated alkanesulfonate uptake can supply an aerobic two-component desulfonation system in which a flavin reductase provides reduced FMN and SsuD cleaves the carbon–sulfur bond to release sulfite and an aldehyde. The sampled native implementations are E. coli K-12 and Pseudomonas putida KT2440 and S-313. Their transporter alternatives, substrate ranges and reductase requirements differ. Sulfite assimilation, TauD chemistry, regulatory induction and aromatic-sulfonate accessory pathways lie outside this boundary. |
Metabolic Pathway | COMPLETE | Escherichia coli K-12 Gammaproteobacteria Pseudomonas putida Pseudomonas putida KT2440 |
0 | alkanesulfonate catabolic process |
13 | 9 | 9 | 1 | 3 | 6 | 15/15 | 0 | ✓ | modules/bacterial_alkanesulfonate_uptake_desulfonation.yaml | |
Bacterial aminoacyl-tRNA chargingMODULE:bacterial_aminoacyl_trna_chargingCONCRETE Production of the twenty canonical aminoacyl-tRNAs used in bacterial protein synthesis, through direct aminoacyl-tRNA synthetases and... [more...][less]Production of the twenty canonical aminoacyl-tRNAs used in bacterial protein synthesis, through direct aminoacyl-tRNA synthetases and species-matched indirect amino-acid conversion on tRNA. The reusable program distinguishes class I and class II LysRS, homodimeric and heterotetrameric GlyRS, heteromeric PheRS, direct versus GatCAB-dependent Asn/Gln formation, and the rare bacterial SepRS–SepCysS route to Cys-tRNA. The boundary ends at a correctly aminoacylated tRNA. It excludes ribosomal elongation, initiation-specific formylation, tRNA maturation, selenocysteine/pyrrolysine recoding and off-tRNA amino-acid synthesis. Editing improves fidelity but is not modeled as a universally obligatory independent enzyme for each output. |
Biological Process | COMPLETE | Bacillus subtilis subsp. subtilis str. 168 Bacteria Borreliella burgdorferi B31 Escherichia coli K-12 Parcubacteria bacterium DG_74_2 Pseudomonas aeruginosa PAO1 Pseudomonas putida KT2440 Thermosynechococcus vestitus BP-1 Thermus thermophilus HB8 |
0 | tRNA charging |
66 | 40 | 44 | 7 | 21 | 5 | 42/42 | 0 | ✓ | modules/bacterial_aminoacyl_trna_charging.yaml | |
Bacterial and eukaryotic selenocysteine biosynthesis and co-translational incorporationMODULE:selenocysteine_biosynthesis_incorporationCONCRETE A reusable module for the bacterial and eukaryotic synthesis of selenocysteyl-tRNA(Sec) and recoding of UGA as selenocysteine. Selenophosphate... [more...][less]A reusable module for the bacterial and eukaryotic synthesis of selenocysteyl-tRNA(Sec) and recoding of UGA as selenocysteine. Selenophosphate synthetase activates selenium, and seryl-tRNA synthetase charges tRNA(Sec) with serine. Bacteria convert Ser-tRNA(Sec) directly with SelA, whereas the represented eukaryotic route first phosphorylates it with PSTK and then uses SepSecS. The completed Sec-tRNA(Sec) is delivered by a lineage-specific elongation system to a UGA codon in a SECIS-dependent translation context. |
Biological Process | DRAFT | bacteria eukaryotes |
4 | L-selenocysteine biosynthetic process selenocysteine incorporation |
12 | 9 | 9 | 1 | 2 | 6 | 9/14 | 0 | ✓ | modules/selenocysteine_biosynthesis_incorporation.yaml | |
Bacterial assimilatory nitrate uptake and reductionMODULE:bacterial_assimilatory_nitrate_reductionCONCRETE Bacterial nitrate utilization supplies ammonium for biosynthesis through successive nitrate-to-nitrite and nitrite-to-ammonium reductions. Four... [more...][less]Bacterial nitrate utilization supplies ammonium for biosynthesis through successive nitrate-to-nitrite and nitrite-to-ammonium reductions. Four species-native implementations distinguish ferredoxin-dependent cyanobacterial enzymes, a multisubunit Bacillus nitrate reductase, and fused pyridine-nucleotide-linked nitrate reductases in Pseudomonas and Mycolicibacterium. Uptake assemblies are required when extracellular nitrate is the input; an intracellular-nitrate boundary permits omission of uptake. A separate E. coli comparison illustrates nitrate-fed assimilation during respiration and depends on an upstream respiratory nitrate reductase outside the represented protein panel. The module ends at ammonium, before its incorporation into glutamine or glutamate. |
Metabolic Pathway | COMPLETE | Bacillus subtilis subsp. subtilis str. 168 Escherichia coli K-12 Mycolicibacterium smegmatis MC2 155 Pseudomonas putida KT2440 Synechococcus elongatus PCC 7942 = FACHB-805 |
0 | 19 | 13 | 14 | 1 | 4 | 7 | 21/21 | 0 | ✗ | modules/bacterial_assimilatory_nitrate_reduction.yaml | ||
Bacterial beta-aryl ether cleavage of lignin-derived dimersMODULE:bacterial_beta_aryl_ether_dimer_cleavageCONCRETE A three-stage glutathione-dependent route converts lignin-derived beta-O-4 dimers into aromatic monomers. NAD+-dependent Calpha oxidation produces... [more...][less]A three-stage glutathione-dependent route converts lignin-derived beta-O-4 dimers into aromatic monomers. NAD+-dependent Calpha oxidation produces MPHPV; stereospecific ether cleavage releases guaiacol and an inverted GS-HPV conjugate; reductive deglutathionylation consumes a second glutathione to yield HPV and GSSG. The complete SYK-6 implementation requires coverage of both alpha and beta configurations. F199 provides an independently assayed downstream subroute with a BaeAB heterodimer alternative, and E. coli YghU provides a bounded isolated-activity comparator. Polymer depolymerization, uptake, downstream monomer assimilation and cofactor regeneration lie outside the boundary. |
Metabolic Pathway | COMPLETE | Bacteria Escherichia coli K-12 Novosphingobium aromaticivorans DSM 12444 Sphingobium sp. SYK-6 Sphingomonas paucimobilis |
0 | glutathione-dependent catabolism of lignin-derived beta-O-4 dimers |
30 | 17 | 19 | 5 | 10 | 9 | 16/16 | 0 | ✗ | modules/bacterial_beta_aryl_ether_dimer_cleavage.yaml | |
Bacterial carboxyspermidine route to spermidineMODULE:bacterial_carboxyspermidine_biosynthesisCONCRETE A bacterial two-reaction route that converts putrescine and L-aspartate 4-semialdehyde to spermidine. NADPH-dependent carboxyspermidine... [more...][less]A bacterial two-reaction route that converts putrescine and L-aspartate 4-semialdehyde to spermidine. NADPH-dependent carboxyspermidine dehydrogenase first forms carboxyspermidine, which a PLP-dependent decarboxylase converts to spermidine and carbon dioxide. The route draws its added carbon unit from aspartate metabolism rather than decarboxylated S-adenosylmethionine. It occurs across multiple bacterial lineages, but neither universal occurrence nor universal exclusion of other polyamine routes is implied. Related family members differ in substrate preference and can support norspermidine, tetraamine or agmatine-series chemistry; membership alone does not establish this putrescine route. Substrate supply, transport and downstream polyamine effects lie outside the two-reaction boundary. |
Metabolic Pathway | COMPLETE | Bacteria |
0 | spermidine biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 12/12 | 0 | ✓ | modules/bacterial_carboxyspermidine_biosynthesis.yaml | |
Bacterial cellulose biosynthesisMODULE:bacterial_cellulose_biosynthesisCONCRETE Bacterial UDP-glucose-dependent cellulose polymerization coupled to architecture-dependent membrane translocation, periplasmic support and... [more...][less]Bacterial UDP-glucose-dependent cellulose polymerization coupled to architecture-dependent membrane translocation, periplasmic support and extracellular passage. BcsA-family synthases provide the conserved catalytic role. Characterized BcsB/BcsC systems coexist with typeIII BcsC-independent and cyanobacterial BcsB-independent architectures whose envelope mechanisms remain incompletely resolved. A distinct monoderm CslA–GlxA complex establishes cellulose-synthesizing capacity in vitro, with native polymer composition unresolved. PilZ-dependent activation and accessory assembly factors are modeled in their applicable implementations. The taxon context describes diverse bacterial lineages, not universal occurrence or a universally sufficient protein inventory. |
Biological Process | COMPLETE | Bacteria Cereibacter Cyanobacteriota Enterobacterales Komagataeibacter Pseudomonas Rhizobiaceae |
0 | bacterial cellulose biosynthetic process |
21 | 16 | 15 | 1 | 5 | 9 | 20/20 | 2 | ✓ | modules/bacterial_cellulose_biosynthesis.yaml | |
Bacterial chemotaxis signal transduction to flagellar motor outputMODULE:bacterial_chemotaxis_signal_transductionCONCRETE Reusable bacterial chemotaxis module linking methyl-accepting chemoreceptor input and CheR/CheB methylation-dependent adaptation through... [more...][less]Reusable bacterial chemotaxis module linking methyl-accepting chemoreceptor input and CheR/CheB methylation-dependent adaptation through CheW-coupled CheA autophosphorylation and phosphotransfer to the response regulator CheY, CheZ-dependent CheY-P dephosphorylation, CheY-P action on the FliG/FliM/FliN C-ring switch, and ion-conducting MotA/MotB-family stators that power flagellar rotation. Escherichia coli K-12 proteins ground the paradigm relay and Pseudomonas putida KT2440 proteins ground a second, polar-flagellate realization with two stator systems; receptor ligand specificity is not made universal. |
Signaling Pathway | COMPLETE | Bacteria Pseudomonas |
0 | chemotaxis |
13 | 11 | 8 | 2 | 4 | 8 | 22/22 | 1 | ✗ | modules/bacterial_chemotaxis_signal_transduction.yaml | |
Bacterial choline uptake and glycine betaine biosynthesisMODULE:bacterial_choline_to_glycine_betaine_biosynthesisCONCRETE A reusable bacterial module for choline uptake followed by its two-step oxidation to the compatible solute glycine betaine. A BCCT-family BetT... [more...][less]A reusable bacterial module for choline uptake followed by its two-step oxidation to the compatible solute glycine betaine. A BCCT-family BetT transporter imports choline, the FAD-dependent, membrane-associated choline dehydrogenase BetA oxidizes choline to betaine aldehyde using a respiratory electron acceptor, and the soluble NAD-dependent betaine-aldehyde dehydrogenase BetB oxidizes the aldehyde to glycine betaine. The route was defined genetically and biochemically in Escherichia coli K-12. It is conserved in Pseudomonas, where P. putida KT2440 requires betBA for glycine-betaine synthesis from choline, and in other proteobacteria and Gram-positive bacteria that carry betA and betB. |
Metabolic Pathway | COMPLETE | bacteria |
0 | glycine betaine biosynthetic process from choline |
4 | 3 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/bacterial_choline_to_glycine_betaine_biosynthesis.yaml | |
Bacterial choline-O-sulfate uptake and desulfationMODULE:bacterial_choline_o_sulfate_uptake_and_desulfationABSTRACT A bacterial uptake-and-hydrolysis mechanism in which intact choline-O-sulfate enters the cell and is cleaved by BetC to choline, sulfate and a... [more...][less]A bacterial uptake-and-hydrolysis mechanism in which intact choline-O-sulfate enters the cell and is cleaved by BetC to choline, sulfate and a proton. Import implementations and molecular assignments vary among lineages. Uptake for osmoprotection without hydrolysis is a distinct outcome; downstream choline oxidation and sulfur assimilation lie outside this boundary. |
Metabolic Pathway | COMPLETE | bacteria |
0 | choline-O-sulfate utilization |
8 | 6 | 5 | 1 | 2 | 1 | 10/10 | 0 | ✓ | modules/bacterial_choline_o_sulfate_uptake_and_desulfation.yaml | |
Bacterial chromosomal DNA replicationMODULE:bacterial_chromosomal_dna_replicationCONCRETE Bacterial chromosome duplication coordinates origin recognition and helicase loading with template unwinding, protection and priming, replicative... [more...][less]Bacterial chromosome duplication coordinates origin recognition and helicase loading with template unwinding, protection and priming, replicative synthesis and proofreading, clamp-dependent processivity, RNA-primer replacement, nick sealing and topological separation. Alternative loader and polymerase architectures are grounded in Proteobacteria, Bacillota and Actinomycetota examples. |
Biological Process | COMPLETE | Bacteria Mycobacterium tuberculosis H37Rv |
0 | DNA replication |
30 | 32 | 14 | 6 | 15 | 6 | 52/52 | 0 | ✗ | modules/bacterial_chromosomal_dna_replication.yaml | |
Bacterial cyclic di-AMP second-messenger signallingMODULE:bacterial_c_di_amp_signalingABSTRACT A bacterial second-messenger motif in which diadenylate cyclases synthesize cyclic di-AMP, phosphodiesterases control its turnover, and protein... [more...][less]A bacterial second-messenger motif in which diadenylate cyclases synthesize cyclic di-AMP, phosphodiesterases control its turnover, and protein receptors couple ligand occupancy to physiology. The characterized Bacillota implementations combine membrane CdaA/DacA or cytoplasmic DisA cyclases with GdpP or PgpH hydrolysis to pApA. A separable Pde2 clearance step converts pApA to AMP and can relieve feedback inhibition of GdpP. Receptor outputs differ: Ktr/CabP and KdpD restrain potassium uptake, OpuCA is associated with reduced osmolyte uptake, KhtT stimulates potassium export through ligand-dependent release of restraint, and apo-DarB regulates metabolic enzymes. PII-like DarA/PstA proteins bind the messenger but their direct targets remain unresolved. |
Signaling Pathway | COMPLETE | Bacillota (Firmicutes) |
0 | cyclic di-AMP |
16 | 12 | 4 | 3 | 11 | 5 | 17/17 | 0 | ✗ | modules/bacterial_c_di_amp_signaling.yaml | |
Bacterial cyclic di-GMP second-messenger signallingMODULE:bacterial_c_di_gmp_signalingABSTRACT A reusable bacterial intracellular second-messenger motif comprising GGDEF-mediated c-di-GMP synthesis, turnover by EAL or HD-GYP... [more...][less]A reusable bacterial intracellular second-messenger motif comprising GGDEF-mediated c-di-GMP synthesis, turnover by EAL or HD-GYP phosphodiesterases, and recognition by protein receptors. Synthesis and hydrolysis alter ligand availability, either in shared cellular pools or through local enzyme–effector interactions. The model samples Pseudomonadota, Bacillota and Spirochaetota; it does not imply that every bacterium has the motif, both phosphodiesterase classes or every receptor class. PilZ proteins and catalytically inactive GGDEF/EAL proteins provide distinct receptor implementations. Motility, adhesion, extracellular-polysaccharide production and host adaptation are receptor-specific outputs outside the core boundary. |
Signaling Pathway | COMPLETE | Bacteria Bordetella bronchiseptica |
0 | c-di-GMP |
9 | 6 | 4 | 2 | 4 | 3 | 17/17 | 0 | ✗ | modules/bacterial_c_di_gmp_signaling.yaml | |
Bacterial cytochrome c maturation system IMODULE:bacterial_cytochrome_c_maturation_system_iABSTRACT Bacterial cytochrome c maturation System I couples heme handling and ATP-dependent processing to covalent attachment of heme to exported c-type... [more...][less]Bacterial cytochrome c maturation System I couples heme handling and ATP-dependent processing to covalent attachment of heme to exported c-type cytochrome apoproteins. The canonical histidine-CcmE route uses CcmG-supported redox preparation and CcmFH ligation, with lineage-dependent fused or separate CcmI-like accessories. The experimentally reconstructed G20 System I* route uses cysteine-linked CcmE and functions without CcmG/H; its CcmI enhances yield. Sec export, heme biosynthesis and lineage-specific upstream reductant supply are external dependencies. Archaeal and mitochondrial implementations are outside this bacterial module. |
Biological Process | COMPLETE | bacteria |
1 | cytochrome c-heme linkage |
13 | 16 | 10 | 1 | 2 | 6 | 29/29 | 0 | ✓ | modules/bacterial_cytochrome_c_maturation_system_i.yaml | |
Bacterial de novo phosphatidic acid synthesis (PlsX/PlsY and PlsB routes)MODULE:bacterial_phosphatidic_acid_synthesisCONCRETE A reusable bacterial module for de novo synthesis of phosphatidic acid, the branch-point precursor of all membrane glycerophospholipids, from... [more...][less]A reusable bacterial module for de novo synthesis of phosphatidic acid, the branch-point precursor of all membrane glycerophospholipids, from sn-glycerol 3-phosphate and the activated fatty acids made by type II fatty acid synthase. The module has two steps. The first acylation esterifies a fatty acyl group to the sn-1 position of sn-glycerol 3-phosphate to give 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid), and is implemented by either of two routes: the ubiquitous acyl-phosphate route, in which PlsX converts acyl-[ACP] into acyl-phosphate and the polytopic membrane protein PlsY transfers that acyl group to glycerol 3-phosphate, or the PlsB route, in which a single peripheral membrane acyltransferase acylates glycerol 3-phosphate directly from acyl-CoA or acyl-[ACP]. The second acylation, by PlsC of the AGPAT/LPAAT family, adds a fatty acyl group to the sn-2 position of lysophosphatidic acid to give phosphatidic acid, and is common to both routes. |
Metabolic Pathway | DRAFT | bacteria |
2 | phosphatidic acid biosynthetic process |
7 | 4 | 4 | 1 | 2 | 2 | 2/7 | 0 | ✗ | modules/bacterial_phosphatidic_acid_synthesis.yaml | |
Bacterial dimethylglycine and sarcosine catabolismMODULE:bacterial_dimethylglycine_sarcosine_catabolismCONCRETE A reusable two-step bacterial module for sequential N-demethylation of dimethylglycine to sarcosine and then glycine. In the first step a DgcA-type... [more...][less]A reusable two-step bacterial module for sequential N-demethylation of dimethylglycine to sarcosine and then glycine. In the first step a DgcA-type flavoprotein oxidizes dimethylglycine and reduces a membrane-anchored DgcB-type 2[4Fe-4S] ferredoxin. Reduced DgcB is proposed to pass the electrons to a pathway-associated heterodimeric ETF. The second step is performed either by a tetrahydrofolate-coupled heterotetrameric SoxABDG sarcosine oxidase or by a monomeric sarcosine oxidase that releases formaldehyde. Upstream glycine-betaine demethylation and downstream glycine cleavage or serine conversion are outside the module boundary. |
Metabolic Pathway | COMPLETE | bacteria |
0 | 5 | 5 | 2 | 1 | 2 | 3 | 17/17 | 0 | ✓ | modules/bacterial_dimethylglycine_sarcosine_catabolism.yaml | ||
Bacterial divisome peptidoglycan polymerization and crosslinkingMODULE:bacterial_divisome_peptidoglycan_transpeptidationCONCRETE A focused FtsW/class-B-PBP septal peptidoglycan-synthesis mechanism with two required reactions: lipid-II-derived glycan polymerization and... [more...][less]A focused FtsW/class-B-PBP septal peptidoglycan-synthesis mechanism with two required reactions: lipid-II-derived glycan polymerization and serine-dependent D,D peptide crosslinking. FtsW requires a compatible bPBP activation interface, whereas crosslink catalysis can be supplied conditionally by Bacillus PBP3 while physical PBP2B remains present. The acceptor amino group may lie on a stem peptide or an attached bridge; mDAP is not universal. Sampled E. coli, Bacillus, Staphylococcus and Streptococcus implementations illustrate this mechanism, which is not a universal description of bacterial division. Precursor supply, divisome positioning and upstream activation, class-A-PBP alternatives and cell separation lie outside this focused boundary. |
Biological Process | COMPLETE | Bacillus subtilis subsp. subtilis str. 168 bacteria Escherichia coli K-12 Staphylococcus aureus subsp. aureus NCTC 8325 Streptococcus thermophilus LMG 18311 |
0 | division septum assembly peptidoglycan biosynthetic process |
12 | 10 | 2 | 2 | 9 | 1 | 9/9 | 0 | ✗ | modules/bacterial_divisome_peptidoglycan_transpeptidation.yaml | |
Bacterial ethanolamine access, deamination and acetaldehyde dispositionMODULE:bacterial_ethanolamine_uptake_catabolismCONCRETE Ethanolamine reaches a compatible adenosylcobamide-dependent EutB/EutC complex through condition-dependent protein transport or experimentally... [more...][less]Ethanolamine reaches a compatible adenosylcobamide-dependent EutB/EutC complex through condition-dependent protein transport or experimentally supported diffusion. The enzyme releases acetaldehyde and ammonium. The oxidative pathway routes acetaldehyde to acetyl-CoA through EutE or to acetate through a non-acylating NAD-dependent aldehyde dehydrogenase. A parallel EutG branch forms ethanol and can regenerate NAD+. Selected implementations couple EutD and acetate kinase to CoA recycling and ATP formation, use EutA to replace inactivated cofactor, or organize enzymes in a bacterial microcompartment. The chemical nitrogen-release, oxidative and reductive endpoints are distinct from sustained native carbon growth. |
Metabolic Pathway | COMPLETE | bacteria Salmonella enterica subsp. enterica serovar Typhimurium str. LT2 |
2 | ethanolamine catabolic process |
13 | 10 | 8 | 2 | 4 | 11 | 20/20 | 0 | ✗ | modules/bacterial_ethanolamine_uptake_catabolism.yaml | |
Bacterial fatty acid beta-oxidation spiralMODULE:bacterial_fatty_acid_beta_oxidationCONCRETE A four-reaction bacterial mechanism that converts an accepted fatty acyl-CoA into acetyl-CoA and a two-carbon-shorter acyl-CoA. Dehydrogenation,... [more...][less]A four-reaction bacterial mechanism that converts an accepted fatty acyl-CoA into acetyl-CoA and a two-carbon-shorter acyl-CoA. Dehydrogenation, hydration, NAD-dependent oxidation and thiolysis are implemented by distinct enzyme families and compatible multifunctional complexes. The sampled enterobacterial, pseudomonad, mycobacterial and Bacillus systems differ in assembly, substrate range, electron-transfer evidence and native endpoint. Fatty-acid transport/activation, cofactor recycling, unsaturated-substrate auxiliary reactions and odd-chain product disposal are external requirements rather than hidden steps of this core. |
Metabolic Pathway | COMPLETE | bacteria |
0 | fatty acid beta-oxidation |
15 | 10 | 4 | 4 | 10 | 4 | 19/19 | 0 | ✗ | modules/bacterial_fatty_acid_beta_oxidation.yaml | |
Bacterial flagellar assembly and type III exportMODULE:bacterial_flagellar_assembly_exportCONCRETE Gammaproteobacterial flagellar assembly and export mechanisms connecting the MS/C-ring platform, protein export, rod/hook construction and length... [more...][less]Gammaproteobacterial flagellar assembly and export mechanisms connecting the MS/C-ring platform, protein export, rod/hook construction and length control, late transcription, and filament completion. Pseudomonas putida, Escherichia coli and Salmonella exemplars ground the assembly/export roles; P. putida MotAB/MotCD and Vibrio alginolyticus PomAB resolve conditional motor function and coupling-ion differences. |
Biological Process | COMPLETE | Gammaproteobacteria Pseudomonas putida KT2440 Vibrio alginolyticus |
0 | bacterial-type flagellum assembly |
11 | 31 | 7 | 1 | 3 | 7 | 38/38 | 0 | ✗ | modules/bacterial_flagellar_assembly_export.yaml | |
Bacterial free-acid 4-hydroxybutyrate oxidation to succinateMODULE:bacterial_4_hydroxybutyrate_oxidationCONCRETE Two consecutive non-CoA reactions oxidize 4-hydroxybutyrate to succinate: NAD-dependent Gbd forms succinate semialdehyde, and a nonacylating... [more...][less]Two consecutive non-CoA reactions oxidize 4-hydroxybutyrate to succinate: NAD-dependent Gbd forms succinate semialdehyde, and a nonacylating succinate-semialdehyde dehydrogenase forms succinate. The experimentally supported implementation is grounded in selected or experimentally expressing Cupriavidus necator backgrounds. Pseudomonas putida candidates and a distinct 3-hydroxybutyrate enzyme provide comparative context without establishing a complete native free-acid route. Uptake, upstream diol oxidation, GABA supply, CoA-dependent beta-oxidation, PHA synthesis and reverse succinate degradation are outside the boundary. |
Metabolic Pathway | COMPLETE | Bacteria Cupriavidus necator Escherichia coli K-12 Pseudomonas putida KT2440 |
0 | 9 | 7 | 8 | 0 | 0 | 1 | 7/7 | 0 | ✓ | modules/bacterial_4_hydroxybutyrate_oxidation.yaml | ||
Bacterial fructose PTS uptake and entry into central carbon catabolismMODULE:fructose_pts_uptake_and_catabolism A reusable two-part bacterial module in which a fructose-specific phosphoenolpyruvate-dependent phosphotransferase system imports fructose while... [more...][less]A reusable two-part bacterial module in which a fructose-specific phosphoenolpyruvate-dependent phosphotransferase system imports fructose while converting it to fructose 1-phosphate, and 1-phosphofructokinase then converts fructose 1-phosphate to fructose 1,6-bisphosphate. The module stops at fructose 1,6-bisphosphate. Downstream central-carbon reactions, PTS regulatory cross-talk, transcriptional control by Cra/FruR, and pathways for other hexoses are outside the boundary. |
Metabolic Pathway | DRAFT | 0 | phosphoenolpyruvate-dependent sugar phosphotransferase system fructose catabolic process |
3 | 3 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/fructose_pts_uptake_and_catabolism.yaml | ||
Bacterial fused-relay fructose PTS uptake and catabolismMODULE:bacterial_fructose_pts_catabolismCONCRETE A bacterial fused-relay mechanism couples phosphoenolpyruvate-driven histidine phosphorylation to fructose translocation and formation of fructose... [more...][less]A bacterial fused-relay mechanism couples phosphoenolpyruvate-driven histidine phosphorylation to fructose translocation and formation of fructose 1-phosphate, followed by ATP-dependent formation of fructose 1,6-bisphosphate. A FruB polypeptide carries enzyme-I, HPr and fructose-specific EIIA regions; a separate FruA polypeptide combines EIIB phosphotransfer and EIIC translocation functions. Additional EIIB-like regions occur in several FruA exemplars. Nitrogen-regulatory PTS signaling and metabolism downstream of fructose 1,6-bisphosphate are outside the boundary. |
Metabolic Pathway | COMPLETE | bacteria |
0 | 5 | 4 | 4 | 0 | 0 | 3 | 16/16 | 0 | ✓ | modules/bacterial_fructose_pts_catabolism.yaml | ||
Bacterial gallate catabolism via 4-oxalomesaconateMODULE:bacterial_gallate_catabolismCONCRETE A bacterial aromatic-acid catabolic module that opens the gallate ring by extradiol dioxygenation and converts the ring-cleavage product to... [more...][less]A bacterial aromatic-acid catabolic module that opens the gallate ring by extradiol dioxygenation and converts the ring-cleavage product to pyruvate and oxaloacetate. A two-domain type II extradiol gallate dioxygenase cleaves gallate to the keto tautomer of 4-oxalomesaconate (OMA). OMA is then converted to 4-carboxy-4-hydroxy-2-oxoadipate (CHA) by one of two enzyme pairs that are not homologous at the hydration step: a keto-enol tautomerase plus an OMA-enol hydratase of the PIG-L/MshB zinc-hydratase fold, or a 1,3-allylic isomerase that forms (3Z)-2-keto-4-carboxy-3-hexenedioate (KCH) plus a KCH hydratase of the amidohydrolase fold. A metal-dependent class II CHA aldolase of the RraA-like fold finally cleaves CHA to pyruvate and oxaloacetate. An outer-membrane porin encoded with the pathway genes can optionally support substrate entry. Upstream reactions that generate gallate (for example demethylation of syringate-derived 3-O-methylgallate), regulation, and the metabolism of the end products are outside the module boundary. |
Metabolic Pathway | COMPLETE | bacteria |
0 | gallate catabolic process |
11 | 7 | 8 | 1 | 2 | 5 | 9/9 | 0 | ✗ | modules/bacterial_gallate_catabolism.yaml | |
Bacterial glutamate-to-P5C branch of proline biosynthesisMODULE:bacterial_glutamate_to_p5c_biosynthesisCONCRETE Bacterial split-enzyme conversion of L-glutamate to L-glutamate 5-semialdehyde: a ProB-family kinase, including the Bacillus ProJ paralog,... [more...][less]Bacterial split-enzyme conversion of L-glutamate to L-glutamate 5-semialdehyde: a ProB-family kinase, including the Bacillus ProJ paralog, phosphorylates glutamate with ATP, and ProA reduces L-glutamyl 5-phosphate with NADPH. Spontaneous cyclization yields pyrroline-5-carboxylate (P5C). The module ends before ProC-type P5C reduction to proline and does not require a ProB–ProA complex. |
Metabolic Pathway | COMPLETE | bacteria |
2 | L-proline biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 9/9 | 0 | ✓ | modules/bacterial_glutamate_to_p5c_biosynthesis.yaml | |
Bacterial glycerol uptake and catabolism through glycerol 3-phosphateMODULE:bacterial_glycerol_uptake_catabolismCONCRETE Aerobic glycerol utilisation in bacteria by the phosphorylating route, from channel-mediated uptake to dihydroxyacetone phosphate. A GlpF... [more...][less]Aerobic glycerol utilisation in bacteria by the phosphorylating route, from channel-mediated uptake to dihydroxyacetone phosphate. A GlpF aquaglyceroporin lets glycerol diffuse across the cytoplasmic membrane down its concentration gradient. The ATP-dependent glycerol kinase GlpK traps it in the cell as sn-glycerol 3-phosphate. The FAD-dependent glycerol-3-phosphate:quinone dehydrogenase GlpD then oxidizes that intermediate to dihydroxyacetone phosphate on the cytoplasmic face of the plasma membrane, passing the electrons to the respiratory quinone pool. The same GlpF-GlpK-GlpD route is used by Escherichia coli and Pseudomonas putida and is encoded by the glp genes of many other bacteria. |
Metabolic Pathway | COMPLETE | bacteria |
4 | glycerol catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 6/6 | 0 | ✗ | modules/bacterial_glycerol_uptake_catabolism.yaml | |
Bacterial glycogen and related alpha-glucan metabolismMODULE:glycogen_synthesis_and_mobilizationCONCRETE A reusable bacterial storage-carbon module that distinguishes canonical GlgC/ADP-glucose-dependent glycogen synthesis from Pseudomonas... [more...][less]A reusable bacterial storage-carbon module that distinguishes canonical GlgC/ADP-glucose-dependent glycogen synthesis from Pseudomonas UDP-glucose-dependent production of linear alpha-glucan by GlgA. In Pseudomonas, most GlgA-derived linear glucan enters the TreY/TreZ and TreS-Mak-GlgE network. GlgB can branch GlgA-derived polymer, but that connection is modeled as an unverified capability whose physiological contribution is unknown. The mobilization arm represents GlgP phosphorolysis and GlgX branch removal, while leaving the physiological partitioning of these enzymes among bacterial glycogen and related branched alpha-glucan pools unresolved. The module ends at glucose 1-phosphate; phosphoglucomutase and central carbon metabolism are downstream. |
Metabolic Pathway | DRAFT | bacteria |
0 | glucan metabolic process |
13 | 7 | 10 | 1 | 2 | 7 | 6/9 | 0 | ✗ | modules/glycogen_synthesis_and_mobilization.yaml | |
Bacterial glycolate and glyoxylate assimilation (glycerate pathway)MODULE:glycolate_glyoxylate_assimilationCONCRETE A bacterial central-carbon module that converts glycolate and glyoxylate into D-glycerate, which re-enters core carbon metabolism. The core starts... [more...][less]A bacterial central-carbon module that converts glycolate and glyoxylate into D-glycerate, which re-enters core carbon metabolism. The core starts with oxidation of glycolate to glyoxylate by the membrane-associated, three-subunit GlcDEF glycolate oxidase/dehydrogenase (FAD-linked GlcD and GlcE plus the iron-sulfur subunit GlcF). Glyoxylate carboligase (Gcl), a thiamine diphosphate enzyme, then condenses two glyoxylate molecules into tartronate semialdehyde with release of carbon dioxide, and tartronate semialdehyde reductase (GlxR) reduces tartronate semialdehyde to D-glycerate with NADH or NADPH. Two accessory steps can feed the core: phosphoglycolate phosphatase supplies glycolate from 2-phosphoglycolate, and hydroxypyruvate isomerase (Hyi) interconverts hydroxypyruvate and tartronate semialdehyde. The pathway is best characterized in Escherichia coli K-12 and Pseudomonas putida KT2440, and the same gene set is found widely in Proteobacteria. Glycerate kinase, the glyoxylate shunt and the eukaryotic photorespiratory C2 cycle lie outside this module. |
Metabolic Pathway | COMPLETE | bacteria |
0 | glyoxylate metabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 14/14 | 0 | ✓ | modules/glycolate_glyoxylate_assimilation.yaml | |
Bacterial heptaprenylglyceryl ether-lipid (Ac-HepG) pathwayMODULE:bacterial_heptaprenylglyceryl_ether_lipidCONCRETE The heptaprenylglyceryl ether-lipid pathway characterized in Bacillus subtilis, with homologous PcrB chemistry demonstrated in other Caryophanales.... [more...][less]The heptaprenylglyceryl ether-lipid pathway characterized in Bacillus subtilis, with homologous PcrB chemistry demonstrated in other Caryophanales. It produces heptaprenylglycerol and its acetylated form (Ac-HepG). sn-Glycerol 1-phosphate (G1P) is condensed with all-trans-heptaprenyl diphosphate by the group I GGGPS-family enzyme PcrB to form an ether bond, giving 3-heptaprenyl-sn-glycero-1-phosphate (HepGP); HepGP is dephosphorylated by a phosphatase that has not been assigned to a gene, and the resulting heptaprenylglycerol (HepG) is O-acetylated from acetyl-CoA by YvoF. The product Ac-HepG is not elaborated into a bulk membrane lipid as in Archaea: it is a low-abundance lipophilic acetyl carrier that delivers acetyl groups to the extracytoplasmic face of the membrane, where LhaT (formerly YpjA) transfers them to the alpha-amino group of the N-terminal cysteine of mature diacylglyceryl lipoproteins. The module is of interest because a bacterium here uses three features of archaeal membrane chemistry at once - a G1P backbone, an ether linkage and an isoprenoid chain - to build a carrier cofactor rather than a membrane. Lipoprotein diacylglyceryl transfer and signal-peptide cleavage, which produce LhaT's acceptor, are modelled separately in bacterial_lipoprotein_maturation; isoprenoid (HepPP) supply and the downstream TLR2 immunology are outside the boundary. |
Metabolic Pathway | COMPLETE | Bacillales |
0 | ether lipid biosynthetic process |
7 | 5 | 5 | 1 | 1 | 4 | 6/6 | 1 | ✗ | modules/bacterial_heptaprenylglyceryl_ether_lipid.yaml | |
Bacterial iad-type aerobic indole-3-acetic acid catabolismMODULE:bacterial_iad_auxin_catabolism A conserved rhizosphere bacterial pathway module mediating aerobic uptake and catabolism of the plant hormone indole-3-acetic acid (IAA) via the... [more...][less]A conserved rhizosphere bacterial pathway module mediating aerobic uptake and catabolism of the plant hormone indole-3-acetic acid (IAA) via the iad gene cluster. The module comprises the MarR-family IAA-sensing transcriptional repressor IadR, the high-affinity periplasmic subcluster B-III ABC transporter solute-binding protein IadK2 (paired with its non-IAA-binding paralog IadK3), the Class IA NADH:ferredoxin oxidoreductase component IadC, the heterohexameric Rieske non-heme iron aromatic-ring-hydroxylating dioxygenase complex IadD/IadE that catalyzes the initial oxidative conversion of IAA into biologically inactive 2-oxindole-3-acetic acid (oxIAA), and the downstream cytoplasmic enzymes—including the heterodimeric TPP/[4Fe-4S]-dependent 2-oxoacid:ferredoxin oxidoreductase complex IadA/IadB and the putative cyclic-amide amidohydrolase / isatin hydrolase IadI (KynB2)—that participate in processing oxidized indole intermediates through dioxindole-3-acetic acid, dioxindole, isatin, and isatinic acid to anthranilic acid, thereby buffering rhizosphere auxin levels and preventing root growth inhibition. |
Metabolic Pathway | DRAFT | 0 | indoleacetic acid catabolic process |
7 | 6 | 6 | 0 | 0 | 5 | 8/8 | 0 | ✗ | modules/bacterial_iad_auxin_catabolism.yaml | ||
Bacterial lipopolysaccharide transportMODULE:bacterial_lps_transportCONCRETE Reusable module for ATP-driven extraction of lipopolysaccharide (LPS) from the outer leaflet of the inner membrane of diderm bacteria, its transfer... [more...][less]Reusable module for ATP-driven extraction of lipopolysaccharide (LPS) from the outer leaflet of the inner membrane of diderm bacteria, its transfer across the periplasm along the trans-envelope Lpt protein bridge, and its insertion into the outer leaflet of the outer membrane. The module separates the LptB2FGC inner-membrane extraction machine, the soluble LptA bridge, and the LptD/LptE outer-membrane translocon, which together form the seven-protein lipopolysaccharide transport system. |
Biological Process | COMPLETE | bacteria |
3 | lipopolysaccharide transport lipopolysaccharide transport system |
4 | 4 | 3 | 0 | 0 | 2 | 14/14 | 0 | ✗ | modules/bacterial_lps_transport.yaml | |
Bacterial lipoprotein maturationMODULE:bacterial_lipoprotein_maturationCONCRETE Bacterial lipoprotein maturation begins with Lgt transfer of a diacylglyceryl group to a lipobox cysteine and LspA removal of the signal peptide.... [more...][less]Bacterial lipoprotein maturation begins with Lgt transfer of a diacylglyceryl group to a lipobox cysteine and LspA removal of the signal peptide. The resulting diacylglyceryl lipoprotein may remain unmodified at its amino terminus or undergo lineage- and substrate-dependent tailoring: Lnt, Lnb or a compatible LnsAB complex adds a third long acyl chain; Lit relocates an existing chain to form a two-chain lyso-lipoprotein; LhaT transfers a lipid-carried acetyl group. These are distinct product routes, not interchangeable definitions of maturation. The bacterial occurrence envelope includes exemplars from Pseudomonadota, Bacillota and Bacteroidota; it does not assert universal enzyme presence or essentiality. Precursor export, lipid-donor synthesis, Lol trafficking and client functions are outside the boundary. |
Biological Process | COMPLETE | bacteria |
3 | lipoprotein biosynthetic process |
9 | 7 | 3 | 1 | 5 | 6 | 14/14 | 0 | ✓ | modules/bacterial_lipoprotein_maturation.yaml | |
Bacterial lipoyl-dependent acetoin and stereoisomer-specific butanediol catabolismMODULE:bacterial_2_3_butanediol_acetoin_catabolismCONCRETE Lipoyl-dependent acetoin cleavage produces acetaldehyde and acetyl-CoA through an AcoA/AcoB E1 reaction, AcoC acetyl transfer and E3-mediated... [more...][less]Lipoyl-dependent acetoin cleavage produces acetaldehyde and acetyl-CoA through an AcoA/AcoB E1 reaction, AcoC acetyl transfer and E3-mediated carrier regeneration. NAD-dependent R,R/meso oxidation and metal-dependent PQQ-mediated S,S-butanediol oxidation can supply acetoin upstream. The compared bacterial implementations differ in E2 architecture, availability of a dedicated E3 and strength of direct biochemical evidence. Native systems are kept separate; the bacterial envelope does not imply universal conservation. |
Metabolic Pathway | COMPLETE | Bacillus subtilis subsp. subtilis str. 168 Bacteria Cupriavidus necator H16 Pseudomonas putida KT2440 Syntrophotalea carbinolica |
0 | 21 | 15 | 13 | 2 | 7 | 15 | 19/19 | 2 | ✗ | modules/bacterial_2_3_butanediol_acetoin_catabolism.yaml | ||
Bacterial medium-chain-length PHA synthesis and mobilizationMODULE:bacterial_mcl_pha_synthesis_and_mobilizationCONCRETE A reusable bacterial module for production and intracellular turnover of medium-chain-length poly(3-hydroxyalkanoate) storage polyester. The... [more...][less]A reusable bacterial module for production and intracellular turnover of medium-chain-length poly(3-hydroxyalkanoate) storage polyester. The required core begins with an externally supplied (R)-3-hydroxyacyl-CoA pool: class II PhaC enzymes polymerize these monomers at PHA granules, and intracellular PhaZ depolymerases remobilize stored polymer. PhaG-dependent routing from de novo fatty-acid synthesis is an optional upstream submodule whose physiological chemistry is not fixed here. Beta-oxidation-derived monomer supply and phasin-mediated granule organization are adjacent processes outside the core reaction boundary. |
Metabolic Pathway | DRAFT | bacteria |
0 | poly(3-hydroxyalkanoate) metabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 4/9 | 0 | ✗ | modules/bacterial_mcl_pha_synthesis_and_mobilization.yaml | |
Bacterial methionine cycle and homocysteine remethylationMODULE:bacterial_methionine_cycle A reusable bacterial cycle that converts L-methionine to S-adenosyl-L-methionine (SAM), channels SAM through methyl-transfer reactions that produce... [more...][less]A reusable bacterial cycle that converts L-methionine to S-adenosyl-L-methionine (SAM), channels SAM through methyl-transfer reactions that produce S-adenosyl-L-homocysteine (SAH), hydrolyzes SAH to L-homocysteine, and remethylates L-homocysteine to regenerate L-methionine. The boundary begins with methionine adenosylation and ends with methionine regeneration; de novo production of methionine and sulfur assimilation are adjacent pathways rather than parts of this cycle. |
Metabolic Pathway | COMPLETE | 0 | L-methionine cycle |
11 | 7 | 6 | 2 | 4 | 5 | 6/6 | 1 | ✗ | modules/bacterial_methionine_cycle.yaml | ||
Bacterial naringenin A-ring degradationMODULE:bacterial_flavonoid_degradationCONCRETE The Fde-associated oxidative route in Pseudomonadota begins with naringenin hydroxylation and oxygenolytic A-ring cleavage. Herbaspirillum... [more...][less]The Fde-associated oxidative route in Pseudomonadota begins with naringenin hydroxylation and oxygenolytic A-ring cleavage. Herbaspirillum seropedicae SmR1 supplies FdeE/FdeC mutant and metabolite evidence, and purified FdeE establishes NADPH-dependent hydroxylation. Related loci and whole-cell phenotypes extend the comparison across alpha-, beta- and gammaproteobacteria. Six chemical steps retain the proposed KEGG R13074-R13079 sequence, with unverified late enzyme assignments explicitly separated from demonstrated entry chemistry. FdeD and FdeH are associated proteins whose reaction position and physiological necessity remain unresolved. Pseudomonas putida KT2440 and Bradyrhizobium diazoefficiens USDA110 provide sequence-grounded comparisons, not demonstrated complete pathway reconstructions. |
Metabolic Pathway | COMPLETE | Pseudomonadota |
0 | flavonoid catabolic process |
9 | 8 | 8 | 0 | 0 | 5 | 21/21 | 0 | ✗ | modules/bacterial_flavonoid_degradation.yaml | |
Bacterial nitrogen-regulatory PTS phosphorelayMODULE:bacterial_nitrogen_regulatory_ptsCONCRETE A species-neutral proteobacterial signaling module in which enzyme I(Ntr) accepts phosphate from phosphoenolpyruvate, NPr relays it, and EIIA(Ntr)... [more...][less]A species-neutral proteobacterial signaling module in which enzyme I(Ntr) accepts phosphate from phosphoenolpyruvate, NPr relays it, and EIIA(Ntr) acts as the terminal phosphorylation-state-dependent regulator. Unlike carbohydrate PTS pathways, this module does not transport or phosphorylate a sugar. |
Biological Process | COMPLETE | Pseudomonadota |
2 | protein phosphorylation |
4 | 3 | 3 | 0 | 0 | 2 | 6/6 | 0 | ✗ | modules/bacterial_nitrogen_regulatory_pts.yaml | |
Bacterial non-homologous end joiningMODULE:bacterial_nonhomologous_end_joiningCONCRETE A reusable bacterial DNA double-strand-break repair module in which a Ku homodimer recognizes, protects, and aligns broken duplex ends, a... [more...][less]A reusable bacterial DNA double-strand-break repair module in which a Ku homodimer recognizes, protects, and aligns broken duplex ends, a LigD-family enzyme conditionally remodels non-ligatable termini through polymerase and 3-prime-phosphoesterase activities, and an ATP-dependent LigD ligase domain seals the DNA backbone. The module excludes homologous recombination, single-strand annealing, eukaryotic NHEJ factors, and accessory bacterial backup routes that do not require the Ku-LigD core. |
Biological Process | DRAFT | bacteria |
2 | double-strand break repair via nonhomologous end joining |
4 | 4 | 3 | 0 | 0 | 3 | 2/6 | 0 | ✓ | modules/bacterial_nonhomologous_end_joining.yaml | |
Bacterial nucleotide-excision repair systemMODULE:bacterial_nucleotide_excision_repairCONCRETE A reusable bacterial nucleotide-excision repair module in which UvrA and UvrB recognize bulky, helix-distorting DNA lesions, UvrC incises the... [more...][less]A reusable bacterial nucleotide-excision repair module in which UvrA and UvrB recognize bulky, helix-distorting DNA lesions, UvrC incises the damaged strand on both sides of the lesion, UvrD releases the damage-containing oligonucleotide, DNA polymerase I fills the resulting gap, and an NAD-dependent DNA ligase seals the nick. Mfd supplies an optional transcription-coupled entry route by removing lesion-stalled RNA polymerase and recruiting the Uvr machinery. Base-excision repair, mismatch repair, homologous-recombination repair, translesion synthesis, and eukaryotic XPD/TFIIH excision repair are outside this module. |
Biological Process | DRAFT | 1 | nucleotide-excision repair |
8 | 7 | 7 | 0 | 0 | 6 | 8/14 | 0 | ✗ | modules/bacterial_nucleotide_excision_repair.yaml | ||
Bacterial phosphatidylethanolamine biosynthesis through phosphatidylserineMODULE:bacterial_phosphatidylethanolamine_biosynthesisCONCRETE A reusable two-reaction module for de novo phosphatidylethanolamine biosynthesis from CDP-diacylglycerol in bacteria. Phosphatidylserine synthase... [more...][less]A reusable two-reaction module for de novo phosphatidylethanolamine biosynthesis from CDP-diacylglycerol in bacteria. Phosphatidylserine synthase (PssA) transfers the phosphatidyl group of CDP-diacylglycerol to L-serine to form phosphatidylserine, and pyruvoyl-dependent phosphatidylserine decarboxylase (Psd) converts phosphatidylserine to phosphatidylethanolamine and CO2 at the cytoplasmic membrane. The first step is carried out by two unrelated enzyme architectures: a type-I, peripheral-membrane PssA of the phospholipase D superfamily, typical of gamma- and some beta-proteobacteria such as Escherichia coli, and a type-II, integral-membrane CDP-alcohol phosphatidyltransferase PssA, typical of Gram-positive bacteria such as Bacillus subtilis. Some genomes, such as Pseudomonas putida KT2440, encode both. The decarboxylation step is performed by a single conserved Psd family whose proenzyme self-cleaves to generate the pyruvoyl prosthetic group. |
Metabolic Pathway | COMPLETE | bacteria |
2 | phosphatidylethanolamine biosynthetic process |
5 | 3 | 2 | 1 | 2 | 1 | 7/7 | 0 | ✓ | modules/bacterial_phosphatidylethanolamine_biosynthesis.yaml | |
Bacterial phosphatidylglycerol and cardiolipin biosynthesisMODULE:bacterial_phosphatidylglycerol_cardiolipin_biosynthesisCONCRETE A reusable bacterial membrane-lipid module from CDP-diacylglycerol to phosphatidylglycerol and on to phospholipase-D-family cardiolipin. PgsA forms... [more...][less]A reusable bacterial membrane-lipid module from CDP-diacylglycerol to phosphatidylglycerol and on to phospholipase-D-family cardiolipin. PgsA forms phosphatidylglycerol phosphate, PgpA-type phosphatases remove its terminal phosphate to give phosphatidylglycerol, and one or more Cls lineages form cardiolipin. ClsA and ClsB transfer a phosphatidyl group between two phosphatidylglycerol molecules; ClsC transfers it from phosphatidylethanolamine to phosphatidylglycerol. The route is conserved across Proteobacteria and is exemplified here by Escherichia coli K-12, where every step is characterized experimentally, and by Pseudomonas putida KT2440. |
Metabolic Pathway | COMPLETE | bacteria Pseudomonadota |
0 | phosphatidylglycerol biosynthetic process cardiolipin biosynthetic process |
8 | 5 | 4 | 1 | 3 | 4 | 9/9 | 0 | ✗ | modules/bacterial_phosphatidylglycerol_cardiolipin_biosynthesis.yaml | |
Bacterial preQ1 incorporation and queuosine maturationMODULE:bacterial_preq1_incorporation_queuosine_maturationCONCRETE A reusable bacterial pathway that converts preQ0 to the mature queuosine modification at wobble position 34 of tRNA(Asp), tRNA(Asn), tRNA(His), and... [more...][less]A reusable bacterial pathway that converts preQ0 to the mature queuosine modification at wobble position 34 of tRNA(Asp), tRNA(Asn), tRNA(His), and tRNA(Tyr). QueF reduces preQ0 to preQ1, Tgt exchanges guanine-34 for preQ1, QueA transfers and rearranges the ribose moiety of S-adenosylmethionine to form epoxyqueuosine, and either QueG or the nonhomologous QueH family reduces epoxyqueuosine to queuosine. |
Metabolic Pathway | COMPLETE | bacteria |
0 | tRNA queuosine(34) biosynthetic process |
7 | 5 | 4 | 1 | 2 | 3 | 10/10 | 0 | ✓ | modules/bacterial_preq1_incorporation_queuosine_maturation.yaml | |
Bacterial purine base oxidation to urateMODULE:bacterial_purine_base_oxidation_to_urateCONCRETE A reusable bacterial pathway realization in which xanthine is supplied by either zinc-dependent guanine deamination or NAD+-dependent hypoxanthine... [more...][less]A reusable bacterial pathway realization in which xanthine is supplied by either zinc-dependent guanine deamination or NAD+-dependent hypoxanthine oxidation and is then oxidized to urate. In the two-subunit realization, the same XdhAB molybdo-flavo-iron-sulfur complex performs both NAD+-dependent oxidation reactions. |
Metabolic Pathway | COMPLETE | bacteria |
1 | purine nucleobase catabolic process |
5 | 3 | 2 | 1 | 2 | 2 | 6/6 | 0 | ✓ | modules/bacterial_purine_base_oxidation_to_urate.yaml | |
Bacterial putrescine biosynthesis by arginine and ornithine routesMODULE:bacterial_putrescine_biosynthesisCONCRETE A reusable bacterial module for putrescine supply through alternative amino-acid routes. In the two-reaction arginine/agmatine route, SpeA... [more...][less]A reusable bacterial module for putrescine supply through alternative amino-acid routes. In the two-reaction arginine/agmatine route, SpeA decarboxylates L-arginine to agmatine and SpeB hydrolyzes agmatine to putrescine. In the direct ornithine route, SpeC decarboxylates L-ornithine to putrescine. Organisms may encode either or both routes. Upstream amino-acid supply, downstream spermidine synthesis, uptake, and putrescine catabolism are outside the boundary. |
Metabolic Pathway | DRAFT | bacteria |
0 | putrescine biosynthetic process |
5 | 3 | 2 | 1 | 2 | 1 | 3/6 | 0 | ✗ | modules/bacterial_putrescine_biosynthesis.yaml | |
Bacterial pyruvate oxidation, anaplerosis, and PEP interconversionMODULE:bacterial_pyruvate_metabolismCONCRETE A reusable bacterial central-carbon module centered on three direct fates of pyruvate and phosphoenolpyruvate: oxidative conversion of pyruvate to... [more...][less]A reusable bacterial central-carbon module centered on three direct fates of pyruvate and phosphoenolpyruvate: oxidative conversion of pyruvate to acetyl-CoA by the pyruvate dehydrogenase complex, replenishment of oxaloacetate by pyruvate carboxylase or phosphoenolpyruvate carboxylase, and direct interconversion between phosphoenolpyruvate and pyruvate. The module excludes complete glycolysis, the tricarboxylic acid cycle, lactate and acetate utilization, amino-acid degradation, methylglyoxal detoxification, fatty-acid synthesis, and other reactions included on broad pathway maps. |
Metabolic Pathway | DRAFT | 0 | pyruvate metabolic process |
8 | 8 | 5 | 1 | 2 | 4 | 10/10 | 0 | ✗ | modules/bacterial_pyruvate_metabolism.yaml | ||
Bacterial respiratory complex I (proton-translocating NADH:quinone oxidoreductase)MODULE:bacterial_respiratory_complex_iCONCRETE Reusable bacterial module for the conserved 14-subunit respiratory complex I, also called NDH-1 or NADH:quinone oxidoreductase. The peripheral arm... [more...][less]Reusable bacterial module for the conserved 14-subunit respiratory complex I, also called NDH-1 or NADH:quinone oxidoreductase. The peripheral arm oxidizes NADH, transfers electrons through FMN and iron-sulfur centers, and reduces the quinone pool. The membrane arm couples this redox chemistry to proton translocation. The module separates the NADH-input, quinone-reduction, membrane-interface, and antiporter-like proton-pumping parts so that fused subunits such as NuoC/D can be represented without collapsing the enzyme to a single step. It excludes the non-homologous, non-proton-pumping type-II NADH dehydrogenase (Ndh/NDH-2). |
Protein Complex | COMPLETE | bacteria |
0 | respiratory chain complex I |
5 | 8 | 4 | 0 | 0 | 3 | 26/26 | 0 | ✗ | modules/bacterial_respiratory_complex_i.yaml | |
Bacterial sodium-coupled proline uptake and fused-PutA catabolismMODULE:bacterial_fused_puta_proline_catabolismCONCRETE A reusable bacterial module in which a PutP-family sodium/proline symporter imports L-proline and a fused PutA (proline utilization A) protein... [more...][less]A reusable bacterial module in which a PutP-family sodium/proline symporter imports L-proline and a fused PutA (proline utilization A) protein oxidizes it to L-glutamate in two catalytic steps. The FAD-dependent PutA proline dehydrogenase (PRODH) domain transfers electrons to a membrane quinone while forming 1-pyrroline-5-carboxylate (P5C), and after nonenzymatic ring opening the NAD-dependent glutamate-5-semialdehyde dehydrogenase (GSALDH) domain oxidizes glutamate 5-semialdehyde to L-glutamate. Fused PutA proteins occur mainly in Gram-negative bacteria. In lineages whose putA and putP genes are transcribed divergently, including Escherichia coli, Salmonella and Pseudomonas putida, PutA is trifunctional: an N-terminal ribbon-helix-helix (RHH) DNA-binding domain lets the same protein repress the put genes until proline accumulates. Other PutAs lack the RHH domain and have only the two catalytic activities. |
Metabolic Pathway | COMPLETE | bacteria |
0 | L-proline catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✓ | modules/bacterial_fused_puta_proline_catabolism.yaml | |
Bacterial succinylarginine catabolism to glutamate and succinateMODULE:bacterial_succinylarginine_catabolismCONCRETE A five-reaction bacterial pathway that transfers a succinyl group from succinyl-CoA to L-arginine, hydrolyzes the guanidino group, transaminates... [more...][less]A five-reaction bacterial pathway that transfers a succinyl group from succinyl-CoA to L-arginine, hydrolyzes the guanidino group, transaminates the resulting N-succinyl-L-ornithine, oxidizes the semialdehyde, and removes the succinyl group to produce L-glutamate and succinate. The initiating transferase may be a single-chain enzyme or a two-chain complex. Arginine transport, regulation, alternative arginine-catabolic routes, and downstream central metabolism are outside the module boundary. |
Metabolic Pathway | COMPLETE | Pseudomonadota |
2 | L-arginine catabolic process |
8 | 6 | 5 | 1 | 2 | 4 | 14/14 | 0 | ✗ | modules/bacterial_succinylarginine_catabolism.yaml | |
Bacterial sulfoquinovose catabolism (sulfoglycolysis and sulfo-SMO)MODULE:bacterial_sulfoquinovose_catabolismCONCRETE A reusable bacterial module for breakdown of sulfoquinovose (SQ; 6-deoxy-6-sulfo-D-glucose), the polar head group of the plant and cyanobacterial... [more...][less]A reusable bacterial module for breakdown of sulfoquinovose (SQ; 6-deoxy-6-sulfo-D-glucose), the polar head group of the plant and cyanobacterial sulfolipid sulfoquinovosyl diacylglycerol. An optional glycoside hydrolase first releases free SQ from sulfoquinovosyl glycerides. SQ is then consumed by one of several alternative, biochemically characterized routes. Three C-C bond cleavage (sulfoglycolytic) routes split the C6 sulfosugar into a non-sulfonated C3 unit used for growth and the C3 organosulfonate 3-sulfolactaldehyde (SLA), which is then reduced to 2,3-dihydroxypropane-1-sulfonate (DHPS) or oxidized to 3-sulfolactate (SL) for excretion: the sulfo-EMP route (SQ isomerase, sulfofructose kinase, sulfofructose-1-phosphate aldolase), the sulfo-ED route (SQ dehydrogenase, sulfogluconolactonase, sulfogluconate dehydratase, KDSG aldolase), and the sulfo-SFT route (SQ isomerase and sulfofructose transaldolase). In the oxidative sulfo-SMO route a two-component flavin-dependent SQ monooxygenase cleaves the C-S bond, releasing sulfite and 6-dehydroglucose, which is reduced to glucose so that all six carbons are used. Uptake, regulation, and downstream mineralization of DHPS, SL or sulfite by other enzymes or community members are outside the module boundary. |
Metabolic Pathway | COMPLETE | bacteria |
2 | 6-sulfoquinovose(1-) catabolic process |
21 | 16 | 16 | 1 | 4 | 11 | 22/22 | 0 | ✗ | modules/bacterial_sulfoquinovose_catabolism.yaml | |
Bacterial taurine uptake and desulfonationMODULE:taurine_uptake_and_desulfonationABSTRACT A reusable two-part bacterial module in which the TauABC ATP-binding cassette transporter imports extracellular taurine and TauD oxidatively... [more...][less]A reusable two-part bacterial module in which the TauABC ATP-binding cassette transporter imports extracellular taurine and TauD oxidatively cleaves the imported sulfonate to aminoacetaldehyde and sulfite. The module represents acquisition of taurine as a sulfur source. Downstream aminoacetaldehyde metabolism, sulfite assimilation, sulfur-starvation regulation, and alternative organosulfonate transport or cleavage systems are outside the boundary. |
Metabolic Pathway | COMPLETE | 1 | taurine transmembrane transport taurine catabolic process |
3 | 2 | 2 | 0 | 0 | 1 | 12/12 | 0 | ✓ | modules/taurine_uptake_and_desulfonation.yaml | ||
Bacterial thiamine diphosphate biosynthesisMODULE:thiamine_diphosphate_biosynthesis Species-neutral bacterial pathway for de novo synthesis of thiamine diphosphate (ThDP), the active thiamine cofactor. The pathway has two... [more...][less]Species-neutral bacterial pathway for de novo synthesis of thiamine diphosphate (ThDP), the active thiamine cofactor. The pathway has two converging branches: a hydroxymethylpyrimidine branch in which ThiC converts an AIR-derived precursor to HMP phosphate and ThiD phosphorylates it to the diphosphate, and a thiazole branch in which Dxs, alternative ThiO or ThiH routes, sulfur-relay proteins, and ThiG form the thiazole phosphate moiety. ThiE couples the pyrimidine and thiazole moieties to thiamine phosphate, and ThiL phosphorylates thiamine phosphate to ThDP. The thiazole branch includes the ThiS sulfur-carrier activation/thiocarboxylation relay rather than treating sulfur delivery as a single enzyme reaction. |
Metabolic Pathway | DRAFT | 0 | thiamine biosynthetic process thiamine diphosphate biosynthetic process |
13 | 12 | 10 | 1 | 2 | 10 | 5/14 | 0 | ✓ | modules/thiamine_diphosphate_biosynthesis.yaml | ||
Bacterial trans-4-hydroxy-L-proline catabolism to 2-oxoglutarateMODULE:hydroxyproline_catabolismCONCRETE A reusable bacterial four-reaction route that converts trans-4-hydroxy-L-proline to 2-oxoglutarate. A PLP-independent epimerase first forms... [more...][less]A reusable bacterial four-reaction route that converts trans-4-hydroxy-L-proline to 2-oxoglutarate. A PLP-independent epimerase first forms cis-4-hydroxy-D-proline. An FAD-dependent oxidoreductase generates 4-hydroxy-1-pyrroline-2-carboxylate, a deaminase converts that cyclic imine to 2,5-dioxopentanoate and ammonium, and an aldehyde dehydrogenase-family enzyme completes oxidation to 2-oxoglutarate. |
Metabolic Pathway | DRAFT | 0 | trans-4-hydroxy-L-proline catabolic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/6 | 0 | ✗ | modules/hydroxyproline_catabolism.yaml | ||
Bacterial translation initiationMODULE:bacterial_translation_initiationCONCRETE A reusable bacterial module for assembly of a translation-competent 70S initiation complex. IF2 and IF3 associate with the 30S subunit early, IF1... [more...][less]A reusable bacterial module for assembly of a translation-competent 70S initiation complex. IF2 and IF3 associate with the 30S subunit early, IF1 stabilizes their binding and organizes the preinitiation complex, and IF2 promotes initiator fMet-tRNA accommodation and 50S joining while hydrolyzing GTP. The boundary ends with factor release and formation of the mature 70S initiation complex. Ribosome biogenesis, initiator-tRNA aminoacylation and formylation, elongation, and termination are excluded. RRF/EF-G-driven recycling is outside the module, but IF3 stabilization of newly split 30S subunits is retained as the recycling-to-initiation interface. |
Biological Process | DRAFT | bacteria |
0 | translational initiation |
4 | 4 | 3 | 0 | 0 | 2 | 3/6 | 0 | ✓ | modules/bacterial_translation_initiation.yaml | |
Bacterial trehalose synthesis from alpha-glucans and maltoseMODULE:bacterial_trehalose_synthesis_from_alpha_glucansCONCRETE A reusable bacterial module covering two alternative routes that form trehalose from alpha-glucosides. In the coupled TreY-TreZ route, TreY... [more...][less]A reusable bacterial module covering two alternative routes that form trehalose from alpha-glucosides. In the coupled TreY-TreZ route, TreY rearranges the reducing-end linkage of an alpha-1,4-glucan to form maltooligosyltrehalose and TreZ hydrolytically releases trehalose. In the standalone TreS route, one enzyme reversibly interconverts maltose and trehalose. Trehalose synthesis from nucleotide sugars, trehalose degradation, and upstream alpha-glucan or maltose supply are outside the boundary. |
Metabolic Pathway | DRAFT | bacteria |
0 | trehalose biosynthetic process |
5 | 3 | 2 | 1 | 2 | 1 | 5/6 | 0 | ✗ | modules/bacterial_trehalose_synthesis_from_alpha_glucans.yaml | |
Bacterial twin-arginine protein translocationMODULE:bacterial_twin_arginine_translocationCONCRETE A species-neutral bacterial membrane-translocation module for export of folded proteins bearing an N-terminal twin-arginine signal peptide by the... [more...][less]A species-neutral bacterial membrane-translocation module for export of folded proteins bearing an N-terminal twin-arginine signal peptide by the Tat machinery. TatC and TatB form the substrate receptor that binds the signal peptide and the folded precursor; TatA is then recruited in a proton-motive-force-dependent manner and oligomerizes to carry out passage across the cytoplasmic membrane without ATP. Signal-peptide recognition, receptor organization and translocation are modeled as separate roles. |
Biological Process | COMPLETE | bacteria |
3 | protein transport by the Tat complex |
4 | 3 | 3 | 0 | 0 | 2 | 9/9 | 0 | ✗ | modules/bacterial_twin_arginine_translocation.yaml | |
Bacterial type I secretionMODULE:bacterial_type_i_secretionCONCRETE A species-neutral module for one-step export of a cytoplasmic protein across both membranes of a diderm bacterium through a tripartite type I... [more...][less]A species-neutral module for one-step export of a cytoplasmic protein across both membranes of a diderm bacterium through a tripartite type I secretion conduit. An inner-membrane ABC transporter recognizes an uncleaved secretion signal in its substrate and hydrolyzes ATP; a periplasmic membrane-fusion adaptor anchored in the inner membrane bridges to, and opens, an oligomeric outer-membrane exit duct. Because the three components form a continuous channel, the substrate never appears as a folded periplasmic intermediate. Substrate maturation before export, folding and cofactor acquisition after release, Sec- and Tat-dependent routes, and small-molecule efflux through the same family of outer-membrane ducts are outside this module. |
Biological Process | DRAFT | bacteria |
0 | protein secretion by the type I secretion system |
6 | 4 | 3 | 1 | 2 | 2 | 1/10 | 0 | ✗ | modules/bacterial_type_i_secretion.yaml | |
Bacterial type II secretionMODULE:bacterial_type_ii_secretion A species-neutral module for export of folded proteins from the periplasm across the outer membrane by the type II secretion system. A multiprotein... [more...][less]A species-neutral module for export of folded proteins from the periplasm across the outer membrane by the type II secretion system. A multiprotein inner-membrane platform recruits the secretion ATPase and supports assembly of a dynamic pseudopilus, which displaces substrates through an oligomeric outer-membrane secretin. Delivery of substrates into the periplasm by Sec or Tat, substrate folding, and unrelated fimbrial or pilus systems are outside this module. |
Biological Process | DRAFT | bacteria |
0 | protein secretion by the type II secretion system |
5 | 13 | 4 | 0 | 0 | 3 | 19/24 | 0 | ✗ | modules/bacterial_type_ii_secretion.yaml | |
Bacterial type III secretion injectisomeMODULE:bacterial_type_iii_secretion_injectisomeCONCRETE A species-neutral module for the injectisome, the envelope-spanning type III secretion machine that moves unfolded substrates from the bacterial... [more...][less]A species-neutral module for the injectisome, the envelope-spanning type III secretion machine that moves unfolded substrates from the bacterial cytoplasm through a continuous conduit and across a second, target-cell membrane in one step. A cytoplasmic sorting platform and ATPase select substrates and strip their chaperones; an inner-membrane export apparatus forms the narrow channel; rings in the inner membrane and an outer-membrane secretin complete the basal body; an inner rod and a helical needle extend the conduit beyond the cell surface; and a translocon inserted in the target membrane completes the passage. The substrates themselves are excluded from this module, as are chaperone-substrate pairing for individual cargo, transcriptional regulation of the locus, and the flagellar export system, which is homologous but builds a different structure. |
Biological Process | DRAFT | bacteria |
0 | protein secretion by the type III secretion system |
9 | 21 | 6 | 1 | 2 | 6 | 2/41 | 0 | ✗ | modules/bacterial_type_iii_secretion_injectisome.yaml | |
Bacterial type IV secretion apparatusMODULE:bacterial_type_iv_secretion_apparatusCONCRETE A species-neutral module for the envelope-spanning machine that transfers macromolecules from a donor bacterium directly into a recipient cell or... [more...][less]A species-neutral module for the envelope-spanning machine that transfers macromolecules from a donor bacterium directly into a recipient cell or into the extracellular space. A coupling protein at the inner membrane receives the substrate and feeds it into a channel formed by a conserved three-protein envelope core complex; a VirB4-family ATPase, joined in many lineages by a second VirB11-family ATPase, energizes translocation and the assembly of an extracellular pilus built from processed pilin subunits. In conjugative systems an outer-membrane adhesin stabilizes the donor-recipient pair. The cargo is excluded from this module: the same apparatus transfers a relaxase covalently bound to plasmid DNA in conjugative systems and unrelated protein effectors in others. Relaxosome assembly and DNA nicking, plasmid replication, events inside the recipient cell, and transcriptional regulation of the transfer region are also outside this module. |
Biological Process | DRAFT | bacteria |
0 | secretion by the type IV secretion system |
7 | 9 | 6 | 0 | 0 | 6 | 3/15 | 0 | ✗ | modules/bacterial_type_iv_secretion_apparatus.yaml | |
Bacterial type V secretionMODULE:bacterial_type_v_secretionCONCRETE A species-neutral module for delivery of a passenger protein to the surface of a diderm bacterium by the type V route. The precursor crosses the... [more...][less]A species-neutral module for delivery of a passenger protein to the surface of a diderm bacterium by the type V route. The precursor crosses the inner membrane through Sec and is held in a translocation-competent, unfolded state in the periplasm by holdase chaperones. A beta-barrel translocator, which is either a domain of the passenger's own polypeptide or a separate partner protein, is installed in the outer membrane by the BAM complex. The passenger then crosses the outer membrane through that barrel and folds on the far side. No ATP or ion gradient is available at the outer membrane, so vectorial folding of the emerging passenger supplies the directionality. Sec translocation itself, the biological activity of the displayed passenger, and the general biogenesis of outer-membrane proteins unrelated to secretion lie outside this module. |
Biological Process | DRAFT | bacteria |
0 | protein secretion by the type V secretion system |
11 | 13 | 3 | 2 | 7 | 2 | 4/19 | 0 | ✗ | modules/bacterial_type_v_secretion.yaml | |
Bacterial type VI secretion apparatusMODULE:bacterial_type_vi_secretion_apparatus A contractile bacterial secretion nanomachine assembled from an envelope-spanning membrane complex, a cytoplasmic baseplate, an Hcp tube surrounded... [more...][less]A contractile bacterial secretion nanomachine assembled from an envelope-spanning membrane complex, a cytoplasmic baseplate, an Hcp tube surrounded by a TssBC sheath, a VgrG puncturing tip, and the ClpV ATPase that recycles contracted sheath. Cargo effectors, cognate immunity proteins, cargo-specific adapters, and global transcriptional regulation are outside this conserved structural boundary. |
Biological Process | DRAFT | bacteria |
0 | protein secretion by the type VI secretion system type VI protein secretion system complex |
6 | 13 | 5 | 0 | 0 | 4 | 13/26 | 0 | ✗ | modules/bacterial_type_vi_secretion_apparatus.yaml | |
Bacterial undecaprenyl-phosphate carrier supplyMODULE:bacterial_undecaprenyl_phosphate_carrier_supplyCONCRETE A reusable bacterial module that supplies the C55 polyprenyl-phosphate lipid carrier used for cell-envelope glycan assembly. A soluble... [more...][less]A reusable bacterial module that supplies the C55 polyprenyl-phosphate lipid carrier used for cell-envelope glycan assembly. A soluble cis-prenyltransferase, UppS, elongates (2E,6E)-farnesyl diphosphate with eight isopentenyl diphosphates to form di-trans,octa-cis-undecaprenyl diphosphate (C55-PP). An integral inner-membrane undecaprenyl-diphosphatase of the BacA/UppP family then removes the terminal phosphate to make undecaprenyl phosphate (C55-P). The same phosphatase reaction also returns C55-PP, released after glycan transfer, to the usable C55-P pool. The carrier supports several pathways, including peptidoglycan, lipopolysaccharide O-antigen and enterobacterial common antigen synthesis. Transfer of pathway-specific sugars onto the carrier, glycan polymerization, carrier flipping, and the unrelated PAP2-family phosphatases that partly overlap the second step are outside this module. |
Biological Process | COMPLETE | bacteria |
3 | polyprenol biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/bacterial_undecaprenyl_phosphate_carrier_supply.yaml | |
Bacteriophage Capsid Morphogenesis, Genome Packaging, and Tail AssemblyMODULE:phage_capsid_packaging_and_tail_assemblyCONCRETE A reusable module capturing bacteriophage virion morphogenesis (`GO:0019068`) across tailed dsDNA phages (Caudoviricetes), tailless icosahedral... [more...][less]A reusable module capturing bacteriophage virion morphogenesis (`GO:0019068`) across tailed dsDNA phages (Caudoviricetes), tailless icosahedral phages, internal-membrane phages (Tectiviridae), and segmented dsRNA cystoviruses. The core tailed-phage assembly pathway comprises procapsid assembly on a portal vertex (`GO:0019069`, `GO:0046798`), proteolytic or conformational procapsid maturation and expansion (`GO:0046797`, `GO:0019082`), ATP-driven genome packaging (`GO:0019073`) via a `VariantSetDescriptor` distinguishing 5'-cos (`GO:0098037`), headful pac/non-pac (`GO:0098006`), terminal-protein-primed phi29 packaging, PRD1 vertex ATPase P9 packaging, and phi6 hexameric P4 ssRNA packaging, followed by head completion/decoration (`GO:0098021`), independent tail and tail fiber assembly (`GO:0098003`, `GO:0098004`), and head-tail joining (`GO:0098005`). Also captures satellite phage capsid hijacking (such as P4 Sid redirecting helper P2 gpN procapsids into small T=4 heads). |
Biological Process | COMPLETE | Bacteria Viruses |
0 | virion assembly viral capsid assembly viral DNA genome packaging viral tail assembly |
10 | 10 | 3 | 1 | 6 | 0 | 8/10 | 0 | ✗ | modules/phage_capsid_packaging_and_tail_assembly.yaml | |
Bacteriophage Genome Replication, Transcriptional Takeover, and Counter-DefenseMODULE:phage_genome_replication_and_transcriptionCONCRETE A reusable module capturing the intracellular phage replication and host takeover program across major Baltimore classes of bacteriophages: (1)... [more...][less]A reusable module capturing the intracellular phage replication and host takeover program across major Baltimore classes of bacteriophages: (1) genome replication (`GO:0039693`, `GO:0039694`) modeled as a variant set across bidirectional theta + recombination-dependent dsDNA replication (`GO:0039686`, e.g. T4, early lambda, T7), rolling-circle dsDNA/ssDNA replication (`GO:0039683`, e.g. phiX174 gpA, M13 pII, late lambda, P2 gpA), protein-primed linear dsDNA replication (`GO:0039693`, `GO:0003887`, phi29 gp2/gp3, PRD1 P1/P8), and RNA-directed RNA replication (`GO:0039694`, `GO:0003968`, e.g. MS2/Qbeta replicase, phi6 P2); (2) an optional viral transcriptional takeover and translational cascade part (`GO:0019083`, `GO:0019080`, `GO:0039653`, `GO:0031564`), modeled as a variant set across transcription antitermination (lambda N/Q, P4 Psu), host RNAP sigma-factor remodeling or inhibition coupled to phage-encoded single-subunit RNA polymerases (T4 AsiA/gp55, T7 gp1/gp2), and direct (+)ssRNA translational regulation (MS2, Qbeta), whereas small ssDNA phages (phiX174, M13) that rely on unmodified host RNAP without a phage-encoded takeover or translational regulator omit this optional part; and (3) an optional host chromosome degradation (`GO:0099015`, T4 denA/ndd, gp46/gp47) and evasion of host restriction-modification and nuclease defenses (`GO:0099018`, T4 agt/bgt, Arn, Stp, T7 Ocr) part. |
Biological Process | COMPLETE | Bacteria Viruses |
0 | viral DNA genome replication viral RNA genome replication viral transcription symbiont-mediated evasion of host restriction-modification system |
10 | 9 | 2 | 2 | 7 | 0 | 9/9 | 0 | ✗ | modules/phage_genome_replication_and_transcription.yaml | |
Bacteriophage Host Attachment and Genome Ejection SystemsMODULE:phage_attachment_and_genome_ejectionCONCRETE A reusable module capturing the mechanisms by which bacteriophages recognize host surface receptors, penetrate the bacterial cell envelope, and... [more...][less]A reusable module capturing the mechanisms by which bacteriophages recognize host surface receptors, penetrate the bacterial cell envelope, and deliver their viral genome into the host cytoplasm. Adsorption proceeds via reversible binding to primary adhesion receptors (`GO:0098671`, including LPS `GO:0039638`, outer membrane porins, pili `GO:0039666`, or flagella `GO:0098931`) followed by irreversible commitment to secondary entry receptors (`GO:0098670`). Genome delivery (`GO:0039678`) is modeled as a variant set across six morphologically distinct architectures: (1) contractile myovirus tail sheath contraction and cell-puncturing needle penetration (`GO:0099000`, e.g. T4), (2) long non-contractile siphovirus tail tip/tape-measure channel translocation (`GO:0099001`, e.g. lambda, T5), (3) short podovirus tail extendable internal core/ejectosome formation (`GO:0099002`, e.g. T7, P22), (4) pilus retraction and TolQRA-dependent translocation in ssDNA/ssRNA filamentous and leviphages (e.g. M13, MS2, Qbeta), (5) spike-guided DNA pilot tube translocation in icosahedral Microviridae (e.g. phiX174 gpG/gpH), and (6) envelope membrane fusion + nucleocapsid shell peptidoglycan digestion in enveloped dsRNA Cystoviridae (e.g. phi6 P3/P6/P5). |
Biological Process | COMPLETE | Bacteria Viruses |
0 | virion attachment to host cell symbiont genome ejection through host cell envelope symbiont entry into host cell |
10 | 9 | 3 | 1 | 6 | 2 | 9/9 | 0 | ✗ | modules/phage_attachment_and_genome_ejection.yaml | |
Bacteriophage Virion Release and Host Cell Lysis SystemsMODULE:phage_virion_release_and_lysisCONCRETE A reusable module capturing the four principal bacteriophage progeny release architectures across bacterial hosts, structured as a variant set for... [more...][less]A reusable module capturing the four principal bacteriophage progeny release architectures across bacterial hosts, structured as a variant set for host-envelope-aware pathway satisfiability and abduction: (1) the canonical three-step dsDNA phage lysis system for Gram-negative diderm hosts (holin / pinholin inner membrane pore formation, endolysin peptidoglycan degradation, and two-component Rz/Rz1 or unimolecular o-spanin outer membrane disruption), modulated in Tevenvirinae by antiholin-mediated lysis inhibition (LIN); (2) the two-step holin + endolysin system sufficient for Gram-positive monoderm hosts lacking an outer membrane (with an optional mycolate esterase LysB step in mycobacteriophages); (3) single-gene lysis (SGL) systems of small ssDNA and ssRNA phages that inhibit host peptidoglycan biosynthesis enzymes (such as MraY or MurA) or destabilize the cell envelope via an amrazin membrane protein; and (4) non-lytic chronic filamentous phage extrusion through a trans-envelope pIV/pI/pXI assembly complex. |
Biological Process | COMPLETE | Bacteria Viruses |
0 | viral release from host cell viral release from host cell by cytolysis |
11 | 9 | 6 | 1 | 4 | 2 | 7/7 | 2 | ✗ | modules/phage_virion_release_and_lysis.yaml | |
Basement membrane laminin and collagen network in Drosophila melanogasterMODULE:dmel_basement_membrane_networkCONCRETE Basement membranes are sheet-like extracellular matrices beneath epithelia and around muscles and organs. Their two self-assembling networks are... [more...][less]Basement membranes are sheet-like extracellular matrices beneath epithelia and around muscles and organs. Their two self-assembling networks are made of laminin and type IV collagen. Drosophila has two laminin trimers, each made of one alpha chain (LanA or Wing blister) with the shared beta (LanB1) and gamma (LanB2) chains; laminins polymerise at the cell surface and initiate basement membrane assembly. Type IV collagen trimers of Col4a1 and Viking are made mainly by the fat body and hemocytes and then incorporated into basement membranes, where they form a cross-linked network that gives strength and shapes organs. Multiplexin (the collagen XV/XVIII homolog) and Pericardin (a collagen IV-like protein of the cardiac extracellular matrix) are additional collagens grouped with them. |
Cellular Component | DRAFT | Drosophila melanogaster |
0 | basement membrane |
6 | 5 | 3 | 1 | 2 | 1 | 0/8 | 0 | ✗ | modules/dmel_basement_membrane_network.yaml | |
Benzoate upper degradation pathwayMODULE:benzoate_upper_pathwayCONCRETE A bacterial aromatic-catabolism module for the aerobic upper benzoate degradation route that converts benzoate to catechol in two reactions. A... [more...][less]A bacterial aromatic-catabolism module for the aerobic upper benzoate degradation route that converts benzoate to catechol in two reactions. A multicomponent (class IB) Rieske benzoate 1,2-dioxygenase first dihydroxylates benzoate to the cis-dihydrodiol 1,6-dihydroxycyclohexa-2,4-diene-1-carboxylate. This enzyme is built from a BenA-family catalytic alpha subunit carrying the Rieske [2Fe-2S] cluster and the mononuclear iron, a BenB-family non-catalytic beta subunit, and a BenC-family NADH-dependent ferredoxin-reductase that delivers electrons directly to the oxygenase. A BenD-family NAD+-dependent short-chain cis-diol dehydrogenase then oxidatively decarboxylates the diol to catechol, which feeds catechol ring-cleavage and beta-ketoadipate modules. The route is conserved, with the same four-protein architecture and benABCD gene organization, in Gammaproteobacteria (Pseudomonas, Acinetobacter) and in Actinobacteria (Rhodococcus). |
Metabolic Pathway | COMPLETE | bacteria |
0 | benzoate catabolic process via hydroxylation |
3 | 3 | 2 | 0 | 0 | 1 | 12/12 | 0 | ✓ | modules/benzoate_upper_pathway.yaml | |
Beta-adrenergic receptor signaling — epinephrine acting through ADRB1/ADRB2, Gs, adenylyl cyclase/cAMP, PKA-dependent Gi switching, and GRK/beta-arrestin desensitizationMODULE:beta_adrenergic_signalingCONCRETE The catecholamine hormone and neurotransmitter epinephrine (adrenaline) signals through the beta-1 and beta-2 adrenergic receptors (ADRB1, ADRB2),... [more...][less]The catecholamine hormone and neurotransmitter epinephrine (adrenaline) signals through the beta-1 and beta-2 adrenergic receptors (ADRB1, ADRB2), class A G protein-coupled receptors that couple to the stimulatory G protein. Agonist binding lets the receptor act as a guanine nucleotide exchange factor for G alpha s (GNAS); GTP-bound G alpha s stimulates adenylyl cyclase, and the cAMP produced activates protein kinase A (PKA), whose targets in cardiac myocytes include proteins of excitation-contraction coupling. The signal is limited at the G protein by the GTPase-accelerating activity of the RGS-domain sorting nexin SNX13 (RGS-PX1), a Gs-alpha-selective GTPase activator. The receptors are switched off by G protein-coupled receptor kinases (GRK2, GRK5), whose phosphorylation of the occupied receptor promotes binding of beta-arrestins (ARRB1, ARRB2); arrestin binding sterically blocks G protein coupling (desensitization) and targets the receptor to clathrin-mediated internalization. PKA also phosphorylates the receptors; for ADRB2 this both uncouples it from Gs (heterologous desensitization) and switches its coupling to inhibitory Gi proteins. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | adenylate cyclase-activating adrenergic receptor signaling pathway |
10 | 7 | 7 | 1 | 2 | 7 | 3/8 | 0 | ✗ | modules/beta_adrenergic_signaling.yaml | |
Beta-cell glucose-stimulated insulin secretion (K-ATP triggering pathway)MODULE:beta_cell_glucose_stimulated_insulin_secretion The triggering pathway by which the pancreatic beta cell converts a rise in blood glucose into insulin release. Glucokinase phosphorylates glucose... [more...][less]The triggering pathway by which the pancreatic beta cell converts a rise in blood glucose into insulin release. Glucokinase phosphorylates glucose at a rate that tracks the physiological glucose range and so sets the threshold of the pathway; glycolytic and mitochondrial oxidation of the resulting glucose 6-phosphate raises the cytosolic ATP/ADP ratio; the rise in ATP/ADP closes the ATP-sensitive potassium (K-ATP) channel formed by the Kir6.2 pore and the SUR1 regulatory subunit; the loss of K+ efflux depolarises the plasma membrane, opening L-type voltage-gated calcium channels; and the Ca2+ influx triggers exocytosis of insulin-containing dense-core granules. Glutamate dehydrogenase couples amino-acid (leucine/glutamine) oxidation into the same ATP/ADP signal, and the mitochondrial enzyme HADH restrains glutamate dehydrogenase; gain of the first and loss of the second both produce hyperinsulinism. |
Biological Process | DRAFT | human |
0 | insulin secretion involved in cellular response to glucose stimulus |
6 | 8 | 5 | 0 | 0 | 4 | 8/8 | 0 | ✗ | modules/beta_cell_glucose_stimulated_insulin_secretion.yaml | |
Beta-ketoadipate lower pathway from 3-oxoadipate to central metabolitesMODULE:beta_ketoadipate_lower_pathwayCONCRETE Species-neutral bacterial module for the shared lower beta-ketoadipate pathway that converts 3-oxoadipate and CoA to acetyl-CoA and succinate while... [more...][less]Species-neutral bacterial module for the shared lower beta-ketoadipate pathway that converts 3-oxoadipate and CoA to acetyl-CoA and succinate while recycling a succinyl-CoA CoA donor. A two-subunit PcaIJ-like CoA-transferase first transfers CoA from succinyl-CoA to 3-oxoadipate, producing 3-oxoadipyl-CoA and succinate. A PcaF-like thiolase then cleaves 3-oxoadipyl-CoA with CoA to acetyl-CoA and succinyl-CoA, regenerating the donor consumed in the first reaction. The module begins after catechol- and protocatechuate-derived upper branches converge at 3-oxoadipate and excludes those branch-specific ring-cleavage reactions. The same two-enzyme organization is conserved in aromatic-degrading Gammaproteobacteria of the orders Pseudomonadales and Moraxellales, represented here by biochemically and genetically characterized members from Pseudomonas putida and Acinetobacter baylyi. |
Metabolic Pathway | COMPLETE | bacteria |
0 | beta-ketoadipate pathway |
3 | 2 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/beta_ketoadipate_lower_pathway.yaml | |
Bidirectional transsulfuration between homocysteine and cysteine (fungal)MODULE:fungal_sulfur_amino_acid_transsulfuration Interconversion of L-homocysteine and L-cysteine through the thioether intermediate L-cystathionine, catalysed by four pyridoxal 5'-phosphate (PLP)... [more...][less]Interconversion of L-homocysteine and L-cysteine through the thioether intermediate L-cystathionine, catalysed by four pyridoxal 5'-phosphate (PLP) dependent enzymes acting in two opposite directions. In the homocysteine-to-cysteine direction, cystathionine beta-synthase condenses L-homocysteine with L-serine to L-cystathionine, and cystathionine gamma-lyase cleaves cystathionine to L-cysteine, 2-oxobutanoate and ammonia; this transfers the sulfur atom of methionine-derived homocysteine onto the serine carbon skeleton and is the only transsulfuration route of mammals. In the cysteine-to-homocysteine direction, cystathionine gamma-synthase condenses L-cysteine with an O-acylated L-homoserine to cystathionine, and cystathionine beta-lyase cleaves cystathionine to L-homocysteine, pyruvate and ammonia; this is the main route to homocysteine in enteric bacteria and plants. Budding yeast and other fungi that assimilate reduced sulfur primarily into the four-carbon chain of homocysteine (by direct sulfhydrylation of O-acetylhomoserine) possess both directions, so they can make cysteine from homocysteine and can also use cysteine as a sole sulfur source for methionine synthesis. Other lineages carry only one direction, and the module is therefore satisfied by either direction or by both. |
Metabolic Pathway | DRAFT | 0 | homocysteine metabolic process |
7 | 4 | 4 | 1 | 2 | 2 | 8/10 | 0 | ✗ | modules/fungal_sulfur_amino_acid_transsulfuration.yaml | ||
Bile acid synthesis I — ring modification (cholesterol -> 5-beta-cholestane intermediates); CYP7A1/CYP7B1/HSD3B7/AKR1D1MODULE:bile_acid_synthesis_ring_modification The first phase of bile-acid biosynthesis modifies the cholesterol steroid nucleus, producing the 7-alpha-hydroxylated, 3-oxo, 5-beta-reduced... [more...][less]The first phase of bile-acid biosynthesis modifies the cholesterol steroid nucleus, producing the 7-alpha-hydroxylated, 3-oxo, 5-beta-reduced cholestane intermediates that are later shortened in the side chain to the C24 bile acids. Two entry routes converge: the CLASSIC (neutral) pathway begins with cholesterol 7-alpha-hydroxylase (CYP7A1), the rate-limiting, feedback-regulated enzyme that hydroxylates cholesterol at C7-alpha; the ACIDIC (alternative) pathway begins when oxysterols (25- and 27-hydroxycholesterol, from CH25H/CYP27A1) are 7-alpha-hydroxylated by oxysterol 7-alpha-hydroxylase (CYP7B1). The 7-alpha-hydroxy sterols are then oxidised and isomerised by the 3-beta-hydroxy-Delta5-C27- steroid dehydrogenase HSD3B7 to the 3-oxo-Delta4 intermediate (7-alpha-hydroxy-4-cholesten- 3-one), and the Delta4 double bond is reduced to the 5-beta configuration by steroid 5-beta-reductase (AKR1D1), giving the cis-fused (5-beta) A/B ring junction characteristic of bile acids. (CYP8B1 branches here to specify cholic vs chenodeoxycholic acid.) Inherited defects: CYP7A1 deficiency (hypercholesterolemia/gallstones); CYP7B1 deficiency (hereditary spastic paraplegia type 5A and severe neonatal liver failure); HSD3B7 deficiency (congenital bile acid synthesis defect type 1); and AKR1D1 deficiency (bile acid synthesis defect type 2) — the HSD3B7/AKR1D1 defects present as neonatal cholestasis with fat-soluble-vitamin malabsorption. |
Metabolic Pathway | DRAFT | 0 | bile acid biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/bile_acid_synthesis_ring_modification.yaml | ||
Bile acid synthesis II — side-chain oxidation, peroxisomal shortening and amino-acid conjugation; CYP27A1/AMACR/ACOX2/SLC27A5/BAATMODULE:bile_acid_synthesis_sidechain_conjugation After the sterol nucleus of cholesterol has been hydroxylated (the ring-modification segment: CYP7A1/CYP7B1/HSD3B7/AKR1D1), the C27 side chain must... [more...][less]After the sterol nucleus of cholesterol has been hydroxylated (the ring-modification segment: CYP7A1/CYP7B1/HSD3B7/AKR1D1), the C27 side chain must be oxidised and shortened by three carbons to give the mature C24 bile acids, which are then conjugated to an amino acid before secretion. Mitochondrial sterol 27-hydroxylase (CYP27A1) initiates side-chain oxidation, hydroxylating C27 of the 5beta-cholestane-3alpha,7alpha,12alpha-triol (and the 7alpha-hydroxy-diol) and further oxidising it to the C27 bile-acid intermediates 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid (THCA) and its 12-deoxy congener DHCA. These C27 acids are activated to their CoA thioesters and imported into the peroxisome, where alpha-methylacyl-CoA racemase (AMACR) converts the (25R) diastereomer to the (25S) form required for beta-oxidation, and the peroxisomal branched-chain acyl-CoA oxidase ACOX2 catalyses the first (oxidase) step of one round of beta-oxidation; the downstream MFP2/SCPx steps release propionyl-CoA to give the C24 bile-acyl-CoAs choloyl-CoA and chenodeoxychenoyl-CoA. Bile acid-CoA:amino acid N-acyltransferase (BAAT) then transfers the C24 bile acid from CoA onto glycine or taurine, forming the glyco- and tauro-conjugated bile salts that are the major biliary species; the ER-membrane bile acyl-CoA synthetase SLC27A5 (cholate-CoA ligase / FATP5) re-activates free bile acids to their CoA esters, chiefly in the enterohepatic recycling loop, feeding BAAT for re-conjugation. Inherited defects across this segment cause cerebrotendinous xanthomatosis (CYP27A1), AMACR deficiency (an adult sensorimotor neuropathy with bile-acid abnormalities), ACOX2 deficiency (a bile-acid synthesis defect with liver disease/dystonia) and familial hypercholanemia / bile acid conjugation defect (BAAT). |
Metabolic Pathway | DRAFT | 0 | bile acid biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/bile_acid_synthesis_sidechain_conjugation.yaml | ||
Bile-acid biosynthesis (classic + alternative pathways from cholesterol to conjugated bile acids)MODULE:bile_acid_biosynthesis Bile acids are the amphipathic end-products of hepatic cholesterol catabolism; their synthesis is the major route of cholesterol elimination and... [more...][less]Bile acids are the amphipathic end-products of hepatic cholesterol catabolism; their synthesis is the major route of cholesterol elimination and produces the detergents that emulsify dietary lipids. Two pathways convert cholesterol to the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA). In the CLASSIC (neutral) pathway, the rate-limiting ER cytochrome P450 CYP7A1 7-alpha-hydroxylates cholesterol; HSD3B7 then oxidises/isomerises the 3-beta-hydroxy-Delta5 sterol to a 3-oxo-Delta4 intermediate; the branch-point enzyme CYP8B1 (sterol 12-alpha-hydroxylase) 12-alpha-hydroxylates that intermediate to commit flux toward CA (its absence yields CDCA), setting the CA:CDCA ratio; AKR1D1 (Delta4-3-oxosteroid 5-beta-reductase) and AKR1C4 (3-alpha-hydroxysteroid dehydrogenase) then reduce the A/B-ring to the 5-beta-3-alpha-hydroxy configuration. In the ALTERNATIVE (acidic) pathway, the sterol side chain is oxidised first: the mitochondrial CYP27A1 (sterol 27-hydroxylase), the ER di-iron enzyme CH25H (25-hydroxylase) and the neuron-specific CYP46A1 (24-hydroxylase, the main route of brain cholesterol elimination) generate oxysterols, which the oxysterol 7-alpha-hydroxylases CYP7B1 (25-/27-OHC) and CYP39A1 (24S-OHC) route into bile-acid synthesis. Both pathways converge on side-chain shortening: CYP27A1 oxidises the C27 side chain to a C27 acid, AMACR racemises the (25R)- to the (25S)-acyl-CoA, and peroxisomal beta-oxidation (ACOX2 -> the D-bifunctional protein -> the SCPx thiolase, curated in the peroxisomal module) removes a propionyl unit to give the C24 bile-acyl-CoA. Finally the bile acid is activated by the CoA ligase SLC27A5 (BACS) and conjugated to glycine or taurine by BAAT. Inherited defects across the pathway cause bile-acid synthesis disorders: CYP7B1 (oxysterol 7-alpha-hydroxylase deficiency / SPG5), HSD3B7, AKR1D1, ACOX2, BAAT and SLC27A5 deficiencies, and CYP27A1 causes cerebrotendinous xanthomatosis. |
Metabolic Pathway | DRAFT | 0 | bile acid biosynthetic process cholesterol metabolic process |
9 | 13 | 8 | 0 | 0 | 7 | 13/13 | 0 | ✗ | modules/bile_acid_biosynthesis.yaml | ||
Bioactive gibberellin (GA4/GA1) biosynthesis from geranylgeranyl diphosphateMODULE:gibberellin_biosynthesisABSTRACT Biosynthesis of the bioactive gibberellins GA4 and GA1 in vascular plants from the plastid diterpene precursor (E,E,E)-geranylgeranyl diphosphate... [more...][less]Biosynthesis of the bioactive gibberellins GA4 and GA1 in vascular plants from the plastid diterpene precursor (E,E,E)-geranylgeranyl diphosphate (GGPP), decomposed into three compartment-defined stages that use three enzyme classes. (1) In the plastid stroma two terpene cyclases make the tetracyclic hydrocarbon ent-kaurene: the class II cyclase ent-copalyl diphosphate synthase (CPS) converts GGPP to ent-copalyl diphosphate (the first committed step) and the class I cyclase ent-kaurene synthase (KS) converts ent-CPP to ent-kaurene with release of diphosphate. (2) Two multifunctional cytochrome P450 monooxygenases at the plastid envelope and endoplasmic reticulum oxidize ent-kaurene to GA12: ent-kaurene oxidase (KO, CYP701A) performs three oxidations of C-19 to give ent-kaurenoic acid, and ent-kaurenoic acid oxidase (KAO, CYP88A) performs three further oxidations, including B-ring contraction, to give GA12, the first gibberellin. (3) Soluble 2-oxoglutarate/Fe(II)-dependent dioxygenases in the cytosol complete the pathway: GA 20-oxidase (GA20ox) oxidizes and removes C-20 of GA12 (via GA15 and GA24) to give the C19 gibberellin GA9, and GA 3-oxidase (GA3ox) 3beta-hydroxylates GA9 to bioactive GA4. The same two dioxygenases act on the 13-hydroxylated series (GA53 to GA20 to GA1). The early stages are encoded by single or few genes, whereas GA20ox and GA3ox are multigene families whose transcription is the main point of control of bioactive GA levels (feedback repression through DELLA signaling, light and developmental regulation). GGPP supply, GA 13-hydroxylation, GA 2-oxidase and other deactivation routes, GA transport, and GA perception/DELLA signaling are outside this module's boundary. |
Metabolic Pathway | DRAFT | Tracheophyta |
0 | gibberellin biosynthetic process |
10 | 6 | 9 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/gibberellin_biosynthesis.yaml | |
Biological nitrogen cycle moduleMODULE:nitrogen_cycle A taxon-neutral decomposition of the biological nitrogen cycle: the set of microbially driven redox transformations that interconvert dinitrogen,... [more...][less]A taxon-neutral decomposition of the biological nitrogen cycle: the set of microbially driven redox transformations that interconvert dinitrogen, ammonia, hydroxylamine, nitrite, nitrate, nitric oxide, nitrous oxide, and hydrazine. The module is organized by transformation (fixation, nitrification, denitrification, DNRA, anammox, assimilatory reduction, and ammonification) rather than by organism, and uses variant sets where convergent enzyme chemistries (e.g. cd1 vs Cu nitrite reductase) implement the same step. Leaf steps are grounded to canonical reviewed Swiss-Prot exemplars where one exists; abstract function selectors are used where no reviewed exemplar is available (nitrite-oxidizer NXR). Companion to projects/NITROGEN_CYCLE.md and the GO:0071941 obsoletion project (projects/NITROGEN_CYCLE_OBSOLETION.md). |
Metabolic Pathway | DRAFT | 0 | nitrogen cycle metabolic process |
26 | 19 | 19 | 3 | 6 | 11 | 6/25 | 1 | ✗ | modules/nitrogen_cycle.yaml | ||
Biotin cycle — holocarboxylase synthetase and biotinidase (multiple carboxylase deficiency)MODULE:biotin_cycle The biotin cycle activates and recycles the cofactor biotin for the five human biotin-dependent carboxylases, and its two enzymes are the causes of... [more...][less]The biotin cycle activates and recycles the cofactor biotin for the five human biotin-dependent carboxylases, and its two enzymes are the causes of multiple carboxylase deficiency. Holocarboxylase synthetase (HLCS, biotin-protein ligase) covalently attaches biotin to a specific lysine in the biotin-carboxyl-carrier domain of each apo-carboxylase — pyruvate carboxylase (PC), propionyl-CoA carboxylase (PCCA/PCCB), 3-methylcrotonyl-CoA carboxylase (MCCC1/MCCC2) and the cytosolic and mitochondrial acetyl-CoA carboxylases (ACACA, ACACB) — via a two-step reaction (biotin + ATP -> biotinyl-5'-AMP, then transfer to the carrier lysine), converting inactive apo-enzymes to active holo-carboxylases. When these holo-carboxylases are proteolytically degraded, the biotin remains bound as biocytin (biotinyl-lysine) or short biotinyl-peptides; biotinidase (BTD) hydrolyses these to liberate free biotin for reuse, and also releases dietary protein-bound biotin, making it bioavailable. Free biotin then re-enters the cycle as the HLCS substrate. Inherited deficiency of either enzyme produces multiple carboxylase deficiency (simultaneous functional loss of all biotin carboxylases, with lactic acidosis and organic aciduria): HLCS deficiency is the early-onset (neonatal) form, and BTD (biotinidase) deficiency is the late-onset form — a classic treatable, newborn-screened disorder rescued by biotin supplementation. |
Metabolic Pathway | DRAFT | 0 | biotin metabolic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/biotin_cycle.yaml | ||
Bombesin receptor signaling pathway moduleMODULE:bombesin_receptor_signaling The bombesin receptor signaling pathway (GO:0031989) is initiated when the secreted, C-terminally alpha-amidated mammalian bombesin-like... [more...][less]The bombesin receptor signaling pathway (GO:0031989) is initiated when the secreted, C-terminally alpha-amidated mammalian bombesin-like neuropeptide hormones gastrin-releasing peptide (GRP, PANTHER:PTHR16866:SF2) and neuromedin B (NMB, PANTHER:PTHR16866:SF3) bind and activate their cognate seven-transmembrane G protein-coupled receptors GRPR (BB2, PANTHER:PTHR45695:SF7) and NMBR (BB1, PANTHER:PTHR45695:SF8) at the plasma membrane of central nervous system neurons, gastrointestinal endocrine/smooth-muscle cells, and anterior pituitary thyrotrophs. Agonist-bound GRPR and NMBR couple primarily to heterotrimeric Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to stimulate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), generating inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) to mobilize intracellular Ca2+ and regulate gastrin secretion, smooth-muscle contraction, sighing, itch transmission, and circadian/neuroendocrine rhythms. |
Signaling Pathway | DRAFT | Euteleostomi |
1 | bombesin receptor signaling pathway |
3 | 6 | 2 | 0 | 0 | 1 | 3/6 | 0 | ✗ | modules/bombesin_receptor_signaling.yaml | |
Brahma (SWI/SNF) chromatin remodeling complexes in Drosophila melanogasterMODULE:dmel_brahma_complexesCONCRETE Brahma complexes are the Drosophila SWI/SNF-family ATP-dependent chromatin remodelers. They use the Brahma (brm) ATPase to slide or evict... [more...][less]Brahma complexes are the Drosophila SWI/SNF-family ATP-dependent chromatin remodelers. They use the Brahma (brm) ATPase to slide or evict nucleosomes, making DNA accessible to transcription factors, and act as trithorax group regulators that oppose Polycomb silencing. All forms share a core of brm, Moira, Bap55, Bap60, Brd7-9 and actin. The BAP form contains the ARID protein Osa, the PBAP form instead contains Polybromo, Bap170 and e(y)3, and a non-canonical form (ncBAP) contains Bicra. Different forms control different target genes in development. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | brahma complex |
4 | 3 | 0 | 1 | 3 | 0 | 0/15 | 0 | ✗ | modules/dmel_brahma_complexes.yaml | |
Branched-chain amino acid (BCAA) catabolism — transamination and the BCKDH complexMODULE:branched_chain_amino_acid_catabolism The committed, shared initial steps of the catabolism of the three branched-chain amino acids (BCAAs: L-leucine, L-isoleucine, L-valine), operating... [more...][less]The committed, shared initial steps of the catabolism of the three branched-chain amino acids (BCAAs: L-leucine, L-isoleucine, L-valine), operating in the mitochondrial matrix. Branched-chain aminotransferase (BCAT2, the mitochondrial isozyme; BCAT1 is cytosolic) first reversibly transaminates each BCAA with 2-oxoglutarate to the corresponding branched-chain 2-oxo (alpha-keto) acid (BCKA: alpha-ketoisocaproate from Leu, alpha-keto-beta- methylvalerate from Ile, alpha-ketoisovalerate from Val) plus L-glutamate. The branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex — a large mitochondrial multienzyme complex homologous to the pyruvate and 2-oxoglutarate dehydrogenase complexes — then catalyses the irreversible, rate-limiting, committed oxidative decarboxylation of the BCKAs to the corresponding branched-chain acyl-CoA thioesters + CO2 + NADH. The complex has three catalytic components: E1 (a thiamine-pyrophosphate-dependent decarboxylase, an alpha2-beta2 heterotetramer of BCKDHA/E1-alpha and BCKDHB/E1-beta) which decarboxylates the BCKA and reductively acylates the lipoyl arm; E2 (DBT, dihydrolipoyllysine-residue (2-methylpropanoyl)transferase) which forms the structural core and transfers the acyl group to CoA; and E3 (DLD, dihydrolipoyl dehydrogenase, an FAD flavoenzyme) which reoxidises the dihydrolipoyl arm and passes electrons to NAD+. E3/DLD is not BCKDH-specific: it is the common E3 shared with the pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and 2-oxoadipate dehydrogenase complexes and the glycine cleavage system. BCKDH flux is regulated by reversible phosphorylation of E1-alpha (inhibitory kinase BCKDK; activating phosphatase PPM1K). Inherited deficiency of BCKDHA, BCKDHB or DBT causes maple syrup urine disease (MSUD, from accumulation of BCAAs and their neurotoxic BCKAs); DLD deficiency causes a combined E3-deficiency phenotype (MSUD-like plus lactic acidosis / 2-oxoglutaric aciduria because PDH and OGDH are simultaneously impaired). Downstream, the branched-chain acyl-CoAs are degraded by substrate-specific dehydrogenases and hydratases (out of scope here) to acetyl-CoA, acetoacetate and/or succinyl-CoA (via propionyl-CoA/methylmalonyl-CoA for Ile and Val). |
Metabolic Pathway | DRAFT | 0 | branched-chain amino acid catabolic process |
3 | 5 | 2 | 0 | 0 | 1 | 5/6 | 0 | ✗ | modules/branched_chain_amino_acid_catabolism.yaml | ||
Brassinosteroid signal perception and relay to BZR1/BES1 transcription factorsMODULE:brassinosteroid_signalingCONCRETE Brassinosteroid (BR) signalling converts perception of a steroid hormone at the cell surface into a change in nuclear gene expression through a... [more...][less]Brassinosteroid (BR) signalling converts perception of a steroid hormone at the cell surface into a change in nuclear gene expression through a chain of phosphorylation and dephosphorylation steps. In the absence of BR, the receptor kinase BRI1 is held inactive by its cytoplasmic inhibitor BKI1, and the constitutively active GSK3-like kinase BIN2 phosphorylates the BZR1 and BES1 transcription factors, which inhibits their DNA binding, promotes 14-3-3 binding and cytoplasmic retention, and targets them for degradation. Brassinolide binds the extracellular LRR domain of BRI1, which recruits the coreceptor kinase BAK1; transphosphorylation activates BRI1, which phosphorylates BKI1 (releasing it from the membrane) and the receptor-like cytoplasmic kinases BSK1 (and CDG1). Phosphorylated BSK1 binds the Kelch-repeat phosphatase BSU1, which (after CDG1 phosphorylation) dephosphorylates the conserved pTyr200 of BIN2 and inactivates it. With BIN2 off, PP2A dephosphorylates BZR1/BES1, which accumulate in the nucleus and bind BRRE and E-box elements to repress BR biosynthetic genes (feedback) and activate or repress thousands of growth-related genes. BR biosynthesis, receptor endocytosis/turnover, and downstream transcriptional networks are outside this module's boundary. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | brassinosteroid mediated signaling pathway |
7 | 8 | 6 | 0 | 0 | 6 | 8/8 | 0 | ✗ | modules/brassinosteroid_signaling.yaml | |
Budding yeast (S. cerevisiae) high-osmolarity (Ssk2-Pbs2-Hog1) MAPK cascade moduleMODULE:scer_hog1_cascade A decomposition of the Saccharomyces cerevisiae high-osmolarity glycerol (HOG) MAP kinase cascade, the osmostress-activated fungal realization of... [more...][less]A decomposition of the Saccharomyces cerevisiae high-osmolarity glycerol (HOG) MAP kinase cascade, the osmostress-activated fungal realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). High external osmolarity is sensed by two functionally redundant upstream branches that converge on the single MAP2K Pbs2. In the Sln1 branch the hybrid histidine kinase Sln1 is constitutively active in the absence of stress and keeps phosphate flowing through the Hpt protein Ypd1 to the response regulator Ssk1, holding the cascade off; a drop in turgor silences Sln1, Ssk1 accumulates unphosphorylated and binds and activates the MAP3Ks Ssk2/Ssk22, so in this section of the pathway signalling output runs inversely to phosphorylation. In the Sho1 branch the tetraspan osmosensor Sho1, with the signalling mucins Msb2 and Hkr1 and the adaptor Ste50, assembles a membrane complex that brings the MAP3K Ste11 to Pbs2, which also acts as the scaffold of this branch. Pbs2 then dually phosphorylates the MAPK Hog1 on its TGY activation-loop motif. Active Hog1 translocates to the nucleus and activates transcription factors (Hot1, Msn2/Msn4, Sko1) that induce glycerol-biosynthesis and stress-response genes restoring osmotic balance. The kinase relay - Ssk2/Ssk22 -> Pbs2 -> Hog1 - is declared as an inner bundle that `conforms_to` mapk_relay, while the two osmosensing inputs and the Hog1 transcriptional output are this cascade's free extensions around the conforming core. Grounded in GO:0007231 (osmosensory signaling pathway). |
Signaling Pathway | DRAFT | Saccharomyces cerevisiae |
0 | osmosensory signaling pathway |
13 | 12 | 12 | 0 | 0 | 8 | 8/12 | 1 | ✗ | modules/scer_hog1_cascade.yaml | |
Budding yeast (S. cerevisiae) pheromone-response (Ste11-Ste7-Fus3) MAPK cascade moduleMODULE:scer_mating_fus3_cascade A decomposition of the Saccharomyces cerevisiae pheromone-response (mating) MAP kinase cascade, the fungal realization of the generic three-tier... [more...][less]A decomposition of the Saccharomyces cerevisiae pheromone-response (mating) MAP kinase cascade, the fungal realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Mating pheromone (a-factor or alpha-factor) activates a G-protein-coupled receptor (Ste2/Ste3); the released G-protein beta-gamma dimer and the PAK kinase Ste20, organized on the scaffold Ste5, activate the MAP3K Ste11, which phosphorylates the MAP2K Ste7, which dually phosphorylates the MAPK Fus3 (and the partially redundant Kss1) on its TEY activation-loop motif. Active Fus3 phosphorylates the transcription factor Ste12 and the cell-cycle inhibitor Far1, driving the mating transcriptional program, G1 arrest, and polarized shmoo formation for conjugation. The kinase relay - Ste11 -> Ste7 -> Fus3 - is declared as an inner bundle that `conforms_to` mapk_relay, while the pheromone/GPCR input and the Ste12/Far1 output are this cascade's free extensions around the conforming core. Grounded in GO:0071507 (pheromone response MAPK cascade); the pre-composed term GO:0000750 (pheromone-dependent signal transduction involved in conjugation with cellular fusion) was obsoleted in GO release 2026-05-19 with replaced_by GO:0071507. |
Signaling Pathway | DRAFT | Saccharomyces cerevisiae |
0 | pheromone response MAPK cascade |
7 | 5 | 6 | 0 | 0 | 4 | 4/4 | 2 | ✗ | modules/scer_mating_fus3_cascade.yaml | |
C4 carbon shuttleMODULE:c4_carbon_shuttleABSTRACT The C4 carbon-concentrating shuttle, which raises the CO2 concentration at Rubisco by fixing inorganic carbon twice in two cell types. Mesophyll... [more...][less]The C4 carbon-concentrating shuttle, which raises the CO2 concentration at Rubisco by fixing inorganic carbon twice in two cell types. Mesophyll carbonic anhydrase supplies bicarbonate, PEP carboxylase fixes it into a C4 acid, the acid moves to the bundle sheath and is decarboxylated there, and the released CO2 accumulates around Rubisco while the C3 product returns to the mesophyll for PEP regeneration by pyruvate, phosphate dikinase. The decarboxylation step is the classic three-way variation (NADP-malic enzyme, NAD-malic enzyme, PEP carboxykinase), modelled as a variant set; real species often run more than one route at once. The Calvin-Benson-Bassham cycle that consumes the released CO2 is included by reference rather than restated. Single-cell C4 (Bienertia, Suaeda aralocaspica), which performs the same shuttle between two compartments of one cell, is a realization of this module rather than an exception to it, but its compartment assignments are not modelled here. CAM, which separates the two carboxylations in time rather than in space, is a sibling module (MODULE:cam_carbon_shuttle). |
Metabolic Pathway | DRAFT | 0 | C4 photosynthesis carbon fixation |
11 | 9 | 7 | 1 | 3 | 6 | 0/7 | 0 | ✗ | modules/c4_carbon_shuttle.yaml | ||
CAM carbon shuttleMODULE:cam_carbon_shuttleABSTRACT Crassulacean acid metabolism, the temporal counterpart of the C4 shuttle: the two carboxylations are separated across the day/night cycle in one... [more...][less]Crassulacean acid metabolism, the temporal counterpart of the C4 shuttle: the two carboxylations are separated across the day/night cycle in one cell rather than between two cell types. At night, with stomata open, PEP carboxylase fixes bicarbonate into oxaloacetate, which is reduced to malate and stored as malic acid in the vacuole, acidifying it. By day, with stomata shut, malate leaves the vacuole and is decarboxylated, and the released CO2 is refixed by Rubisco behind closed stomata, which is what makes the pathway water-conserving. PEP is regenerated from the C3 product, usually via starch or soluble sugar. The phase switch is enforced by reciprocal phosphorylation of PEP carboxylase: a circadian-controlled kinase phosphorylates it at night, relieving malate inhibition, and dephosphorylation by day prevents futile refixation of the CO2 being released. The Calvin-Benson-Bassham cycle is included by reference. The C4 spatial shuttle is a sibling module (MODULE:c4_carbon_shuttle); the two share most of their enzymology and differ in what separates the carboxylations. |
Metabolic Pathway | DRAFT | 0 | CAM photosynthesis carbon fixation |
9 | 9 | 6 | 1 | 2 | 6 | 0/5 | 0 | ✗ | modules/cam_carbon_shuttle.yaml | ||
CCR4-NOT deadenylase complex in Drosophila melanogasterMODULE:dmel_ccr4_not_complexCONCRETE CCR4-NOT is the major cytoplasmic mRNA deadenylase in eukaryotes and also acts in transcription and translational repression. Its large scaffold... [more...][less]CCR4-NOT is the major cytoplasmic mRNA deadenylase in eukaryotes and also acts in transcription and translational repression. Its large scaffold subunit Not1 binds two deadenylases, Pop2 (CAF1) and twin (CCR4), which shorten poly(A) tails, the first step of most mRNA decay. Not1 also binds Rcd-1 (CNOT9), Not10 and Not11, and a NOT module of Rga (Not2) and Not3. RNA-binding proteins, microRNA silencing complexes and translational repressors recruit CCR4-NOT to specific mRNAs; in Drosophila it controls maternal mRNA decay and germline stem cell maintenance. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | CCR4-NOT complex |
4 | 3 | 3 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_ccr4_not_complex.yaml | |
CCT/TRiC chaperonin-mediated foldingMODULE:cct_chaperonin_foldingCONCRETE The chaperonin containing TCP-1 (CCT, also called TRiC) is the group II chaperonin of the eukaryotic cytosol. It is a double ring of two... [more...][less]The chaperonin containing TCP-1 (CCT, also called TRiC) is the group II chaperonin of the eukaryotic cytosol. It is a double ring of two hetero-octameric rings, each made of one copy of eight paralogous subunits (CCT1/alpha to CCT8/theta), and this subunit set is conserved from yeast to nematodes and mammals. Each subunit has an equatorial ATP-binding domain, an intermediate hinge and an apical client-binding domain with a built-in lid, so CCT closes its folding chamber without a separate co-chaperonin. Cycles of ATP binding and hydrolysis drive lid closure and folding of clients held in the chamber. Nucleotide use is asymmetric: only four subunits (CCT1, CCT2, CCT4 and CCT5) bind ATP at physiological concentrations, and ATP binding by the other four is dispensable in vivo. The main obligate clients are actin and tubulin. Nascent actin and tubulin chains are captured by prefoldin (GimC in budding yeast), a jellyfish-shaped heterohexamer of two alpha-class and four beta-class subunits that binds non-native chains without ATP, docks on CCT and hands them over, raising the rate and yield of folding. In yeast, loss of prefoldin or CCT impairs actin- and tubulin-based cytoskeletal functions. In C. elegans, CCT depletion disrupts actin and microtubule organization and causes intestinal microvillus loss, prefoldin loss lowers alpha-tubulin levels and slows microtubule growth, and raising the CCT8 subunit level in somatic tissues extends lifespan in a CCT-dependent way. |
Biological Process | DRAFT | Eukaryota |
0 | protein folding |
3 | 2 | 2 | 0 | 0 | 1 | 30/30 | 0 | ✗ | modules/cct_chaperonin_folding.yaml | |
CDP-diacylglycerol pathway of phospholipid synthesis (PS, PE, PC by methylation, PI, PG and cardiolipin)MODULE:cdp_dag_phospholipid_synthesisCONCRETE In the CDP-diacylglycerol (CDP-DAG) pathway, phosphatidic acid is activated with CTP to the liponucleotide CDP-DAG, which then donates its... [more...][less]In the CDP-diacylglycerol (CDP-DAG) pathway, phosphatidic acid is activated with CTP to the liponucleotide CDP-DAG, which then donates its phosphatidyl group to a polar head-group acceptor, releasing CMP. Different CDP-alcohol phosphatidyltransferases use serine (phosphatidylserine synthase), myo-inositol (phosphatidylinositol synthase) and glycerol-3-phosphate (phosphatidylglycerophosphate synthase). In the aminophospholipid branch, phosphatidylserine (PS) is decarboxylated to phosphatidylethanolamine (PE) by pyruvoyl-dependent PS decarboxylases, and PE is converted to phosphatidylcholine (PC) by three successive S-adenosylmethionine-dependent N-methylations, performed by two enzymes in fungi or by a single PEMT enzyme in animals. In the mitochondrial branch, phosphatidylglycerophosphate is dephosphorylated to phosphatidylglycerol (PG), which is condensed with a second CDP-DAG by a eukaryotic CDP-alcohol phosphotransferase-type cardiolipin synthase to form cardiolipin. The pathway is distributed between compartments: CDP-DAG for PS and PI is made in the endoplasmic reticulum, whereas cardiolipin synthesis uses CDP-DAG made in the mitochondrial inner membrane by a distinct, Tam41-type CDP-DAG synthase; the major PS decarboxylase acts in the mitochondrial inner membrane and a second one in the endomembrane system, so PS and PE must move between the ER and mitochondria. In fungi this route makes PE and PC when ethanolamine and choline are not supplied, whereas the Kennedy pathway makes them from those precursors. |
Metabolic Pathway | DRAFT | Fungi |
0 | CDP-diacylglycerol biosynthetic process phosphatidylserine biosynthetic process phosphatidylethanolamine biosynthetic process phosphatidylcholine biosynthetic process phosphatidylinositol biosynthetic process phosphatidylglycerol biosynthetic process cardiolipin biosynthetic process |
17 | 12 | 10 | 3 | 6 | 9 | 23/23 | 0 | ✗ | modules/cdp_dag_phospholipid_synthesis.yaml | |
CLAVATA-WUSCHEL negative feedback loop in shoot apical meristem stem-cell homeostasisMODULE:shoot_meristem_clv_wus_feedbackCONCRETE The size of the stem-cell pool in the shoot apical meristem is held steady by a two-cell-layer negative feedback loop. The homeodomain... [more...][less]The size of the stem-cell pool in the shoot apical meristem is held steady by a two-cell-layer negative feedback loop. The homeodomain transcription factor WUSCHEL (WUS) is made in the organizing center (OC), moves through plasmodesmata into the overlying central zone, and there both specifies stem-cell fate and directly activates CLAVATA3 (CLV3). CLV3 is processed and secreted as an arabinosylated 12/13-amino-acid CLE peptide. It is perceived at the plasma membrane of the underlying cells by parallel receptor systems: the LRR receptor kinase CLV1 and its paralogs BAM1/BAM2, which bind the peptide directly, and a heteromeric complex of the kinase-less LRR receptor-like protein CLV2 with the pseudokinase CORYNE (CRN). Whether CLV2/CRN binds the ligand directly is disputed; it acts at least as a co-receptor. Receptor signalling, relayed through CIK co-receptor kinases and PBL-type cytoplasmic kinases, represses WUS transcription and confines the OC. More stem cells therefore make more CLV3, which reduces WUS and so limits stem-cell number. When CLV1 is lost, BAM genes are de-repressed in the meristem centre and partly compensate. The KNOX homeodomain protein SHOOT MERISTEMLESS (STM), which keeps meristem cells undifferentiated and interacts genetically with the CLV genes, is shown only as optional context. RPK2, the CIK and PBL relay kinases, CLE processing, floral-meristem termination by AGAMOUS, and the root CLE40-ACR4 and CLE45-BAM3 pathways are outside this module boundary. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | homeostasis of number of meristem cells stem cell population maintenance |
7 | 7 | 4 | 1 | 2 | 4 | 7/7 | 0 | ✗ | modules/shoot_meristem_clv_wus_feedback.yaml | |
CMP-KDO biosynthesisMODULE:kdo_biosynthesisABSTRACT A four-reaction pathway that converts the pentose-phosphate intermediate D-ribulose 5-phosphate into CMP-3-deoxy-D-manno-octulosonate (CMP-KDO),... [more...][less]A four-reaction pathway that converts the pentose-phosphate intermediate D-ribulose 5-phosphate into CMP-3-deoxy-D-manno-octulosonate (CMP-KDO), the activated donor of the KDO residues that link lipid A to the core oligosaccharide of Gram-negative lipopolysaccharide. An arabinose-5-phosphate isomerase (KdsD, or a paralog such as GutQ) forms D-arabinose 5-phosphate; KDO 8-phosphate synthase (KdsA) condenses it with phosphoenolpyruvate; KDO 8-phosphate phosphatase (KdsC) releases free KDO; and CMP-KDO synthetase (KdsB) activates KDO with CTP. Transfer of KDO to lipid A by WaaA and the separate ADP-heptose pathway are outside the module boundary. |
Metabolic Pathway | COMPLETE | Gram-negative bacteria that make KDO-containing lipopolysaccharide |
0 | KDO biosynthetic process CMP-KDO biosynthetic process |
7 | 5 | 4 | 1 | 2 | 3 | 11/11 | 0 | ✗ | modules/kdo_biosynthesis.yaml | |
CNC/NRF oxidative and xenobiotic stress responseMODULE:nrf_oxidative_stress_responseCONCRETE A cross-species module for the oxidative and xenobiotic stress response driven by cap'n'collar (CNC) basic-leucine-zipper transcription factors:... [more...][less]A cross-species module for the oxidative and xenobiotic stress response driven by cap'n'collar (CNC) basic-leucine-zipper transcription factors: NRF2 (NFE2L2) in vertebrates, CncC in Drosophila and SKN-1 in Caenorhabditis elegans. In unstressed cells the CNC factor is kept scarce by constitutive cullin-RING ubiquitin ligase-dependent degradation, and its nuclear activity is further restrained by glycogen synthase kinase-3 (GSK-3) phosphorylation. Two degradation arms are known. In vertebrates and insects the BTB-Kelch protein KEAP1 binds the CNC factor and presents it to a CUL3-RING ligase, and reactive KEAP1 cysteines act as sensors whose modification by oxidants and electrophiles stops degradation. Nematodes have no KEAP1; there the WD40 protein WDR-23, the ortholog of human DCAF11, restrains SKN-1 together with the CUL-4/DDB-1 (CRL4) ligase, and DCAF11 also targets human NRF2 for degradation through a separate degron. Stress-activated kinases promote nuclear accumulation of the factor; in C. elegans the NSY-1/SEK-1/PMK-1 p38 MAPK cascade phosphorylates SKN-1. Nuclear CNC factors then induce a phase II detoxification program that includes glutamate-cysteine ligase, the rate-limiting enzyme of glutathione synthesis, and glutathione S-transferases, and loss of the CNC factor makes animals sensitive to oxidative stress. NRF2 binds antioxidant response elements as a heterodimer with small MAF proteins, whereas SKN-1 binds DNA as a monomer through its Skn domain. |
Signaling Pathway | DRAFT | Bilateria |
2 | cellular response to oxidative stress cellular detoxification |
8 | 12 | 5 | 1 | 2 | 6 | 17/17 | 0 | ✗ | modules/nrf_oxidative_stress_response.yaml | |
COMPASS-family histone H3K4 methyltransferase complexes in Drosophila melanogasterMODULE:dmel_compass_family_complexesCONCRETE Drosophila has three COMPASS-family complexes, each built around a different SET-domain histone H3 lysine 4 methyltransferase. Set1/COMPASS... [more...][less]Drosophila has three COMPASS-family complexes, each built around a different SET-domain histone H3 lysine 4 methyltransferase. Set1/COMPASS performs most bulk H3K4 di- and trimethylation, the Trithorax (Trx) complex maintains expression of Hox and other developmental genes against Polycomb silencing, and the Trithorax-related (Trr) complex monomethylates H3K4 at enhancers and carries the H3K27 demethylase Utx. All three share the WRAD core (Wds, Rbbp5, Ash2 and Dpy-30L1) that stimulates the methyltransferase. Trx is also found in TAC1, a complex with the CBP acetyltransferase Nejire and Sbf. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | histone methyltransferase complex |
6 | 4 | 2 | 1 | 3 | 0 | 1/18 | 0 | ✗ | modules/dmel_compass_family_complexes.yaml | |
COP9 signalosome in Drosophila melanogasterMODULE:dmel_cop9_signalosomeCONCRETE The COP9 signalosome (CSN) is an eight-subunit complex that removes the ubiquitin-like protein Nedd8 from cullins, thereby controlling the activity... [more...][less]The COP9 signalosome (CSN) is an eight-subunit complex that removes the ubiquitin-like protein Nedd8 from cullins, thereby controlling the activity and assembly of cullin-RING ubiquitin ligases. Six subunits (CSN1, CSN2, CSN3, CSN4, CSN7 and CSN8) contain PCI domains and form a horseshoe-shaped scaffold, and two subunits (CSN5 and CSN6) contain MPN domains; CSN5 is the JAMM metalloprotease that carries the deneddylase activity. Drosophila has two CSN1 paralogs: CSN1b in the ubiquitous complex and CSN1a in a testis-specific variant. The Drosophila CSN2 subunit is encoded by alien. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | COP9 signalosome |
6 | 4 | 3 | 1 | 2 | 0 | 1/9 | 0 | ✗ | modules/dmel_cop9_signalosome.yaml | |
COPI coatomer in Drosophila melanogasterMODULE:dmel_copi_coatCONCRETE Coatomer is the heptameric coat of COPI vesicles, which mediate retrograde transport from the Golgi apparatus to the endoplasmic reticulum and... [more...][less]Coatomer is the heptameric coat of COPI vesicles, which mediate retrograde transport from the Golgi apparatus to the endoplasmic reticulum and transport between Golgi cisternae. Coatomer is recruited en bloc to membranes by the small GTPase Arf1 in its GTP-bound form and binds cargo with dilysine and related sorting signals. Structurally it consists of a B-subcomplex (alpha, beta' and epsilon subunits) that forms the outer cage-like layer and an F-subcomplex (beta, gamma, delta and zeta subunits) that resembles the clathrin adaptor complexes and contacts the membrane. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | COPI vesicle coat |
3 | 2 | 2 | 0 | 0 | 0 | 0/7 | 0 | ✗ | modules/dmel_copi_coat.yaml | |
COPII coat in Drosophila melanogasterMODULE:dmel_copii_coatCONCRETE The COPII coat forms vesicles and tubules that export secretory cargo from endoplasmic reticulum exit sites to the Golgi apparatus. The small... [more...][less]The COPII coat forms vesicles and tubules that export secretory cargo from endoplasmic reticulum exit sites to the Golgi apparatus. The small GTPase Sar1, activated by its ER-membrane exchange factor, inserts into the membrane and recruits the inner coat, a heterodimer of Sec23 and Sec24. Sec24 binds cargo sorting signals, and Sec23 is the GTPase-activating protein for Sar1. The inner coat then recruits the outer coat of Sec13 and Sec31, which forms a cage around the bud and stimulates Sec23 GAP activity. Drosophila has two Sec24 paralogs, Sec24AB and Sec24CD. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | COPII vesicle coat |
6 | 4 | 3 | 1 | 2 | 3 | 0/6 | 0 | ✗ | modules/dmel_copii_coat.yaml | |
CRAC channel (Stim-Orai) complex in Drosophila melanogasterMODULE:dmel_crac_channel_complexCONCRETE The calcium release-activated calcium (CRAC) channel mediates store-operated calcium entry. Stim is a single-pass endoplasmic reticulum membrane... [more...][less]The calcium release-activated calcium (CRAC) channel mediates store-operated calcium entry. Stim is a single-pass endoplasmic reticulum membrane protein whose luminal EF-hand senses ER calcium; when ER stores are depleted, Stim oligomerises, moves to ER-plasma membrane junctions and binds and opens Orai, the pore-forming plasma membrane channel subunit. Stim and Orai were identified in Drosophila S2 cell RNAi screens as essential for store-operated calcium entry. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | calcium channel complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_crac_channel_complex.yaml | |
CRISPR-Cas adaptive immunityMODULE:crispr_cas_adaptive_immunityCONCRETE A reusable prokaryotic module for RNA-guided adaptive immunity against mobile genetic elements. The module has three obligate stages: adaptation,... [more...][less]A reusable prokaryotic module for RNA-guided adaptive immunity against mobile genetic elements. The module has three obligate stages: adaptation, in which a Cas1-Cas2 integrase captures a protospacer from invading DNA and integrates it as a new spacer at the leader-proximal end of a CRISPR array; crRNA biogenesis, in which the transcribed array is processed into mature guides; and interference, in which a crRNA-loaded effector recognises a complementary target and destroys it. Effector architecture is the principal axis of variation and is modelled as alternative implementations rather than as separate modules: multi-subunit class 1 effectors (Cascade-Cas3, Csm/Cmr-Cas10) and single-protein class 2 effectors (Cas9, Cas12a, Cas13a) occupy the same structural slot in the pathway. Phage-encoded suppression of this module is a separate counter-defence module (MODULE:anti_crispr_suppression); host restriction-modification, BREX, retron, and other innate defence systems are outside the boundary, as is the laboratory use of Cas effectors as genome editors. |
Biological Process | DRAFT | archaea bacteria |
0 | CRISPR-cas system |
11 | 13 | 3 | 2 | 7 | 3 | 26/26 | 0 | ✗ | modules/crispr_cas_adaptive_immunity.yaml | |
Calvin-Benson-Bassham reductive pentose-phosphate cycleMODULE:calvin_benson_bassham_cycleABSTRACT Carbon fixation by the Calvin-Benson-Bassham reductive pentose-phosphate cycle, as a taxon-neutral decomposition: Rubisco carboxylation of ribulose... [more...][less]Carbon fixation by the Calvin-Benson-Bassham reductive pentose-phosphate cycle, as a taxon-neutral decomposition: Rubisco carboxylation of ribulose 1,5-bisphosphate, reduction of 3-phosphoglycerate to triose phosphate, and regeneration of the acceptor. Two regulatory parts travel with the cycle because they act on its own enzymes: Rubisco activase, which removes inhibitory sugar phosphates from Rubisco active sites, and the CP12 redox scaffold, which assembles an autoinhibitory PRK-GAPDH complex in the dark and releases it on thioredoxin/NTRC reduction. The cycle consumes the ATP and NADPH produced by MODULE:thylakoid_light_reactions, and is the Rubisco compartment that carbon-concentrating mechanisms feed, including the algal MODULE:pyrenoid_ccm. It is not restricted to oxygenic phototrophs: the same cycle fixes carbon in anoxygenic phototrophs and in chemoautotrophs, which is why it is modelled separately from photosynthesis. The non-CBB fixation routes are siblings rather than parts: MODULE:reductive_tca_cycle, MODULE:wood_ljungdahl_pathway and MODULE:hydroxypropionate_bicycle. The carbon-concentrating mechanisms that raise CO2 at this cycle's Rubisco are also siblings: MODULE:c4_carbon_shuttle and MODULE:cam_carbon_shuttle each include this module by reference, while MODULE:pyrenoid_ccm does not - it models Rubisco carboxylation inline and carries no module_ref - so it feeds this cycle in biology without composing it in the model. Converting it is a separate change against that module. |
Metabolic Pathway | DRAFT | 0 | reductive pentose-phosphate cycle carbon fixation |
6 | 6 | 5 | 0 | 0 | 2 | 1/1 | 0 | ✗ | modules/calvin_benson_bassham_cycle.yaml | ||
Camalexin biosynthesis (tryptophan-derived indole phytoalexin)MODULE:camalexin_biosynthesisCONCRETE Camalexin (3-thiazol-2'-yl-indole) is the main phytoalexin of Arabidopsis thaliana and is made from tryptophan after pathogen attack. The... [more...][less]Camalexin (3-thiazol-2'-yl-indole) is the main phytoalexin of Arabidopsis thaliana and is made from tryptophan after pathogen attack. The ER-anchored cytochrome P450s CYP79B2 and CYP79B3 convert tryptophan to indole-3-acetaldoxime (IAOx), a branch point shared with indole glucosinolate and auxin biosynthesis. CYP71A13, with a minor contribution from its paralog CYP71A12, commits IAOx to the camalexin branch. It monooxygenates IAOx to an alpha-hydroxy-indole-3-acetonitrile (indole-3-cyanohydrin) intermediate and is proposed to dehydrate this to a reactive electrophile (dehydro-IAN) that is captured by the thiol of glutathione or cysteine. CYP71A13 also dehydrates IAOx to indole-3-acetonitrile (IAN), which may be largely an off-pathway product; CYP71A12 releases more of the cyanohydrin as its breakdown products indole-3-carbaldehyde and cyanide. Glutathione transferases, including GSTF6, are implicated in the conjugation, but many GSTs can support it, higher-order phi-class GST mutants make normal camalexin, and the electrophile can react with glutathione without an enzyme. The cytosolic gamma-glutamyl peptidases GGP1 and GGP3 remove the gamma-glutamyl residue of the glutathione conjugate (GS-IAN), and an unidentified peptidase removes glycine to give the cysteine conjugate Cys(IAN). The bifunctional P450 CYP71B15 (PAD3) then closes the thiazoline ring of Cys(IAN) with cyanide release to form dihydrocamalexic acid, and oxidatively decarboxylates it to camalexin. The pathway P450s associate with each other and with P450 reductase in an ER-anchored metabolon that channels intermediates. Pathogen-induced transcription of the biosynthetic genes depends on the MAP kinases MPK3 and MPK6, which phosphorylate the WRKY33 transcription factor; WRKY33 binds and activates the CYP71A13 and PAD3 promoters. These two components regulate the pathway and are not pathway enzymes. |
Metabolic Pathway | DRAFT | Arabidopsis thaliana |
0 | camalexin biosynthetic process |
8 | 9 | 7 | 0 | 0 | 8 | 10/10 | 0 | ✓ | modules/camalexin_biosynthesis.yaml | |
Canonical JAK-STAT cytokine signaling pathway moduleMODULE:jak_stat_signaling A taxon-neutral decomposition of the canonical JAK-STAT signal transduction pathway, the principal route by which type I/II cytokines and many... [more...][less]A taxon-neutral decomposition of the canonical JAK-STAT signal transduction pathway, the principal route by which type I/II cytokines and many hormones convert an extracellular signal into a direct change in gene transcription. The module is phrased as an ordered set of functions rather than a fixed gene list so it can represent the many receptor/JAK/STAT combinations that share the same mechanistic core: (1) a cytokine ligand binds and reorganizes a single-pass transmembrane receptor so that its intracellular domains are brought together; (2) receptor-associated Janus kinases (JAK1, JAK2, JAK3, TYK2) are juxtaposed and trans-activate by reciprocal tyrosine phosphorylation; (3) activated JAKs phosphorylate tyrosines on the receptor tails, creating phosphotyrosine docking sites; (4) latent cytoplasmic STAT transcription factors (STAT1-4, STAT5A, STAT5B, STAT6) are recruited via their SH2 domains and phosphorylated by the JAKs; (5) phosphorylated STATs dimerize through reciprocal SH2-phosphotyrosine contacts and translocate to the nucleus; (6) STAT dimers bind GAS/ISRE elements and drive transcription of cytokine-response genes; and (7) the response is terminated and tuned by SOCS/CIS proteins, protein tyrosine phosphatases (SHP1/SHP2, PTPN2), and PIAS SUMO ligases. Which JAKs and STATs are used is set by the receptor, captured here as variant sets along a receptor-class axis. The pathway is grounded in GO:0007259 (cell surface receptor signaling pathway via JAK-STAT). |
Signaling Pathway | DRAFT | bilaterians |
0 | cell surface receptor signaling pathway via JAK-STAT cytokine-mediated signaling pathway |
27 | 28 | 16 | 2 | 10 | 15 | 10/10 | 9 | ✗ | Boolean | modules/jak_stat_signaling.yaml |
Canonical NF-kappaB signaling pathway moduleMODULE:nfkb_canonical_signaling A compact canonical NF-kappaB module. Pro-inflammatory receptors such as TNFR1 assemble adaptor/ubiquitin ligase complexes, activate the IKK... [more...][less]A compact canonical NF-kappaB module. Pro-inflammatory receptors such as TNFR1 assemble adaptor/ubiquitin ligase complexes, activate the IKK complex, induce phosphorylation and proteasomal destruction of IkappaB inhibitors, and release NF-kappaB dimers to enter the nucleus and drive inflammatory, survival, and immune-response genes. The module is grounded in GO:0007249 and includes curated TNFR1, TRAF2, TAK1-TAB, IKK, IkappaB, and NF-kappaB exemplars, with PTN anchors where PAINT seed rows support the role. |
Signaling Pathway | DRAFT | metazoa |
5 | canonical NF-kappaB signal transduction |
5 | 6 | 4 | 0 | 0 | 3 | 4/10 | 0 | ✗ | modules/nfkb_canonical_signaling.yaml | |
Canonical NLRP3 inflammasome assembly and pyroptotic outputMODULE:canonical_nlrp3_inflammasomeCONCRETE A decomposition of the canonical NLRP3 inflammasome: the cytosolic sensor-adaptor-protease platform that converts a diffuse cellular perturbation... [more...][less]A decomposition of the canonical NLRP3 inflammasome: the cytosolic sensor-adaptor-protease platform that converts a diffuse cellular perturbation into active caspase-1, and the lytic execution arm that caspase-1 then triggers. The chain is linear and each hand-off is a change of molecular currency rather than of chemistry: NLRP3 senses a perturbation indirectly and presents a pyrin-domain filament (GO:0044546), that filament nucleates ASC polymerisation into the one-per-cell speck (GO:0061703), the clustered ASC CARDs recruit procaspase-1 and permit proximity-induced autoprocessing (GO:0061702), the autoprocessed protease cleaves gasdermin D and the interleukin-1-family precursors, the released GSDMD N-terminal fragment oligomerises into wide plasma-membrane pores (GO:0141201), and NINJ1 finally ruptures the membrane. Only one of the seven steps is catalytic - caspase-1 substrate cleavage. NLRP3, ASC and NEK7 supply geometry, and the two terminal effectors (GSDMD and NINJ1) act on the membrane rather than running chemistry, so the module is best read as a geometry cascade with a single proteolytic step in the middle and two independent membrane-acting effectors at the end. Design intent: one ordered chain of parts, like necroptosis and unlike the redundant-suppressor topology of ferroptosis, because there is no second route from the speck to the pore. The two places where the biology is genuinely alternative are handled differently from each other. NEK7 licensing is an optional regulatory part rather than a core step, because human myeloid cells can activate NLRP3 without it when IKKbeta has recruited NLRP3 to PI4P (PMID:36384135) and because raising NLRP3 abundance makes potassium-efflux-driven activation independent of both NEK7 and priming (PMID:42378282). Interleukin-1 beta and interleukin-18 are recorded as caspase-1 substrates inside the cleavage step and are deliberately given no annoton of their own: they are what the protease acts on, they perform none of the work of their own maturation, and their cytokine activity belongs to the receptor pathways downstream of this module. |
Biological Process | DRAFT | Mammalia |
0 | inflammasome-mediated signaling pathway pyroptotic cell death NLRP3 inflammasome complex |
8 | 13 | 7 | 0 | 0 | 7 | 6/6 | 0 | ✗ | modules/canonical_nlrp3_inflammasome.yaml | |
Canonical Notch signaling pathway moduleMODULE:notch_signaling A cross-species decomposition of canonical (CSL-dependent) Notch signaling, a contact-dependent juxtacrine pathway present across eumetazoans. A... [more...][less]A cross-species decomposition of canonical (CSL-dependent) Notch signaling, a contact-dependent juxtacrine pathway present across eumetazoans. A membrane-bound DSL-type ligand on a signal-sending cell is ubiquitylated by a Mind bomb or Neuralized E3 ligase and endocytosed; the resulting pulling force on the bound Notch receptor of the neighboring cell unfolds its negative regulatory region, exposing the S2 site to an ADAM10-family metalloprotease. The membrane-tethered remnant is then cut within its transmembrane segment by gamma-secretase, releasing the Notch intracellular domain (NICD). NICD enters the nucleus, binds the DNA-bound CSL transcription factor (RBPJ, Su(H), LAG-1), and together with a Mastermind-family coactivator converts CSL from a corepressor-bound repressor into an activator of target genes, prominently the HES/E(spl) and HEY bHLH repressors. Receptor competence is set beforehand in the ER and Golgi by POFUT1-type O-fucosylation and, in arthropods and vertebrates, by Fringe elongation of those O-fucose glycans, which tunes receptor responsiveness to Delta- versus Serrate/Jagged-type ligands. The module is written so that each role is a union over the lineage-specific implementations found in vertebrates, insects, nematodes, and cnidarians. |
Signaling Pathway | DRAFT | Eumetazoa |
20 | Notch signaling pathway |
28 | 22 | 14 | 5 | 13 | 11 | 49/54 | 0 | ✓ | modules/notch_signaling.yaml | |
Canonical activin receptor-SMAD signaling pathway moduleMODULE:activin_receptor_signaling Mature activin agonists organize type II/type I serine/threonine kinase receptor complexes. Type II receptors activate type I receptors, which... [more...][less]Mature activin agonists organize type II/type I serine/threonine kinase receptor complexes. Type II receptors activate type I receptors, which phosphorylate activin-branch R-SMADs; R-SMAD/co-SMAD complexes then regulate nuclear transcription. Human activin A and native Drosophila Actbeta provide complementary examples, with ligand-specific receptor usage and shared BMP components explicitly distinguished. |
Signaling Pathway | COMPLETE | Metazoan lineages retaining an activin-like receptor/SMAD relay |
0 | activin receptor signaling pathway |
6 | 5 | 5 | 0 | 0 | 4 | 11/11 | 0 | ✓ | modules/activin_receptor_signaling.yaml | |
Canonical nuclear auxin signaling in land plantsMODULE:auxin_nuclear_signalingCONCRETE Canonical nuclear auxin signaling couples TIR1/AFB–Aux/IAA co-receptor assembly to regulated transcription by ARF proteins. Auxin enhances... [more...][less]Canonical nuclear auxin signaling couples TIR1/AFB–Aux/IAA co-receptor assembly to regulated transcription by ARF proteins. Auxin enhances receptor–degron association, enabling SCF-dependent Aux/IAA turnover and reducing corepression of class-A ARFs. This circuit is represented by native Arabidopsis and Marchantia implementations within land plants; older algal ARF DNA-binding systems alone do not establish the complete circuit. Arabidopsis TIR1 also produces cAMP, and separation-of-function experiments show that substrate degradation alone does not guarantee transcriptional activation. The downstream cAMP effector remains unidentified, and MpTIR1 AC activity is untested. Marchantia class-B MpARF2 provides an additional active TOPLESS-recruiting repression and DNA-competition branch. Paralog combinations, expression domains and promoter/chromatin contexts determine output; neither all ARFs nor all Aux/IAAs share one regulatory behavior. Auxin synthesis/transport, rapid cytoplasmic or cell-surface pathways, noncanonical receptor routes and the downstream developmental programs are outside this boundary. |
Signaling Pathway | COMPLETE | Arabidopsis thaliana land plants Marchantia polymorpha |
0 | auxin-activated signaling pathway |
26 | 19 | 16 | 4 | 9 | 13 | 14/14 | 0 | ✗ | modules/auxin_nuclear_signaling.yaml | |
Cardiac specification transcriptional network moduleMODULE:cardiac_specification_network The evolutionarily conserved core transcriptional network that specifies cardiac progenitors in the mesoderm and launches their myocardial... [more...][less]The evolutionarily conserved core transcriptional network that specifies cardiac progenitors in the mesoderm and launches their myocardial differentiation. An NK-2 class homeodomain factor (Drosophila Tinman, vertebrate NKX2-5) acts with a cardiogenic GATA zinc-finger factor (Pannier, GATA4) and T-box factors (Dorsocross, TBX5/TBX20) in a mutually cross-regulating set; these factors physically associate and synergistically activate cardiac enhancers. Together they activate the bHLH factor Hand and the MADS-box differentiation factor MEF2, which drives the cardiac muscle differentiation program. In the fly the network is deployed in dorsal mesoderm at the intersection of ectodermal Dpp and Wingless signals; in vertebrates its mammalian elaboration underlies first and second heart field development and chamber formation. No single factor is sufficient on its own: heart specification depends on their combination with signalling inputs. |
Developmental Process | DRAFT | Bilateria |
1 | heart development cardiac cell fate specification |
6 | 5 | 5 | 0 | 0 | 7 | 12/12 | 0 | ✗ | modules/cardiac_specification_network.yaml | |
Cardiolipin biosynthesis and remodelling in Drosophila melanogasterMODULE:dmel_cardiolipin_biosynthesis_remodelingCONCRETE Cardiolipin is the signature phospholipid of the inner mitochondrial membrane, where it supports respiratory chain complexes and cristae structure.... [more...][less]Cardiolipin is the signature phospholipid of the inner mitochondrial membrane, where it supports respiratory chain complexes and cristae structure. It is made in mitochondria from CDP-diacylglycerol: Pgs1 forms phosphatidylglycerol phosphate, the phosphatase Ptpmt1 dephosphorylates it to phosphatidylglycerol, and cardiolipin synthase (Cls) joins phosphatidylglycerol with a second CDP-diacylglycerol to make nascent cardiolipin. Nascent cardiolipin is then remodelled: a lipase removes an acyl chain to form monolysocardiolipin, and the transacylase tafazzin (Taz) transfers an acyl chain from another phospholipid to monolysocardiolipin, giving cardiolipin its mature acyl composition. ABHD18 deacylates cardiolipin in flies and mice, and the calcium-independent phospholipase A2 iPLA2-VIA has also been implicated in cardiolipin deacylation. Loss of tafazzin causes monolysocardiolipin to accumulate and models Barth syndrome in flies. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | cardiolipin biosynthetic process cardiolipin acyl-chain remodeling |
6 | 6 | 5 | 0 | 0 | 4 | 0/6 | 0 | ✗ | modules/dmel_cardiolipin_biosynthesis_remodeling.yaml | |
Carnitine acyltransferase shuttle (mitochondrial import of acyl and acetyl units)MODULE:carnitine_shuttle The carnitine shuttle moves activated acyl groups across membranes that are impermeable to acyl-CoA. A carnitine acyltransferase on the donor side... [more...][less]The carnitine shuttle moves activated acyl groups across membranes that are impermeable to acyl-CoA. A carnitine acyltransferase on the donor side transfers the acyl group from CoA to L-carnitine; the resulting acylcarnitine is carried across the mitochondrial inner membrane by a mitochondrial-carrier-family carnitine/acylcarnitine translocase in exchange for free carnitine; and a matrix carnitine acyltransferase reverses the transfer, regenerating acyl-CoA and releasing carnitine for recycling. The same chemistry serves different cargo in different lineages. In animals the shuttle imports long-chain fatty acids for mitochondrial beta-oxidation: carnitine palmitoyltransferase 1 on the outer membrane catalyses the committed, malonyl-CoA-inhibited step and carnitine palmitoyltransferase 2 on the matrix side of the inner membrane regenerates long-chain acyl-CoA. In fungi such as budding yeast, where beta-oxidation is peroxisomal, the shuttle carries acetyl units: carnitine acetyltransferases in the peroxisome, cytosol and at the mitochondrial outer membrane form acetylcarnitine from acetyl-CoA produced by beta-oxidation or by cytosolic acetate and ethanol metabolism, and the mitochondrial isoform regenerates acetyl-CoA in the matrix for the tricarboxylic acid cycle. Cells take up carnitine through a plasma-membrane transporter; budding yeast cannot make carnitine and depends on uptake. Inherited defects of the animal components (SLC22A5, CPT1A, SLC25A20, CPT2) cause fatty-acid-oxidation disorders. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | carnitine shuttle |
11 | 7 | 4 | 3 | 6 | 4 | 9/9 | 0 | ✗ | modules/carnitine_shuttle.yaml | |
Carotenoid biosynthesis I — carotene backbone (GGPP -> phytoene -> lycopene -> cyclic carotenes)MODULE:carotene_backbone_biosynthesis The carotene backbone segment of carotenoid biosynthesis converts two molecules of the C20 isoprenoid geranylgeranyl diphosphate (GGPP) into the... [more...][less]The carotene backbone segment of carotenoid biosynthesis converts two molecules of the C20 isoprenoid geranylgeranyl diphosphate (GGPP) into the C40 cyclic carotenes that seed every downstream carotenoid class. Phytoene synthase performs the head-to-head condensation that commits GGPP to carotenoids, giving 15-cis-phytoene. Phytoene is then desaturated to all-trans-lycopene by one of two mutually exclusive routes: a single FAD-dependent CrtI-type desaturase in most bacteria and fungi, or the four-enzyme poly-cis route of cyanobacteria and plants (PDS, Z-ISO, ZDS, CRTISO) in which two plastoquinone-dependent desaturases each introduce two double bonds and two isomerases convert the poly-cis intermediates to the all-trans product. Lycopene cyclases then form beta rings (giving gamma- and beta-carotene) or, in plants, one epsilon ring (giving delta- and alpha-carotene). Supply of GGPP, xanthophyll formation by ring hydroxylation and epoxidation, ketolation, and oxidative cleavage to apocarotenoids (retinal, abscisic acid, strigolactones, neurosporaxanthin) are outside this module. |
Metabolic Pathway | DRAFT | bacteria cyanobacteria fungi green plants |
2 | carotenoid biosynthetic process carotene biosynthetic process beta-carotene biosynthetic process |
15 | 11 | 9 | 2 | 5 | 6 | 12/16 | 0 | ✓ | modules/carotene_backbone_biosynthesis.yaml | |
Catechol ortho-cleavage branch of the beta-ketoadipate pathwayMODULE:catechol_ortho_cleavageCONCRETE A reusable bacterial aromatic-catabolism module for the catechol ortho-cleavage branch of the beta-ketoadipate pathway, which converts catechol to... [more...][less]A reusable bacterial aromatic-catabolism module for the catechol ortho-cleavage branch of the beta-ketoadipate pathway, which converts catechol to beta-ketoadipate enol-lactone in three cytoplasmic steps. A CatA-type Fe(III) intradiol catechol 1,2-dioxygenase first cleaves catechol between its hydroxylated carbons to cis,cis-muconate; a CatB-type muconate cycloisomerase of the enolase superfamily then forms (4S)-muconolactone; and a CatC-type muconolactone Delta-isomerase produces the enol-lactone. The same three-enzyme chain is found in Proteobacteria, as in Pseudomonas putida KT2440 (which carries two CatA paralogs) and Acinetobacter baylyi ADP1, and in Actinobacteria, as in Rhodococcus opacus 1CP, whose CatA and CatB come from lineages distinct from the proteobacterial enzymes. The module starts at catechol, the product of upper pathways such as benzoate dioxygenation, and stops before the enol-lactone hydrolase, CoA-transferase and thiolase steps that the catechol branch shares with the protocatechuate branch. |
Metabolic Pathway | COMPLETE | bacteria |
0 | catechol catabolic process, ortho-cleavage |
4 | 3 | 3 | 0 | 0 | 2 | 10/10 | 0 | ✓ | modules/catechol_ortho_cleavage.yaml | |
Catecholamine biosynthesis (Tyr -> L-DOPA -> dopamine -> noradrenaline -> adrenaline)MODULE:catecholamine_biosynthesis The catecholamine neurotransmitters and hormones - dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) - are synthesised from the... [more...][less]The catecholamine neurotransmitters and hormones - dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) - are synthesised from the amino acid L-tyrosine by a linear four-enzyme pathway operating in catecholaminergic neurons and adrenal chromaffin cells. Tyrosine hydroxylase (TH), the rate-limiting enzyme, hydroxylates L-tyrosine to L-DOPA using tetrahydrobiopterin (BH4), O2 and a non-heme Fe(II) centre. Aromatic L-amino-acid decarboxylase (DDC/AADC), a pyridoxal-phosphate enzyme, decarboxylates L-DOPA to dopamine (and, on the parallel indoleamine branch, 5-HTP to serotonin). In noradrenergic and adrenergic cells, dopamine is imported into secretory (chromaffin) granules, where the copper- and ascorbate-dependent dopamine beta-hydroxylase (DBH) hydroxylates it to noradrenaline; finally, in adrenal medullary and some central adrenergic cells, the SAM-dependent phenylethanolamine N-methyltransferase (PNMT) N-methylates noradrenaline to adrenaline. Which product predominates depends on the cell type's enzyme complement (dopaminergic cells stop at dopamine; noradrenergic add DBH; adrenergic add PNMT). Inherited defects are severe neurological/autonomic disorders: TH deficiency causes DOPA-responsive dystonia / infantile parkinsonism, AADC (DDC) deficiency a global monoamine-neurotransmitter disease, and DBH deficiency autosomal-recessive orthostatic hypotension. |
Metabolic Pathway | DRAFT | 0 | catecholamine biosynthetic process dopamine biosynthetic process epinephrine biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/catecholamine_biosynthesis.yaml | ||
Chaperone-mediated autophagy (HSPA8 substrate delivery and LAMP-2A translocation)MODULE:chaperone_mediated_autophagyABSTRACT Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway for soluble cytosolic proteins that carry a KFERQ-like pentapeptide... [more...][less]Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway for soluble cytosolic proteins that carry a KFERQ-like pentapeptide motif. The constitutive Hsp70 chaperone HSPA8/Hsc70 recognizes the motif in the cytosol and delivers the substrate to the cytosolic side of the lysosomal membrane, where it binds monomeric LAMP-2A, the CMA-specific splice isoform of LAMP2. Substrate binding drives LAMP-2A multimerization into a high-molecular-weight translocation complex, the unfolded substrate crosses the membrane, and it is degraded by lumenal hydrolases; HSPA8 then disassembles the LAMP-2A complex, returning LAMP-2A to its monomeric, substrate-binding state. The module covers substrate recognition and delivery, translocation through the LAMP-2A complex, and complex recycling. Regulation of CMA (for example lysosomal mTORC2/PHLPP1/AKT signalling or cathepsin A-mediated LAMP-2A turnover), the cochaperones that assist HSPA8 at the membrane, and the downstream consequences of degrading particular substrates (NLRP3, BBC3/PUMA, GPX4) are outside the boundary. |
Biological Process | DRAFT | mammals |
0 | chaperone-mediated autophagy |
3 | 3 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/chaperone_mediated_autophagy.yaml | |
Chaperonin containing TCP-1 (CCT/TRiC) in Drosophila melanogasterMODULE:dmel_cct_chaperoninCONCRETE The chaperonin containing TCP-1 (CCT, also called TRiC) is the group II chaperonin of the eukaryotic cytosol. It is a double ring in which each... [more...][less]The chaperonin containing TCP-1 (CCT, also called TRiC) is the group II chaperonin of the eukaryotic cytosol. It is a double ring in which each ring contains one copy of each of eight paralogous subunits (CCT1-CCT8) in a fixed order. Substrates bind in the central cavity, and ATP hydrolysis by the subunits closes a built-in lid and drives folding of the enclosed polypeptide. Major substrates include actin and tubulin, which receive newly made chains partly from prefoldin. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | chaperonin-containing T-complex |
9 | 9 | 8 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_cct_chaperonin.yaml | |
Chemokine-mediated signaling pathway moduleMODULE:chemokine_signaling Secreted chemokines (exemplified by the ELR-positive CXC chemokine CXCL8/IL-8) bind glycosaminoglycans in the extracellular region and engage... [more...][less]Secreted chemokines (exemplified by the ELR-positive CXC chemokine CXCL8/IL-8) bind glycosaminoglycans in the extracellular region and engage seven-transmembrane Gi-coupled chemokine receptors (such as CXCR1/CXCR2 for CXCL8 and CCR5 for CC chemokines) at the leukocyte plasma membrane. Agonist binding initiates the chemokine-mediated signaling pathway (GO:0070098) and the specific interleukin-8-mediated signaling pathway (GO:0038112), promoting heterotrimeric Gi nucleotide exchange and Gbetagamma/Galpha_i signaling through PI3Kgamma (PIK3CG), phospholipase C beta calcium mobilization, and RhoA-dependent actomyosin remodeling to direct leukocyte chemotaxis (GO:0060326) and neutrophil chemotaxis (GO:0030593). |
Signaling Pathway | DRAFT | metazoa |
12 | chemokine-mediated signaling pathway interleukin-8-mediated signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 4/6 | 0 | ✓ | modules/chemokine_signaling.yaml | |
Chitin biosynthesis and catabolism in Drosophila melanogasterMODULE:dmel_chitin_metabolismCONCRETE Chitin, a beta-1,4-linked polymer of N-acetylglucosamine, is the fibrous scaffold of the insect cuticle, tracheal linings and the peritrophic... [more...][less]Chitin, a beta-1,4-linked polymer of N-acetylglucosamine, is the fibrous scaffold of the insect cuticle, tracheal linings and the peritrophic matrix of the midgut. It is synthesized at the plasma membrane by chitin synthases: Krotzkopf verkehrt (kkv) makes chitin of the epidermal cuticle and trachea, and Chs2 is the second chitin synthase, expressed in the gut. During molting and tissue remodelling, chitin is broken down by family 18 chitinases (Cht genes), which cleave the polymer into oligosaccharides, and by beta-N-acetylhexosaminidases (Hexo1, Hexo2), which release N-acetylglucosamine from the non-reducing ends. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | chitin metabolic process |
4 | 14 | 3 | 0 | 0 | 2 | 0/14 | 0 | ✗ | modules/dmel_chitin_metabolism.yaml | |
Cholesterol biosynthesis I — sterol commitment (squalene -> lanosterol); FDFT1/SQLE/LSSMODULE:sterol_commitment_squalene_to_lanosterol The sterol-commitment segment of cholesterol biosynthesis converts the isoprenoid intermediate farnesyl diphosphate into the first cyclic sterol,... [more...][less]The sterol-commitment segment of cholesterol biosynthesis converts the isoprenoid intermediate farnesyl diphosphate into the first cyclic sterol, lanosterol, committing carbon away from the branched isoprenoid pool (dolichol, ubiquinone, prenylation) and irreversibly toward sterols. Squalene synthase (FDFT1) performs the first committed step: a reductive head-to-head condensation of two farnesyl-diphosphate molecules (via presqualene diphosphate) to the C30 hydrocarbon squalene. Squalene monooxygenase / epoxidase (SQLE), an FAD flavoprotein and the second rate-limiting, cholesterol-feedback- regulated enzyme of the pathway, oxidises squalene to (S)-2,3-epoxysqualene using O2 and NADPH. Lanosterol synthase (LSS, oxidosqualene cyclase) then carries out the remarkable polycyclization of 2,3-epoxysqualene to lanosterol, the tetracyclic sterol scaffold from which cholesterol (and, in other tissues, downstream sterols) is made by the post-lanosterol demethylation/reduction steps. All three enzymes are endoplasmic-reticulum-membrane proteins. Inherited defects: FDFT1 deficiency (squalene synthase deficiency, a congenital cholesterol-biosynthesis disorder with dysmorphism/developmental delay) and LSS mutations (hypotrichosis with juvenile cataract / congenital cataract, and a palmoplantar keratoderma); SQLE is a validated antifungal/anticancer drug target rather than a Mendelian-disease gene. |
Metabolic Pathway | DRAFT | 0 | cholesterol biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/sterol_commitment_squalene_to_lanosterol.yaml | ||
Cholesterol biosynthesis II — lanosterol to cholesterol (post-lanosterol); SLOS, CDPX2, CHILD, lathosterolosisMODULE:cholesterol_synthesis_post_lanosterol The post-lanosterol segment of cholesterol biosynthesis converts lanosterol into cholesterol through a ~19-reaction sequence of demethylations,... [more...][less]The post-lanosterol segment of cholesterol biosynthesis converts lanosterol into cholesterol through a ~19-reaction sequence of demethylations, isomerisation, desaturations and reductions carried out by endoplasmic-reticulum-membrane enzymes. The three lanosterol methyl groups are removed first: CYP51A1 (a cytochrome P450) removes the 14-alpha-methyl group, and the resulting Delta14 bond is reduced by TM7SF2 or LBR; then the two C4 methyls are removed in two rounds by the C4- demethylation machinery in which MSMO1 (a non-heme di-iron methylsterol oxidase) oxidises the C4 methyl to a carboxylate and NSDHL (a 3-beta-hydroxysteroid dehydrogenase/ C4-decarboxylase) decarboxylates it (the 3-ketoreductase HSD17B7 then restores the 3-beta-ol). EBP (sterol Delta(8)-Delta(7) isomerase) shifts the ring double bond from Delta8 to Delta7; SC5D (lathosterol oxidase / sterol-C5-desaturase) introduces the C5-6 double bond; and DHCR7 (7-dehydrocholesterol reductase) reduces the C7-8 double bond to give cholesterol. The pathway runs as two interconvertible arms — the Bloch arm (retaining the side-chain Delta24 double bond until the end) and the Kandutsch-Russell arm (in which DHCR24 reduces the Delta24 bond early) — that differ only in the timing of the DHCR24 step. Isotope tracing shows that tissues mostly combine the Bloch arm with a modified Kandutsch-Russell arm, in which DHCR24 reduces zymosterol, rather than using the canonical Kandutsch-Russell route, in tissue-specific proportions. Inherited enzyme defects cause distinctive malformation/skeletal/skin disorders: DHCR7 -> Smith-Lemli-Opitz syndrome; SC5D -> lathosterolosis; EBP -> X-linked chondrodysplasia punctata 2 (Conradi-Hunermann-Happle); NSDHL -> CHILD syndrome; MSMO1 -> SC4MOL deficiency; and DHCR24 -> desmosterolosis. |
Metabolic Pathway | DRAFT | 0 | cholesterol biosynthetic process |
10 | 10 | 9 | 0 | 0 | 10 | 8/10 | 0 | ✗ | modules/cholesterol_synthesis_post_lanosterol.yaml | ||
Chromatin assembly factor 1 in Drosophila melanogasterMODULE:dmel_chromatin_assembly_factor_1CONCRETE Chromatin assembly factor 1 (CAF-1) is a three-subunit histone chaperone that deposits newly synthesised histone H3-H4 onto DNA behind the... [more...][less]Chromatin assembly factor 1 (CAF-1) is a three-subunit histone chaperone that deposits newly synthesised histone H3-H4 onto DNA behind the replication fork, coupling nucleosome assembly to DNA replication through its interaction with PCNA. It consists of Caf1-180 (p180), Caf1-105 (p105) and the WD-repeat histone-binding protein Caf1-55 (p55). Caf1-55 is also a subunit of several other chromatin complexes. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | CAF-1 complex |
4 | 4 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_chromatin_assembly_factor_1.yaml | |
Chromosomal passenger complexes in Drosophila melanogasterMODULE:dmel_chromosomal_passenger_complexCONCRETE The chromosomal passenger complex (CPC) moves from centromeres in early mitosis to the spindle midzone and midbody in anaphase and telophase. Its... [more...][less]The chromosomal passenger complex (CPC) moves from centromeres in early mitosis to the spindle midzone and midbody in anaphase and telophase. Its enzymatic subunit Aurora B kinase phosphorylates kinetochore substrates to correct erroneous microtubule attachments, supports the spindle assembly checkpoint and later promotes cytokinesis. INCENP binds and activates Aurora B and links it to the localization module, formed by Survivin (Deterin in Drosophila) and Borealin. In Drosophila male meiosis the Borealin paralog Australin replaces Borealin in a meiotic CPC. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | chromosome passenger complex |
5 | 3 | 2 | 1 | 2 | 0 | 5/5 | 0 | ✗ | modules/dmel_chromosomal_passenger_complex.yaml | |
Chylomicron assembly and ER export in enterocytes; MTTP, APOB (apoB-48) and SAR1BMODULE:chylomicron_assembly_secretion Dietary fat is exported from absorptive enterocytes as chylomicrons, large triglyceride-rich lipoproteins built on a single apolipoprotein B-48... [more...][less]Dietary fat is exported from absorptive enterocytes as chylomicrons, large triglyceride-rich lipoproteins built on a single apolipoprotein B-48 molecule. In the endoplasmic reticulum, microsomal triglyceride transfer protein (MTTP, with protein disulfide isomerase as its small subunit) transfers neutral lipid onto apoB-48 as it is translated, producing a primordial lipoprotein that is then expanded into a pre-chylomicron. ApoB-48 is the non-exchangeable structural scaffold of the particle. The pre-chylomicron leaves the ER in a COPII-dependent carrier whose formation is started by the small GTPase SAR1B: GTP-bound SAR1B inserts into the ER membrane at exit sites and recruits the SEC23-SEC24 and SEC13-SEC31 coats. After Golgi maturation, the chylomicron is secreted basolaterally into lymph. The three steps correspond to three recessive fat-malabsorption disorders. Abetalipoproteinemia (MTTP) and homozygous familial hypobetalipoproteinemia 1 (APOB) block particle formation. Chylomicron retention disease (SAR1B) leaves particle formation intact but blocks ER exit. |
Biological Process | DRAFT | 0 | chylomicron assembly |
4 | 3 | 3 | 0 | 0 | 2 | 2/3 | 0 | ✗ | modules/chylomicron_assembly_secretion.yaml | ||
Ciliary transition zone MKS, NPHP and CEP290 modulesMODULE:ciliary_transition_zoneCONCRETE The ciliary transition zone (TZ) is the proximal region of the cilium, just distal to the basal body, where Y-shaped links connect the axonemal... [more...][less]The ciliary transition zone (TZ) is the proximal region of the cilium, just distal to the basal body, where Y-shaped links connect the axonemal microtubules to the ciliary membrane. It acts as a gate that controls which proteins enter and leave the cilium. In nematodes and mammals the TZ is built from the same set of conserved, ciliopathy-associated protein modules. An RPGRIP1L-family assembly hub (MKS-5 in C. elegans) is needed for essentially all other TZ proteins to reach the TZ. CEP290 is a large coiled-coil protein that binds microtubules and membranes; in C. elegans it is a core component of the central cylinder and is needed to localise the MKS module but not the NPHP module. The MKS module contains the three B9-domain proteins MKS1, B9D1 and B9D2, the C2-domain protein CC2D2A, the Tectonic proteins and several transmembrane proteins (TMEM67/meckelin, TMEM216, TMEM107, TMEM231, TMEM237, TMEM17, TMEM218). The NPHP module contains the nephrocystins NPHP1 and NPHP4. The MKS and NPHP modules are partially redundant. Loss of one module leaves cilia nearly normal, whereas combined loss of both causes severe defects in nematodes and mice: the basal body and TZ fail to attach to the membrane, Y-links are lost, axonemes are malformed and non-ciliary membrane proteins leak into the cilium. A further CEP290-dependent branch containing TMEM138 and CDKL1 belongs to neither module. Mutations in the human genes cause Meckel-Gruber syndrome, Joubert syndrome and nephronophthisis. In mammals the nephrocystins also act at epithelial cell-cell junctions, a role outside this module. |
Cellular Component | DRAFT | Bilateria |
0 | ciliary transition zone ciliary transition zone assembly |
6 | 17 | 5 | 0 | 0 | 5 | 27/27 | 0 | ✗ | modules/ciliary_transition_zone.yaml | |
Ciliary transition zone components in Drosophila melanogasterMODULE:dmel_ciliary_transition_zoneCONCRETE The transition zone is the region at the base of the cilium, just above the basal body, where Y-shaped links connect the axoneme to the ciliary... [more...][less]The transition zone is the region at the base of the cilium, just above the basal body, where Y-shaped links connect the axoneme to the ciliary membrane and form a diffusion barrier that controls which proteins enter the cilium. Its components include the MKS module, a membrane-associated complex of B9-domain proteins (B9d1, B9d2, Mks1), Cc2d2a and Tectonic, and Cep290, which links the barrier to the axoneme. In Drosophila, transition zone proteins act in the cilia of sensory neurons and in the long transition-zone-like region of spermatocyte cilia. Cep290, Chibby, Dilatory (Cep131) and Unc localize to the transition zone or basal body and are needed to assemble it and the cilium. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ciliary transition zone |
4 | 5 | 3 | 0 | 0 | 0 | 0/10 | 0 | ✗ | modules/dmel_ciliary_transition_zone.yaml | |
Citrate-malate shuttle in Drosophila melanogasterMODULE:dmel_citrate_malate_shuttleCONCRETE The citrate-malate shuttle moves acetyl units from mitochondria to the cytosol for fatty acid and sterol synthesis and for histone acetylation.... [more...][less]The citrate-malate shuttle moves acetyl units from mitochondria to the cytosol for fatty acid and sterol synthesis and for histone acetylation. Citrate made in the mitochondrial matrix is exported by the mitochondrial citrate carrier, encoded in Drosophila by scheggia (sea), in exchange for malate. In the cytosol ATP-citrate lyase (Acly) cleaves citrate into acetyl-CoA and oxaloacetate, and cytosolic malate dehydrogenase (Mdh1) reduces the oxaloacetate to malate, which can return to the mitochondria through the citrate carrier or be decarboxylated by malic enzyme. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | mitochondrial citrate transmembrane transport |
4 | 3 | 3 | 0 | 0 | 3 | 3/3 | 0 | ✗ | modules/dmel_citrate_malate_shuttle.yaml | |
Classical non-homologous end joining of DNA double-strand breaks — Ku70/Ku80 end binding, DNA-PKcs recruitment and autophosphorylation, Artemis/PNKP/APTX/APLF end processing, pol mu/pol lambda/TdT gap filling, and XRCC4-LIG4 ligation with XLF and PAXX; XRCC6/XRCC5/PRKDC/DCLRE1C/PNKP/APTX/APLF/POLM/POLL/DNTT/XRCC4/LIG4/NHEJ1/PAXXMODULE:nonhomologous_end_joiningCONCRETE Classical non-homologous end joining (c-NHEJ) rejoins the two ends of a DNA double-strand break (DSB) directly, without a homologous template. It... [more...][less]Classical non-homologous end joining (c-NHEJ) rejoins the two ends of a DNA double-strand break (DSB) directly, without a homologous template. It operates throughout the cell cycle, is the predominant DSB repair pathway in G1 and in non-dividing cells, and is the joining step of V(D)J recombination and class switch recombination in lymphocytes. The Ku heterodimer (Ku70/XRCC6 and Ku80/XRCC5) threads onto each broken end through a preformed ring and recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs, PRKDC) to form the DNA-PK holoenzyme, which tethers the two ends in a synaptic complex. DNA-PKcs is activated by the DNA end, autophosphorylates (which remodels the synapse and releases the ends for processing) and phosphorylates other NHEJ factors, including the nuclease Artemis (DCLRE1C). Incompatible or damaged ends are processed by enzymes chosen by end chemistry: the Artemis-DNA-PKcs complex opens hairpins and trims 5' and 3' overhangs; the polynucleotide kinase-phosphatase PNKP restores 5'-phosphate and 3'-hydroxyl termini; aprataxin (APTX) removes 5'-adenylate left by abortive ligation; and APLF, recruited by poly(ADP-ribose) and by Ku, acts as a scaffold that retains the ligase complex and has reported nuclease activity. Gaps are filled by the family X polymerases pol mu (POLM) and pol lambda (POLL), and in developing lymphocytes the template-independent terminal deoxynucleotidyl transferase (TdT, DNTT) adds non-templated nucleotides to V(D)J coding ends. The ends are finally sealed by DNA ligase IV (LIG4) in a constitutive complex with its scaffold XRCC4; the XRCC4 paralogs XLF (NHEJ1) and PAXX bind XRCC4 and Ku respectively, bridge and align the ends, and stimulate ligation, with XLF and PAXX partly redundant. Upstream, the 53BP1-RIF1 axis of ATM signalling protects DSB ends from resection in G1 and so favours c-NHEJ over homologous recombination. |
Biological Process | DRAFT | Homo sapiens |
0 | double-strand break repair via classical nonhomologous end joining |
14 | 13 | 6 | 2 | 7 | 7 | 3/14 | 0 | ✗ | modules/nonhomologous_end_joining.yaml | |
Clathrin and heterotetrameric adaptor protein coats in Drosophila melanogasterMODULE:dmel_clathrin_adaptor_coatsCONCRETE Clathrin-coated vesicles carry cargo from the plasma membrane and the trans-Golgi network into the endosomal system. Clathrin heavy and light... [more...][less]Clathrin-coated vesicles carry cargo from the plasma membrane and the trans-Golgi network into the endosomal system. Clathrin heavy and light chains assemble into three-legged triskelia that polymerize into a lattice over the budding membrane. Heterotetrameric adaptor protein (AP) complexes, each made of two large subunits, a medium (mu) and a small (sigma) subunit, select cargo and link the membrane to the coat. AP-2 acts in endocytosis at the plasma membrane, including synaptic vesicle recycling; AP-1 acts at the trans-Golgi network and endosomes. AP-3 sorts cargo from endosomes towards lysosome-related organelles; in Drosophila the AP-3 subunits are encoded by the classic eye-colour genes garnet (g), ruby (rb), carmine (cm) and orange (or), whose mutants are defective in pigment granule biogenesis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | clathrin vesicle coat |
6 | 4 | 2 | 1 | 3 | 0 | 0/13 | 0 | ✗ | modules/dmel_clathrin_adaptor_coats.yaml | |
Coagulation cascade — tissue-factor initiation, FXI/FIX amplification, prothrombinase, fibrin formation and cross-linking, with the plasma anticoagulant brakesMODULE:coagulation_cascadeCONCRETE The coagulation cascade converts a local vascular injury into an insoluble, cross-linked fibrin clot through a chain of limited proteolytic... [more...][less]The coagulation cascade converts a local vascular injury into an insoluble, cross-linked fibrin clot through a chain of limited proteolytic activations of circulating zymogens and their non-enzymatic protein cofactors. Initiation is extrinsic: tissue factor (F3), an integral membrane protein exposed at the injury site, binds factor VII/VIIa (F7) and the resulting extrinsic tenase complex cleaves both factor X (F10) and factor IX (F9). The small amount of thrombin this generates feeds back to activate the cofactors factor V (F5) and factor VIII (F8) and the zymogen factor XI (F11), switching the system into its amplification mode: factor XIa activates factor IX, and factor IXa together with factor VIIIa forms the intrinsic tenase that sustains factor Xa production. Factor VIII circulates bound to von Willebrand factor (VWF), which carries it and protects it from clearance until thrombin releases it. The pathways converge on the prothrombinase complex, factor Xa with its cofactor factor Va on a procoagulant phospholipid surface, which raises the rate of prothrombin (F2) activation by several orders of magnitude. Thrombin then cleaves fibrinopeptides from fibrinogen (FGA, FGB, FGG); the fibrin monomers polymerise into a branched network by their own end-to-middle and lateral associations, and thrombin-activated factor XIII (the catalytic A subunit F13A1 with its carrier B subunit F13B) covalently cross-links the gamma chains, stabilising the clot and making it resistant to lysis. The same proteases are held in check by plasma anticoagulants: antithrombin (SERPINC1) traps thrombin, factor Xa and factor IXa; tissue factor pathway inhibitor (TFPI) shuts down the extrinsic tenase and factor Xa; the protein C pathway, in which thrombin bound to endothelial thrombomodulin (THBD) activates protein C (PROC) and activated protein C with its cofactor protein S (PROS1) destroys factors Va and VIIIa, removes the cofactors the cascade depends on; and protein Z-dependent protease inhibitor (SERPINA10) with protein Z (PROZ) inactivates factor Xa at the membrane surface. Most of the proteases and protein C, S and Z are vitamin K-dependent, their Gla domains anchoring them to the anionic phospholipid surface. |
Biological Process | DRAFT | Homo sapiens |
0 | blood coagulation, fibrin clot formation |
8 | 24 | 7 | 0 | 0 | 12 | 13/21 | 0 | ✗ | modules/coagulation_cascade.yaml | |
Cobalamin (B12) intracellular processing and trafficking; ABCD4/LMBRD1/MMACHC/MMADHCMODULE:cobalamin_intracellular_processing Once the transcobalamin-cobalamin complex has been endocytosed via CD320 and degraded in the lysosome, the freed cobalamin (vitamin B12) must be... [more...][less]Once the transcobalamin-cobalamin complex has been endocytosed via CD320 and degraded in the lysosome, the freed cobalamin (vitamin B12) must be exported to the cytosol, stripped of its upper axial ligand, and routed to one of its two coenzyme forms. The lysosomal export step is carried out by a two-protein system: the ABC transporter ABCD4 (cblJ), which provides the ATP-dependent transmembrane cobalamin-transport activity, together with the lysosomal membrane protein LMBRD1 (cblF), which is required to target ABCD4 to the lysosome and acts as its escort subunit. In the cytosol the cblC protein MMACHC processes the cobalamin — reductive decyanation of cyanocobalamin and dealkylation of alkylcobalamins remove the beta-axial ligand to give cob(II)alamin. The cblD protein MMADHC then binds MMACHC-cob(II)alamin and acts as the branch-point/trafficking adaptor that directs cobalamin either to the mitochondrion for adenosylcobalamin synthesis (feeding methylmalonyl-CoA mutase, MMUT) or to the cytosolic methylcobalamin route (feeding methionine synthase, MTR). Defects in each step cause combined or isolated methylmalonic aciduria and homocystinuria: cblJ (ABCD4), cblF (LMBRD1), cblC (MMACHC) and cblD (MMADHC). |
Metabolic Pathway | DRAFT | 0 | cobalamin metabolic process |
4 | 4 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/cobalamin_intracellular_processing.yaml | ||
Cobalamin (vitamin B12) absorption and transport; TCN1/CBLIF/CUBN/AMN/TCN2/CD320MODULE:cobalamin_absorption_transport Dietary cobalamin (vitamin B12) reaches the cytoplasm of peripheral cells through a relay of binding proteins and endocytic receptors. In saliva... [more...][less]Dietary cobalamin (vitamin B12) reaches the cytoplasm of peripheral cells through a relay of binding proteins and endocytic receptors. In saliva and the acidic stomach, cobalamin is first bound and protected by haptocorrin (TCN1); in the duodenum pancreatic proteases degrade haptocorrin and the cobalamin is transferred to gastric intrinsic factor (CBLIF/GIF), secreted by parietal cells. The intrinsic-factor-cobalamin complex is then recognised in the ileum by the cubam receptor, a complex of the large peripheral membrane protein cubilin (CUBN) and its transmembrane partner amnionless (AMN), which internalises it by receptor-mediated endocytosis; the cobalamin is released and exported to the blood. In plasma, newly absorbed cobalamin is bound by transcobalamin (TCN2), the physiologically essential delivery carrier, and the transcobalamin-cobalamin complex is taken up by peripheral cells through the cell-surface receptor CD320 (TCblR). Inherited defects along this route cause B12-deficiency disorders: CBLIF (hereditary intrinsic factor deficiency / juvenile pernicious anaemia), CUBN and AMN (Imerslund-Grasbeck syndrome, megaloblastic anaemia with proteinuria), TCN2 (transcobalamin deficiency, severe infantile megaloblastic anaemia with immunodeficiency) and CD320 (a usually mild/transient methylmalonic acidaemia detected on newborn screening). |
Metabolic Pathway | DRAFT | 0 | cobalamin transport receptor-mediated endocytosis |
6 | 6 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/cobalamin_absorption_transport.yaml | ||
Coenzyme Q10 (ubiquinone) biosynthesis (PDSS1/2, COQ2-COQ9)MODULE:coenzyme_q10_biosynthesis Coenzyme Q10 (ubiquinone-10) is the lipophilic electron/proton carrier of the mitochondrial inner membrane that shuttles electrons from respiratory... [more...][less]Coenzyme Q10 (ubiquinone-10) is the lipophilic electron/proton carrier of the mitochondrial inner membrane that shuttles electrons from respiratory Complexes I and II (and from electron-transfer flavoprotein, dihydroorotate dehydrogenase and others) to Complex III, and is a membrane antioxidant. Its biosynthesis has two arms that meet at the matrix face of the inner membrane. First, the C50 polyisoprenoid tail is built: the all-trans-decaprenyl-diphosphate synthase, a heterotetramer of PDSS1 and PDSS2, condenses (2E,6E)-farnesyl diphosphate with isopentenyl diphosphate units to all-trans- decaprenyl diphosphate. The polytopic inner-membrane prenyltransferase COQ2 then attaches this tail to the ring precursor 4-hydroxybenzoate, committing it to the pathway. A series of ring modifications, carried out by a membrane-associated multienzyme assembly (the "COQ synthome"/complex Q), converts the polyprenyl-hydroxybenzoate to ubiquinol: FAD-dependent C5 hydroxylation by COQ6, Zn-dependent C1 decarboxylation by COQ4 followed by C1 hydroxylation by COQ6, C2-methylation by the SAM-dependent methyltransferase COQ5, NADH-dependent di-iron C6 hydroxylation by COQ7 (whose lipophilic substrate is bound and presented by the lipid-binding protein COQ9), and the two O-methylation steps performed by COQ3 (not covered here). Assembly and activity of the synthome require the atypical UbiB-family kinase/ATPases COQ8A and COQ8B. The exact order of the head-group modifications in humans is not fully resolved (in particular, C1 decarboxylation by COQ4 can precede C5 hydroxylation by COQ6), and the enzymes act within the synthome complex rather than as free-standing steps. Defects in any of these genes cause primary coenzyme Q10 deficiency, a clinically heterogeneous mitochondrial disease (encephalomyopathy, cerebellar ataxia, steroid-resistant nephrotic syndrome, Leigh syndrome), some forms of which are partially responsive to oral CoQ10. |
Metabolic Pathway | DRAFT | 0 | ubiquinone biosynthetic process |
9 | 9 | 8 | 0 | 0 | 7 | 10/10 | 0 | ✗ | modules/coenzyme_q10_biosynthesis.yaml | ||
Collagen-DDR signaling pathway moduleMODULE:collagen_ddr_signalingABSTRACT Native triple-helical collagens in the extracellular matrix bind and activate the discoidin domain receptors (DDRs), receptor tyrosine kinases on... [more...][less]Native triple-helical collagens in the extracellular matrix bind and activate the discoidin domain receptors (DDRs), receptor tyrosine kinases on the responding cell. Collagen binding to the discoidin domain triggers slow and sustained autophosphorylation of the receptor, which then recruits intracellular signaling proteins that regulate cell adhesion, migration, proliferation, differentiation and remodelling of the surrounding matrix. |
Signaling Pathway | DRAFT | Eumetazoa |
2 | collagen-activated tyrosine kinase receptor signaling pathway |
6 | 4 | 2 | 1 | 3 | 1 | 8/9 | 0 | ✗ | modules/collagen_ddr_signaling.yaml | |
Complement component C5a signaling pathway moduleMODULE:c5a_signaling Proteolytic cleavage of secreted complement C5 by C3/C5 convertases (or granzyme K) in the extracellular region releases the 74-residue C5a... [more...][less]Proteolytic cleavage of secreted complement C5 by C3/C5 convertases (or granzyme K) in the extracellular region releases the 74-residue C5a anaphylatoxin, which engages the seven-transmembrane complement receptors C5aR1 (CD88) and C5aR2 (C5L2) at the plasma membrane of myeloid leukocytes, endothelial cells, and other target cells. C5a binding to C5aR1 activates pertussis-toxin-sensitive heterotrimeric Gi proteins (exemplified by GNAI2) and beta-arrestins, whereas C5a binding to the non-G-protein-coupled receptor C5aR2 selectively recruits beta-arrestins to modulate C5aR1 signaling. Together these steps execute the complement component C5a signaling pathway (GO:0038178) and drive PI3Kgamma (PIK3CG)- and RhoA-dependent myeloid leukocyte chemotaxis (GO:0006935) and degranulation. |
Signaling Pathway | DRAFT | Euteleostomi |
4 | complement component C5a signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 4/6 | 0 | ✗ | modules/c5a_signaling.yaml | |
Condensin I and condensin II in Drosophila melanogasterMODULE:dmel_condensin_complexesCONCRETE Condensins are SMC complexes that compact and individualize chromosomes for segregation. Both condensin I and condensin II are built on a... [more...][less]Condensins are SMC complexes that compact and individualize chromosomes for segregation. Both condensin I and condensin II are built on a heterodimer of SMC2 and SMC4 (Gluon in Drosophila), whose ATPase heads are bridged by a kleisin subunit that recruits HEAT-repeat subunits. Condensin I contains the kleisin Barren (CAP-H) and the HEAT subunits Cap-D2 and Cap-G. Condensin II contains the kleisin Cap-H2 and the HEAT subunit Cap-D3; in Drosophila condensin II also promotes interphase chromosome territory formation and antagonizes homolog pairing. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | condensin complex |
5 | 3 | 2 | 1 | 2 | 0 | 0/7 | 0 | ✗ | modules/dmel_condensin_complexes.yaml | |
Conidiation (asexual sporulation) central regulatory cascadeMODULE:conidiation_regulatory_cascadeABSTRACT A reusable module for the central genetic regulatory cascade that commits vegetative hyphae to asexual sporulation (conidiation) in filamentous... [more...][less]A reusable module for the central genetic regulatory cascade that commits vegetative hyphae to asexual sporulation (conidiation) in filamentous ascomycetes. The shared logic - light/nutrient gating -> a master transcriptional activator -> stage-specific regulators -> structural output (hydrophobin rodlet layer and pigment) - is realized by two largely non-orthologous programs, captured as taxon variants: the Aspergillus nidulans FluG/Flb -> BrlA -> AbaA -> WetA/velvet pathway with G-protein/FlbA gating, and the Neurospora crassa fluffy (FL) program gated by the blue-light White Collar Complex and the circadian clock. |
Developmental Process | DRAFT | Aspergillus nidulans Neurospora crassa Pezizomycotina |
17 | conidium formation |
13 | 30 | 10 | 1 | 2 | 11 | 30/30 | 0 | ✓ | modules/conidiation_regulatory_cascade.yaml | |
Conserved oligomeric Golgi (COG) complex in Drosophila melanogasterMODULE:dmel_cog_complexCONCRETE The conserved oligomeric Golgi (COG) complex is an eight-subunit multisubunit tethering complex at the Golgi apparatus. It tethers COPI-derived... [more...][less]The conserved oligomeric Golgi (COG) complex is an eight-subunit multisubunit tethering complex at the Golgi apparatus. It tethers COPI-derived vesicles that recycle Golgi resident proteins, such as glycosylation enzymes, between cisternae, and it interacts with Golgi SNAREs, Rab GTPases and COPI coat proteins. The complex is organized into two lobes, lobe A (Cog1-Cog4) and lobe B (Cog5-Cog8). In Drosophila, Cog5 is encoded by four way stop (fws), whose mutants are defective in male meiotic cytokinesis and Golgi organization during spermatogenesis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | COG complex |
3 | 2 | 2 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_cog_complex.yaml | |
Core autophagy machinery for autophagosome biogenesisMODULE:autophagosome_core_biogenesisCONCRETE Autophagosomes form from a cup-shaped phagophore that grows around cytoplasmic cargo and closes into a double-membrane vesicle. Formation needs a... [more...][less]Autophagosomes form from a cup-shaped phagophore that grows around cytoplasmic cargo and closes into a double-membrane vesicle. Formation needs a conserved set of autophagy-related (Atg) proteins: the Atg1/ULK kinase with Atg13 starts assembly; the class III phosphatidylinositol 3-kinase complex (Vps34, Vps15, Atg6/Beclin and Atg14) marks the membrane with phosphatidylinositol 3-phosphate; Atg9 vesicles seed the membrane and the Atg2-Atg18/WIPI bridge feeds it lipid from the ER; and two ubiquitin-like conjugation systems link Atg12 to Atg5 and Atg8 to phosphatidylethanolamine. This module is the eukaryote-wide protein core, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
15 | autophagosome assembly |
7 | 17 | 6 | 0 | 0 | 3 | 17/18 | 0 | ✗ | modules/autophagosome_core_biogenesis.yaml | |
Core binding factor (Runt/CBFbeta) in Drosophila melanogasterMODULE:dmel_core_binding_factorCONCRETE Core binding factors are heterodimeric transcription factors made of a Runt domain DNA-binding alpha subunit and a non-DNA-binding beta subunit... [more...][less]Core binding factors are heterodimeric transcription factors made of a Runt domain DNA-binding alpha subunit and a non-DNA-binding beta subunit that increases the alpha subunit's DNA-binding affinity. Drosophila has four Runt domain proteins, runt, lozenge (lz), RunxA and RunxB, and two beta subunits, Brother (Bro) and Big brother (Bgb). Runt acts as a pair-rule and sex determination gene and in neurogenesis, while lozenge specifies cell fates in the eye and crystal cells among hemocytes. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | core-binding factor complex |
3 | 6 | 2 | 0 | 0 | 0 | 0/6 | 0 | ✗ | modules/dmel_core_binding_factor.yaml | |
Core programmed cell death machinery in Caenorhabditis elegansMODULE:c_elegans_core_apoptosisCONCRETE Most somatic and germline apoptotic deaths in Caenorhabditis elegans are initiated by four proteins acting in a linear pathway. In living cells the... [more...][less]Most somatic and germline apoptotic deaths in Caenorhabditis elegans are initiated by four proteins acting in a linear pathway. In living cells the BCL2-family protein CED-9 sits on mitochondria and binds an asymmetric dimer of the Apaf-1-like adaptor CED-4, holding it in an inactive state. A death signal raises the level of the BH3-only protein EGL-1, whose BH3 helix binds a hydrophobic groove on CED-9 and remodels it so that the CED-4 dimer is released. Free CED-4 dimers assemble into an ATP-bound octameric apoptosome that relocates to the nuclear periphery, recruits two molecules of the CED-3 caspase zymogen into its central hutch and drives their autocatalytic maturation. Active CED-3 then cleaves execution substrates such as DCR-1 and CED-8, which promote chromosome fragmentation and phosphatidylserine exposure for corpse engulfment. In the adult germline, DNA damage feeds into the same machinery through the p53-family transcription factor CEP-1, which induces transcription of egl-1 and of a second BH3-only gene, ced-13. CED-13 can also bind CED-9 and release CED-4, but its loss has only a small effect on DNA damage-induced germline death, so EGL-1 remains the main trigger on that route as well. Unlike the mammalian intrinsic pathway, the worm pathway has no known requirement for mitochondrial outer membrane permeabilization or cytochrome c release; CED-9 inhibits by direct sequestration of CED-4 rather than by controlling a pore. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | apoptotic signaling pathway |
6 | 7 | 5 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/c_elegans_core_apoptosis.yaml | |
Corticotropin-releasing hormone receptor signaling — CRH and urocortins acting through CRHR1/CRHR2, Gs, adenylyl cyclase/cAMP, and GRK/beta-arrestin desensitizationMODULE:crh_receptor_signalingCONCRETE Corticotropin-releasing hormone (CRH) and the related urocortins (UCN, UCN2, UCN3) are secreted peptide hormones that signal through two class B G... [more...][less]Corticotropin-releasing hormone (CRH) and the related urocortins (UCN, UCN2, UCN3) are secreted peptide hormones that signal through two class B G protein-coupled receptors, CRHR1 and CRHR2. The receptors differ in ligand selectivity: CRH acts preferentially on CRHR1, urocortin 1 (UCN) activates either receptor, and urocortin 2 (UCN2) and urocortin 3 (UCN3) are selective CRHR2 ligands. Agonist-occupied receptors activate the stimulatory G alpha subunit (GNAS), which stimulates adenylyl cyclase; the resulting cAMP activates protein kinase A (PKA), which phosphorylates cytoplasmic and nuclear targets including the transcription factor CREB. In the anterior pituitary this cascade drives adrenocorticotropin (ACTH) release, the first step of the hypothalamic-pituitary-adrenal stress axis. A circulating CRH-binding protein (CRHBP) sequesters CRH and urocortin and inhibits their action on the receptors. Signalling is terminated when G protein-coupled receptor kinases (GRK3, GRK6) phosphorylate agonist-occupied CRHR1, promoting beta-arrestin (ARRB1, ARRB2) binding, which uncouples the receptor from Gs and drives its internalization. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cellular response to corticotropin-releasing hormone stimulus |
14 | 10 | 7 | 2 | 6 | 10 | 0/12 | 0 | ✗ | modules/crh_receptor_signaling.yaml | |
Cortisol-cortisone shuttle — pre-receptor glucocorticoid interconversion; HSD11B1/HSD11B2MODULE:cortisol_cortisone_shuttle Tissue glucocorticoid action is set not only by circulating cortisol but by local, pre-receptor interconversion between active cortisol and... [more...][less]Tissue glucocorticoid action is set not only by circulating cortisol but by local, pre-receptor interconversion between active cortisol and inactive cortisone, catalysed by two endoplasmic-reticulum-membrane 11beta-hydroxysteroid dehydrogenases with opposite directionality. 11beta-HSD type 1 (HSD11B1) acts predominantly as an NADPH-dependent reductase — its direction fixed by NADPH generated in the ER lumen by hexose-6-phosphate dehydrogenase (H6PD) — regenerating active cortisol from cortisone and thereby amplifying glucocorticoid signalling in liver, adipose tissue and brain (a validated metabolic-syndrome drug target). 11beta-HSD type 2 (HSD11B2) is an NAD+-dependent, essentially unidirectional dehydrogenase that inactivates cortisol to cortisone; in aldosterone-target epithelia (distal nephron, colon, salivary gland) it destroys cortisol locally so that the non-selective mineralocorticoid receptor is protected from illicit activation by cortisol, conferring aldosterone specificity, and in the placenta it shields the fetus from maternal glucocorticoid. Loss of HSD11B2 causes apparent mineralocorticoid excess (AME), a severe juvenile hypertension with hypokalaemia; altered HSD11B1 activity underlies cortisone reductase deficiency and is implicated in the metabolic syndrome. |
Metabolic Pathway | DRAFT | 0 | glucocorticoid metabolic process |
3 | 2 | 2 | 0 | 0 | 2 | 2/2 | 0 | ✗ | modules/cortisol_cortisone_shuttle.yaml | ||
Cpx envelope-stress periplasmic quality controlMODULE:cpx_envelope_stress_quality_controlCONCRETE A periplasmic envelope-stress quality-control module covering two Cpx-regulated effector branches. CpxP inhibits the CpxA sensor kinase in the... [more...][less]A periplasmic envelope-stress quality-control module covering two Cpx-regulated effector branches. CpxP inhibits the CpxA sensor kinase in the unstressed state and can act as a DegP adaptor for a subset of misfolded periplasmic substrates, while Spy binds non-native periplasmic clients in situ to prevent aggregation and assist refolding. Transcriptional control by CpxR/BaeR and DegP proteolysis itself are outside this CpxP/Spy-focused module. |
Biological Process | DRAFT | Escherichia coli |
0 | negative regulation of phosphorelay signal transduction system protein stabilization |
4 | 4 | 3 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/cpx_envelope_stress_quality_control.yaml | |
Creatine biosynthesis (vertebrate, two-step AGAT to GAMT)MODULE:creatine_biosynthesis De novo biosynthesis of creatine, the two-step pathway that supplies the phosphocreatine/creatine system used for cellular energy buffering in... [more...][less]De novo biosynthesis of creatine, the two-step pathway that supplies the phosphocreatine/creatine system used for cellular energy buffering in tissues with high and fluctuating ATP demand (skeletal and cardiac muscle, brain). The pathway is short and committed: L-arginine and glycine are first condensed by L-arginine:glycine amidinotransferase (AGAT/GATM) to give guanidinoacetate (GAA) and L-ornithine, then guanidinoacetate is methylated by guanidinoacetate N-methyltransferase (GAMT) using S-adenosyl-L-methionine (SAM) as the methyl donor to yield creatine and S-adenosyl-L-homocysteine (SAH). The two activities are characteristically split both by subcellular compartment and, in mammals, by organ: AGAT/GATM is a mitochondrial intermembrane-space enzyme and catalyses the first, committed, feedback- regulated step (creatine represses GATM), whereas GAMT is a cytosolic enzyme and is the second, methylation step. The first step is most active in kidney and pancreas and the second predominates in liver, so guanidinoacetate is an inter-organ intermediate that is exported and taken up before methylation; finished creatine is distributed in the blood and imported into target tissues by the creatine transporter SLC6A8. GAMT is also the largest single consumer of SAM-derived methyl groups in the body, tying creatine synthesis to one-carbon / methionine-cycle metabolism. Inherited deficiency of either enzyme (and of the SLC6A8 transporter) causes cerebral creatine-deficiency syndromes. Creatine utilization by the creatine kinases (the phosphocreatine shuttle and the "futile creatine cycle") is downstream of this module and is not part of the biosynthetic pathway itself. |
Metabolic Pathway | DRAFT | 0 | creatine biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/creatine_biosynthesis.yaml | ||
Creatine-phosphocreatine system (human)MODULE:creatine_phosphocreatine_system A navigational grouping for the biology that Reactome bundles as "Creatine metabolism" (R-HSA-71288), assembled here as an explicit biological... [more...][less]A navigational grouping for the biology that Reactome bundles as "Creatine metabolism" (R-HSA-71288), assembled here as an explicit biological *system* rather than as a single GO metabolic process. The grouping is deliberately not called "creatine metabolism": GO keys metabolism on the chemical entity, and this system spans more than one entity. It comprises (1) de novo synthesis of the creatine molecule (creatine biosynthetic process, GO:0006601; the AGAT/GATM -> GAMT pathway), (2) the creatine kinase energy-buffer that interconverts creatine and phosphocreatine (phosphocreatine metabolic process, GO:0006603; including phosphocreatine biosynthesis GO:0046314 and the thermogenic futile creatine cycle GO:0140651), (3) inter-organ and cellular distribution of creatine by the SLC6A8 transporter, and (4) non-enzymatic disposal of creatine and phosphocreatine to creatinine for excretion (creatinine metabolic process, GO:0046449). In strict GO terms (2) is phosphocreatine metabolism, not creatine metabolism, so the canonical GO umbrella creatine metabolic process (GO:0006600) covers only (1) and the creatinine-forming arm of (4). This node carries both GO:0006600 and GO:0006603 to make that cross-branch span explicit. The detailed, protein-grounded logic lives in the dedicated modules referenced by each part; this document holds no annotons of its own and exists only to relate them. |
Biological Process | DRAFT | 0 | creatine metabolic process phosphocreatine metabolic process creatinine metabolic process |
4 | 1 | 3 | 0 | 0 | 3 | 1/1 | 2 | ✗ | modules/creatine_phosphocreatine_system.yaml | ||
Cuproptosis (copper-induced cell death) moduleMODULE:cuproptosis A decomposition of cuproptosis: the regulated cell-death program in which excess intracellular copper, reduced to Cu(I) by the mitochondrial... [more...][less]A decomposition of cuproptosis: the regulated cell-death program in which excess intracellular copper, reduced to Cu(I) by the mitochondrial ferredoxin FDX1, binds the lipoyl moieties of lipoylated tricarboxylic-acid-cycle enzymes (chiefly the pyruvate dehydrogenase E2 subunit DLAT), driving their disulfide-dependent oligomerization/aggregation while destabilizing iron-sulfur cluster proteins. The resulting proteotoxic stress kills the cell. Cuproptosis is mechanistically distinct from apoptosis, necroptosis, ferroptosis, and pyroptosis. This module is framed for the mammalian in-vivo pathway, with concrete human gene products grounded to UniProt where they are used as representatives of the mammalian implementation. Design intent: the module is organized as an upstream copper-homeostasis layer that sets the death threshold (importer, chaperone, exporters), a copper- reduction trigger (FDX1), the protein-lipoylation machinery that builds the copper "bait", the lipoylated TCA-cycle targets/effectors (the pyruvate dehydrogenase complex, with DLAT as the aggregation-prone effector), and the execution node (cuproptosis proper). Protective and modulatory regulators (MTF1, GLS, CDKN2A) and the non-substituting paralog FDX2 are kept as an optional regulatory sub-module. Genes are grounded to UniProt only where verified; GO ids are grounded only to verified, non-obsolete terms in the matching aspect (MF in function, BP in processes/concepts, CC in locations). |
Biological Process | DRAFT | Mammalia |
0 | cuproptosis |
7 | 15 | 6 | 0 | 0 | 8 | 9/16 | 1 | ✗ | modules/cuproptosis.yaml | |
Cuticle tanning and pigmentation in Drosophila melanogasterMODULE:dmel_cuticle_tanning_pigmentationCONCRETE After each molt and at eclosion, the insect cuticle is hardened (sclerotized) and pigmented using dopamine made by tyrosine hydroxylase (Pale) and... [more...][less]After each molt and at eclosion, the insect cuticle is hardened (sclerotized) and pigmented using dopamine made by tyrosine hydroxylase (Pale) and DOPA decarboxylase. Dopamine is used in three branches. Arylalkylamine N-acetyltransferase (Speck, Aanat1) acetylates it to N-acetyldopamine (NADA), the precursor of colourless sclerotin. Ebony conjugates dopamine with beta-alanine to N-beta-alanyldopamine (NBAD), the precursor of yellow-tan sclerotin, and Tan hydrolyses NBAD back to dopamine, so the Ebony-Tan balance sets cuticle colour. Oxidation of dopamine and DOPA by phenoloxidases yields quinones and chromes that polymerize into black and brown melanins; the Yellow family proteins Yellow-f and Yellow-f2 convert dopachrome and Yellow-h converts dopaminechrome, and Yellow itself is needed for black melanin. Beta-alanine for NBAD comes from decarboxylation of aspartate by Black (Adc) and from uracil degradation through dihydropyrimidine dehydrogenase, dihydropyrimidinase and beta-ureidopropionase. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | cuticle pigmentation chitin-based cuticle sclerotization |
11 | 12 | 10 | 0 | 0 | 5 | 0/12 | 0 | ✗ | modules/dmel_cuticle_tanning_pigmentation.yaml | |
Cyanobacterial septal junction moduleMODULE:septal_junction The septal junction (SJ) is a proteinaceous, gap-junction-like cell-cell junction of filamentous, heterocyst-forming cyanobacteria (e.g.... [more...][less]The septal junction (SJ) is a proteinaceous, gap-junction-like cell-cell junction of filamentous, heterocyst-forming cyanobacteria (e.g. Nostoc/Anabaena sp. PCC 7120). SJs traverse the shared septal peptidoglycan (PG) through nanopores and directly connect the cytoplasms of adjacent cells in a filament, mediating and gating the intercellular diffusion of small molecules (metabolites and signaling compounds) — a prerequisite for multicellular behavior and for diazotrophic growth, in which heterocysts exchange fixed nitrogen for photosynthate with neighboring vegetative cells. In situ cryo-electron tomography with subtomogram averaging resolves the SJ as a five-fold-symmetric assembly with four structural modules: a cytoplasmic cap (five arches), a membrane-embedded plug, a septum-spanning tube, and a transmembrane/periplasmic anchor. This module represents the SJ as a structural cell-cell junction: its two molecularly identified core components — SepN (the plug) and FraD (the membrane/periplasmic anchor) — the still molecularly-unidentified cap and (partly lipidic) tube modules, the cell-wall amidases that drill the septal PG nanopore array the SJ passes through, and the additional septal proteins (SepJ/FraG, FraC, FraE) that influence SJ architecture and filament integrity. |
Protein Complex | DRAFT | filamentous heterocyst-forming cyanobacteria (Nostocales) |
0 | septal junction cell junction (nearest existing GO parent) gated cell-cell signaling / intercellular communication |
6 | 6 | 5 | 0 | 0 | 1 | 7/7 | 2 | ✗ | modules/septal_junction.yaml | |
Cyclin K-Cdk12 complex in Drosophila melanogasterMODULE:dmel_cyclin_k_cdk12_complexCONCRETE Cdk12 and its partner cyclin K form a transcription-associated kinase that phosphorylates the C-terminal domain of elongating RNA polymerase II.... [more...][less]Cdk12 and its partner cyclin K form a transcription-associated kinase that phosphorylates the C-terminal domain of elongating RNA polymerase II. CDK12 activity supports productive elongation and co-transcriptional processing, particularly of long genes. In Drosophila, Cdk12 has also been implicated in the control of transcription and chromatin silencing. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | cyclin K-CDK12 complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_cyclin_k_cdk12_complex.yaml | |
Cytokinin two-component (His-Asp phosphorelay) signaling in ArabidopsisMODULE:cytokinin_two_component_signalingCONCRETE The cytokinin signal transduction pathway of Arabidopsis thaliana is a eukaryotic multistep His-Asp phosphorelay. Cytokinins bind the... [more...][less]The cytokinin signal transduction pathway of Arabidopsis thaliana is a eukaryotic multistep His-Asp phosphorelay. Cytokinins bind the extracytosolic CHASE domains of three partially redundant hybrid sensor histidine kinase receptors (AHK2, AHK3 and CRE1/AHK4), located mainly in the endoplasmic reticulum membrane. Ligand binding activates autophosphorylation of a conserved histidine in the transmitter domain; the phosphoryl group passes to an aspartate in the receptor's receiver domain and then to a conserved histidine of the small, nucleocytosolic histidine phosphotransfer proteins (AHP1, AHP2, AHP3, AHP5). AHPs deliver the phosphoryl group to the receiver aspartate of nuclear type-B response regulators (principally ARR1, ARR10 and ARR12), which are Myb-related (GARP) DNA-binding transcription factors; receiver phosphorylation activates them to bind AGAT(T)-containing cis-elements and induce cytokinin primary-response genes. Among these targets are the type-A response regulators (e.g. ARR5), receiver-only proteins that are themselves phosphorylated and stabilized through the relay and attenuate the pathway, closing a negative feedback loop. Without ligand, CRE1/AHK4 can reverse the relay and dephosphorylate AHPs. The phosphorelay core (receptor -> AHP -> type-B ARR) conforms to the generic two-component relay motif; transcriptional output and type-A feedback are this pathway's extensions. Cytokinin biosynthesis, transport and degradation, the cytokinin-independent histidine kinase CKI1, CRFs, and downstream developmental targets are outside the module boundary. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | cytokinin-activated signaling pathway |
7 | 9 | 6 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/cytokinin_two_component_signaling.yaml | |
Cytoplasmic (80S) ribosome in Drosophila melanogasterMODULE:dmel_cytoplasmic_ribosomeCONCRETE The cytoplasmic 80S ribosome translates nuclear-encoded mRNAs. It consists of a 40S small subunit, which binds mRNA and decodes it, and a 60S large... [more...][less]The cytoplasmic 80S ribosome translates nuclear-encoded mRNAs. It consists of a 40S small subunit, which binds mRNA and decodes it, and a 60S large subunit, which carries the peptidyl transferase centre and the polypeptide exit tunnel. Each subunit is built from ribosomal RNAs and dozens of ribosomal proteins named by the universal (u) and eukaryote-specific (e) nomenclature. In Drosophila several ribosomal proteins are encoded by duplicated genes, and some paralogs are expressed mainly in the germline or testis (for example RpL22-like). FlyBase therefore also defines testis-specific variant compositions of both subunits, in which RpS28-like, RpL22-like and RpL37-2 appear only in the testis variants. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | cytosolic ribosome |
7 | 4 | 2 | 2 | 4 | 0 | 0/94 | 0 | ✗ | modules/dmel_cytoplasmic_ribosome.yaml | |
Cytoplasmic dynein and dynactin in Drosophila melanogasterMODULE:dmel_cytoplasmic_dynein_dynactinCONCRETE Cytoplasmic dyneins are multi-subunit minus-end-directed microtubule motors. Cytoplasmic dynein 1, built around the heavy chain Dhc64C, moves... [more...][less]Cytoplasmic dyneins are multi-subunit minus-end-directed microtubule motors. Cytoplasmic dynein 1, built around the heavy chain Dhc64C, moves organelles, vesicles, mRNAs and chromosomes toward microtubule minus ends and acts in spindle assembly, nuclear positioning and oocyte polarity. It contains intermediate chains (Short wing, sw), light intermediate chains (Dlic) and LC8, Tctex and roadblock families of light chains. Dynein 1 is processive only when bound to dynactin and a cargo adaptor. Dynactin is a large complex with a short filament of Arp1 capped at the barbed end by capping protein and at the pointed end by a complex including Arp10 (Arp11), plus a projecting shoulder and arm formed by p150Glued (DCTN1-p150), p50 dynamitin (DCTN2-p50) and p24 (DCTN3-p24). Cytoplasmic dynein 2, with the heavy chain Beethoven (btv), drives retrograde intraflagellar transport in the cilia of sensory neurons. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | cytoplasmic dynein complex dynactin complex |
13 | 17 | 12 | 0 | 0 | 1 | 2/25 | 0 | ✗ | modules/dmel_cytoplasmic_dynein_dynactin.yaml | |
Cytosolic NADPH regeneration in Drosophila melanogasterMODULE:dmel_cytosolic_nadph_regenerationCONCRETE NADPH supplies reducing power for fatty acid synthesis and for antioxidant systems such as glutathione and thioredoxin reduction. In Drosophila, as... [more...][less]NADPH supplies reducing power for fatty acid synthesis and for antioxidant systems such as glutathione and thioredoxin reduction. In Drosophila, as in other animals, it is regenerated outside mitochondria by three sets of NADP-dependent dehydrogenases. The oxidative branch of the pentose phosphate pathway produces two NADPH per glucose 6-phosphate through glucose-6-phosphate dehydrogenase (G6pd, Zw) and 6-phosphogluconate dehydrogenase (Pgd). NADP-dependent isocitrate dehydrogenase (Idh) oxidizes isocitrate to 2-oxoglutarate, and NADP-dependent malic enzyme (Men) decarboxylates malate to pyruvate, each reducing NADP+. Studies of fly mutants and allozyme variants link these enzymes to lipid accumulation. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | NADPH regeneration |
6 | 5 | 5 | 0 | 0 | 1 | 5/5 | 0 | ✗ | modules/dmel_cytosolic_nadph_regeneration.yaml | |
Cytosolic iron-sulfur protein assembly (CIA) in human cellsMODULE:cytosolic_iron_sulfur_assemblyCONCRETE The cytosolic iron-sulfur protein assembly (CIA) machinery builds [4Fe-4S] clusters in the cytosol and inserts them into cytosolic and nuclear... [more...][less]The cytosolic iron-sulfur protein assembly (CIA) machinery builds [4Fe-4S] clusters in the cytosol and inserts them into cytosolic and nuclear apoproteins, including enzymes of DNA replication and repair, purine metabolism and iron regulation (IRP1). It depends on the mitochondrial iron-sulfur cluster (ISC) machinery, which produces a still-unidentified sulfur-containing compound that the inner-membrane ABC transporter ABCB7 exports to the cytosol. In the cytosol, the NADPH-dependent diflavin reductase NDOR1 passes electrons to the [2Fe-2S] cluster of anamorsin (CIAPIN1). A heterotetrameric scaffold of the P-loop NTPases NUBP1 and NUBP2 assembles [4Fe-4S] clusters. CIAO3 (NARFL) and the CIA targeting complex then transfer the clusters to recipient apoproteins. The targeting complex has a core of the WD40 protein CIAO1, the MIP18-family protein CIAO2B and the HEAT-repeat adaptor MMS19, which binds most client apoproteins. CIAO1 paired with the paralog CIAO2A instead matures IRP1. The client apoproteins are substrates of the pathway, not parts of the machinery. |
Biological Process | DRAFT | Homo sapiens |
0 | [4Fe-4S] cluster assembly |
8 | 7 | 7 | 0 | 0 | 6 | 3/10 | 0 | ✗ | modules/cytosolic_iron_sulfur_assembly.yaml | |
D-amino-acid supply for peptidoglycan precursor biosynthesisMODULE:d_amino_acid_cell_wall_precursor_supply A reusable bacterial precursor-supply module that produces D-glutamate and D-alanine from their L-enantiomers and ligates two D-alanine molecules... [more...][less]A reusable bacterial precursor-supply module that produces D-glutamate and D-alanine from their L-enantiomers and ligates two D-alanine molecules to form D-Ala-D-Ala. These products feed the cytoplasmic Mur ligase pathway for peptidoglycan stem-peptide assembly. The module ends at free D-glutamate and D-Ala-D-Ala and excludes their incorporation by MurD and MurF, downstream lipid II synthesis, polymerization, cross-linking, D-amino-acid catabolism, periplasmic BSR metabolism, and Ldt-mediated peptidoglycan remodeling. |
Metabolic Pathway | DRAFT | 0 | peptidoglycan biosynthetic process |
6 | 4 | 3 | 1 | 2 | 1 | 5/6 | 0 | ✗ | modules/d_amino_acid_cell_wall_precursor_supply.yaml | ||
D-erythroascorbate (dehydro-D-arabinono-1,4-lactone) biosynthesisMODULE:erythroascorbate_biosynthesisABSTRACT In fungi, D-erythroascorbate, the five-carbon analogue of L-ascorbate, is made from D-arabinose in two oxidations. The IUBMB and ChEBI name for it... [more...][less]In fungi, D-erythroascorbate, the five-carbon analogue of L-ascorbate, is made from D-arabinose in two oxidations. The IUBMB and ChEBI name for it is dehydro-D-arabinono-1,4-lactone. First, a cytosolic aldo-keto-reductase-type D-arabinose 1-dehydrogenase oxidises D-arabinose to D-arabinono-1,4-lactone, using NAD+ or NADP+. Second, a membrane-bound, FAD-dependent D-arabinono-1,4-lactone oxidase in the mitochondria oxidises the lactone with O2, giving dehydro-D-arabinono-1,4-lactone and hydrogen peroxide. The terminal oxidase belongs to the aldonolactone oxidoreductase group of the vanillyl alcohol oxidase flavoprotein superfamily. Its homologs make L-ascorbate in animals (L-gulono-1,4-lactone oxidase) and plants (L-galactono-1,4-lactone dehydrogenase), and the yeast enzyme can also oxidise L-gulono- and L-galactono-1,4-lactone. Erythroascorbate is thought to act as an antioxidant: yeast cells lacking the oxidase are more sensitive to oxidative stress, although its importance under normal conditions is debated. |
Metabolic Pathway | DRAFT | Fungi |
0 | dehydro-D-arabinono-1,4-lactone biosynthetic process |
5 | 3 | 2 | 1 | 2 | 1 | 3/3 | 0 | ✗ | modules/erythroascorbate_biosynthesis.yaml | |
D-xylose catabolism to D-xylulose 5-phosphate (oxidoreductase and isomerase routes)MODULE:xylose_oxidoreductase_pathwayCONCRETE D-xylose, the main pentose of plant hemicellulose, is channelled into the pentose phosphate pathway as D-xylulose 5-phosphate. The isomerisation of... [more...][less]D-xylose, the main pentose of plant hemicellulose, is channelled into the pentose phosphate pathway as D-xylulose 5-phosphate. The isomerisation of xylose to xylulose is achieved by one of two routes. In xylose-utilising yeasts and filamentous fungi, an aldo-keto reductase family xylose reductase reduces D-xylose to xylitol with NADPH (or NADH), and an NAD+-dependent medium-chain dehydrogenase, xylitol dehydrogenase (D-xylulose reductase), oxidises xylitol to D-xylulose. Because the two steps use different cofactors, the route can create a redox imbalance and xylitol accumulation under oxygen limitation. Bacteria, and some anaerobic fungi, instead use a single cofactor-free xylose isomerase. In both routes an FGGY-family xylulokinase then phosphorylates D-xylulose with ATP to D-xylulose 5-phosphate, which enters the non-oxidative pentose phosphate pathway. Xylose uptake and downstream pentose phosphate metabolism are outside this module. |
Metabolic Pathway | DRAFT | 0 | D-xylose catabolic process |
7 | 4 | 4 | 1 | 2 | 2 | 4/7 | 0 | ✗ | modules/xylose_oxidoreductase_pathway.yaml | ||
DAF-2 insulin/IGF-1-like signaling to DAF-16/FOXO in Caenorhabditis elegansMODULE:c_elegans_daf2_insulin_signalingCONCRETE In Caenorhabditis elegans a large family of insulin-like peptides, secreted mainly by neurons, acts through a single insulin/IGF-1 receptor... [more...][less]In Caenorhabditis elegans a large family of insulin-like peptides, secreted mainly by neurons, acts through a single insulin/IGF-1 receptor tyrosine kinase, DAF-2. Active DAF-2 signals through the class I PI3K catalytic subunit AGE-1 to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which the PTEN lipid phosphatase DAF-18 removes. PIP3 supports activation of the 3-phosphoinositide-dependent kinase PDK-1, which in turn activates a kinase complex of AKT-1, AKT-2 and SGK-1. These kinases phosphorylate the FOXO transcription factor DAF-16, and phosphorylated DAF-16 is bound by the 14-3-3 protein FTT-2 and held in the cytoplasm. When ligand input falls, as in poor food or high pheromone conditions, or when the pathway is genetically reduced, DAF-16 enters the nucleus and regulates a broad transcriptional program that includes stress-resistance genes such as the mitochondrial manganese superoxide dismutase sod-3, as well as antimicrobial and metabolic genes. The pathway controls the dauer diapause decision, adult lifespan, stress resistance and fat storage, and DAF-16 is its major output. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | insulin receptor signaling pathway dauer larval development determination of adult lifespan |
10 | 11 | 9 | 0 | 0 | 9 | 12/12 | 0 | ✗ | modules/c_elegans_daf2_insulin_signaling.yaml | |
DBL-1 BMP-like Sma/Mab signaling in Caenorhabditis elegans body size controlMODULE:c_elegans_dbl1_body_size_signalingCONCRETE In Caenorhabditis elegans the BMP2/4-related ligand DBL-1 is secreted mainly by neurons and acts on the epidermis (hypodermis) to promote... [more...][less]In Caenorhabditis elegans the BMP2/4-related ligand DBL-1 is secreted mainly by neurons and acts on the epidermis (hypodermis) to promote postembryonic growth and to pattern the male tail. DBL-1 signals through a receptor pair of the type I serine/threonine kinase SMA-6 and the type II kinase DAF-4, and then through the Smads SMA-2 and SMA-3 together with the co-Smad SMA-4. Loss of any of these components gives small (Sma) animals with abnormal male tails (Mab), and the DBL-1 dose sets body length, so overexpression makes animals longer. SMA-3 is the principal receptor-regulated Smad. Signaling is tuned at the cell surface: the glypican LON-2 restrains it, apparently through the matricellular protein SMOC-1, which binds both LON-2 and DBL-1, rather than by binding DBL-1 directly; and the LRIG-family transmembrane protein SMA-10, which binds both receptors and supports SMA-6 endocytic trafficking, enhances it. In the nucleus the Schnurri-family zinc finger protein SMA-9 acts as a transcriptional cofactor that mainly represses targets in body size control. One downstream target is lon-1, which encodes a secreted CAP/CRISP-family protein made in the hypodermis. The pathway represses lon-1, and LON-1 limits body size, binds sterol in vitro and feeds back to dampen pathway output. The same ligand, receptors and SMA-3 also act in epidermal antifungal defense, lipid storage and other outputs. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | BMP signaling pathway positive regulation of multicellular organism growth |
8 | 10 | 7 | 0 | 0 | 7 | 10/10 | 0 | ✗ | modules/c_elegans_dbl1_body_size_signaling.yaml | |
DNA cytosine methylation cycle — de novo CpG methylation, UHRF1/DNMT1 maintenance, TET/TDG active demethylation and methyl-CpG readers; DNMT3A/DNMT3B/DNMT3L/UHRF1/DNMT1/TET1-3/TDG/MBD1/MBD2/MECP2/ZBTB33/ZBTB4/ZBTB38/ZFP57MODULE:dna_cytosine_methylation_cycleCONCRETE In mammalian genomes most CpG dinucleotides carry 5-methylcytosine (5mC), whereas CpG islands at promoters are usually unmethylated. Methylation... [more...][less]In mammalian genomes most CpG dinucleotides carry 5-methylcytosine (5mC), whereas CpG islands at promoters are usually unmethylated. Methylation patterns are written, copied, erased and read by distinct sets of proteins that use the same nucleotide as their substrate. De novo methylation, which establishes patterns in the germline and the early embryo, is carried out by DNMT3A and DNMT3B. These transfer a methyl group from S-adenosyl-L-methionine to C5 of cytosine in unmethylated DNA. DNMT3L, which has no catalytic activity, binds the DNMT3A catalytic domain, stimulates it, and reads histone H3 tails unmethylated at lysine 4; it is needed to set up maternal imprints. After replication, CpGs are hemimethylated, carrying 5mC only on the parental strand. Maintenance methylation copies the pattern onto the daughter strand. UHRF1 binds hemimethylated CpG through its SRA domain and H3K9me3-marked chromatin through its tandem Tudor domain. Its RING domain then mono-ubiquitinates histone H3 at lysines 18 and 23. The replication foci targeting sequence of DNMT1 binds this dual-ubiquitin mark, which recruits DNMT1, relieves its autoinhibition and lets it methylate the daughter-strand cytosine. Active demethylation begins with the TET dioxygenases (TET1, TET2, TET3). These Fe(II)- and 2-oxoglutarate-dependent enzymes oxidise 5mC in turn to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine DNA glycosylase (TDG) excises 5fC and 5caC, but not 5mC or 5hmC, and base excision repair then restores unmodified cytosine. Methylation also passes without repair, because 5hmC is not a substrate for DNMT1 maintenance. Methylated CpG is read by two structural families of proteins, separate from the SRA reader UHRF1. The methyl-CpG-binding-domain proteins are MBD1, MBD2 and MeCP2. The C2H2 zinc-finger proteins are Kaiso (ZBTB33), ZBTB4, ZBTB38 and the KRAB zinc-finger protein ZFP57. These readers recruit corepressor, histone deacetylase and histone methyltransferase complexes to methylated loci, and ZFP57 protects the methylation of imprinting control regions in the early embryo. |
Biological Process | DRAFT | Homo sapiens |
0 | DNA modification |
26 | 21 | 11 | 5 | 14 | 10 | 4/16 | 0 | ✗ | modules/dna_cytosine_methylation_cycle.yaml | |
DXP-dependent de novo pyridoxal 5'-phosphate biosynthesisMODULE:pyridoxal_5_phosphate_biosynthesisCONCRETE De novo synthesis of pyridoxal 5'-phosphate (PLP, vitamin B6) through the DXP-dependent bacterial pathway. One branch converts D-erythrose... [more...][less]De novo synthesis of pyridoxal 5'-phosphate (PLP, vitamin B6) through the DXP-dependent bacterial pathway. One branch converts D-erythrose 4-phosphate to 3-amino-2-oxopropyl phosphate through Epd, PdxB, SerC, and PdxA. PdxJ then condenses this product with the shared metabolite 1-deoxy-D-xylulose 5-phosphate (DXP) to form pyridoxine 5'-phosphate, and PdxH performs the terminal oxidation to PLP. DXP production is shared with thiamine and isoprenoid metabolism and is outside this module boundary. The route is restricted to a subset of eubacteria, most prominently the Gammaproteobacteria. The alternative DXP-independent PdxS/PdxT pathway and vitamin-B6 salvage are separate modules. |
Metabolic Pathway | COMPLETE | 3 | 'de novo' pyridoxal 5'-phosphate biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 12/12 | 0 | ✓ | modules/pyridoxal_5_phosphate_biosynthesis.yaml | ||
De novo GDP-fucose biosynthesis in Drosophila melanogasterMODULE:dmel_gdp_fucose_biosynthesisCONCRETE GDP-L-fucose is the donor substrate for fucosyltransferases, including the O-fucosyltransferase that modifies Notch EGF repeats and the Golgi... [more...][less]GDP-L-fucose is the donor substrate for fucosyltransferases, including the O-fucosyltransferase that modifies Notch EGF repeats and the Golgi fucosyltransferases that fucosylate N-glycans. Drosophila makes it de novo from GDP-mannose in the cytosol: GDP-mannose 4,6-dehydratase (Gmd) forms GDP-4-keto-6-deoxymannose, and GDP-L-fucose synthase (Gmer) epimerizes and reduces this intermediate to GDP-L-fucose. GDP-fucose is then carried into the secretory pathway by two transporters, the Golgi GDP-fucose transporter (Gfr) and the endoplasmic reticulum transporter Efr. Loss of Gmd or of both transporters impairs Notch O-fucosylation and Notch signaling. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | 'de novo' GDP-L-fucose biosynthetic process |
4 | 4 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/dmel_gdp_fucose_biosynthesis.yaml | |
De novo UMP biosynthesis and conversion to UTP and CTPMODULE:de_novo_pyrimidine_synthesis The conserved six-reaction pathway that builds UMP from glutamine, hydrogencarbonate, ATP, aspartate, and PRPP, followed by phosphorylation of UMP... [more...][less]The conserved six-reaction pathway that builds UMP from glutamine, hydrogencarbonate, ATP, aspartate, and PRPP, followed by phosphorylation of UMP to UTP and amination of UTP to CTP. Carbamoyl phosphate is formed first, followed by assembly and oxidation of the pyrimidine ring, attachment to phosphoribose, and decarboxylation to UMP. UMP kinase and nucleoside-diphosphate kinase then make UTP, and CTP synthase transfers the glutamine amide nitrogen to UTP to make CTP. Enzyme architecture varies: bacteria commonly use separate CarA, CarB, PyrB, PyrC, PyrE, and PyrF proteins, whereas animals fuse the first three activities in CAD and the final two activities in UMPS; fungi fuse the carbamoyl-phosphate synthetase and aspartate carbamoyltransferase in one protein that also carries an inactive dihydroorotase-like domain, and use separate dihydroorotase, orotate phosphoribosyltransferase and OMP decarboxylase proteins. These fusions do not change the chemical leaves represented by the module. Dihydroorotate oxidation has two implementations: membrane-associated quinone-dependent (class 2) enzymes, which in eukaryotes sit on the mitochondrial inner membrane and couple pyrimidine synthesis to respiration, and soluble fumarate-dependent (class 1A) enzymes, acquired by Saccharomyces yeasts from bacteria, which allow pyrimidine synthesis without oxygen. Bacteria phosphorylate UMP with a PyrH-type UMP kinase, eukaryotes with a UMP/CMP kinase of the adenylate kinase family. |
Metabolic Pathway | DRAFT | 0 | 'de novo' UMP biosynthetic process 'de novo' CTP biosynthetic process |
15 | 12 | 10 | 2 | 4 | 8 | 29/33 | 0 | ✗ | modules/de_novo_pyrimidine_synthesis.yaml | ||
De novo biotin biosynthesis (pimelate-thioester supply and BioF-BioA-BioD-BioB ring assembly)MODULE:biotin_biosynthesis De novo synthesis of biotin in bacteria, fungi and plants. A seven-carbon pimelate thioester (pimeloyl-ACP or pimeloyl-CoA) is first made by a... [more...][less]De novo synthesis of biotin in bacteria, fungi and plants. A seven-carbon pimelate thioester (pimeloyl-ACP or pimeloyl-CoA) is first made by a lineage-specific route, and four conserved reactions then assemble the two rings of biotin. In many bacteria, BioC methylates malonyl-ACP, the shared fatty-acid-synthase reactions extend the masked intermediate to pimeloyl-ACP methyl ester, and BioH removes the methyl group. Filamentous fungi make pimeloyl-CoA by peroxisomal beta-oxidation, and Saccharomyces yeasts need the oxygen-dependent BIO1 protein, whose reaction is not known. The pimelate thioester is condensed with L-alanine to 8-amino-7-oxononanoate (KAPA) by a PLP-dependent KAPA synthase: bacterial BioF, a peroxisomal BioF in filamentous fungi, or, in Saccharomyces, a step that requires the BIO6 protein, a paralogue of the BioA aminotransferase. BioA then transfers an amino group from S-adenosylmethionine to give 7,8-diaminononanoate (DAPA), BioD closes the ureido ring with CO2 and ATP to give dethiobiotin, and the radical-SAM enzyme BioB inserts sulfur to form biotin. In fungi BioB is mitochondrial, and in filamentous fungi and plants BioD and BioA are fused in one protein. Biotin attachment to carboxylases, biotin uptake and regulation are outside the module. |
Metabolic Pathway | DRAFT | 4 | biotin biosynthetic process |
14 | 9 | 7 | 2 | 6 | 5 | 13/21 | 1 | ✓ | modules/biotin_biosynthesis.yaml | ||
De novo deoxyribonucleoside triphosphate synthesis by class I ribonucleotide reductaseMODULE:dntp_de_novo_synthesis De novo formation of the four DNA precursors dATP, dGTP, dCTP and dTTP from ribonucleoside diphosphates in eukaryotes and other organisms with a... [more...][less]De novo formation of the four DNA precursors dATP, dGTP, dCTP and dTTP from ribonucleoside diphosphates in eukaryotes and other organisms with a class I (oxygen-dependent) ribonucleotide reductase. The reductase replaces the 2'-hydroxyl of ADP, GDP, CDP and UDP with hydrogen using electrons from thioredoxin or glutaredoxin; its large (alpha) subunit binds substrates and the allosteric effectors that balance the four products, and its small (beta) subunit carries the di-iron tyrosyl radical cofactor. In budding yeast the active enzyme is an alpha2 homodimer of Rnr1 (or the damage-induced Rnr3) with a beta heterodimer of the radical-bearing Rnr2 and the catalytically inactive but essential Rnr4. Nucleoside-diphosphate kinase then phosphorylates dADP, dGDP and dCDP to the triphosphates. dTTP cannot be made by direct reduction: dUMP is produced either by hydrolysis of dUTP by dUTP diphosphatase, which also keeps dUTP out of DNA, or by deamination of dCMP by dCMP deaminase; thymidylate synthase then methylates dUMP to dTMP with 5,10-methylenetetrahydrofolate, dTMP kinase makes dTDP and nucleoside-diphosphate kinase makes dTTP. Activity and subunit levels are tightly controlled by the cell cycle and the DNA damage checkpoint. Class II (adenosylcobalamin) and class III (anaerobic, glycyl-radical) reductases of prokaryotes, deoxynucleoside salvage and the mitochondrial dNTP supply pathway of animals are outside the module. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | deoxyribonucleotide biosynthetic process dTTP biosynthetic process |
10 | 7 | 7 | 1 | 2 | 6 | 12/21 | 0 | ✗ | modules/dntp_de_novo_synthesis.yaml | |
De novo inosine monophosphate biosynthesisMODULE:de_novo_purine_synthesis A reusable pathway that assembles the purine ring on 5-phosphoribosyl diphosphate (PRPP) to form inosine monophosphate (IMP). The module represents... [more...][less]A reusable pathway that assembles the purine ring on 5-phosphoribosyl diphosphate (PRPP) to form inosine monophosphate (IMP). The module represents ten ordered reaction positions and separates reaction roles from lineage-specific protein fusions. It includes alternative folate-dependent PurN and ATP/formate-dependent PurT routes for GAR formylation, and alternative two-enzyme and direct routes for AIR carboxylation. Enzyme architecture varies widely: bacteria commonly use separate PurF, PurD, PurN/PurT, PurL, PurM, PurK, PurE, PurC, PurB and PurH proteins; animals fuse PurD, PurM and PurN in GART and direct AIR carboxylase with SAICAR synthetase in PAICS; fungi fuse PurD with PurM in a bifunctional GAR synthetase-AIR synthetase and PurK with PurE in a bifunctional AIR carboxylase that works through the N5-carboxyaminoimidazole ribonucleotide intermediate. In eukaryotes the pathway is cytosolic. The first enzyme, amidophosphoribosyltransferase, is feedback-inhibited by adenine nucleotides. IMP-to-AMP and IMP-to-GMP branches are outside the module, although PurB also has a second physiological role in AMP synthesis. |
Metabolic Pathway | DRAFT | 0 | 'de novo' IMP biosynthetic process |
20 | 15 | 14 | 2 | 5 | 11 | 34/44 | 0 | ✓ | modules/de_novo_purine_synthesis.yaml | ||
De novo riboflavin biosynthesis and flavin cofactor activationMODULE:riboflavin_biosynthesis De novo synthesis of riboflavin (vitamin B2) from GTP and ribulose 5-phosphate, followed by conversion of riboflavin to the active flavin cofactors... [more...][less]De novo synthesis of riboflavin (vitamin B2) from GTP and ribulose 5-phosphate, followed by conversion of riboflavin to the active flavin cofactors FMN and FAD, as found in bacteria, fungi and plants. The ring pathway has two converging branches. In the GTP-derived pyrimidine branch, GTP cyclohydrolase II opens the imidazole ring of GTP; the product then undergoes deamination of the pyrimidine ring and reduction of the ribosyl side chain, and the resulting phosphorylated intermediate is dephosphorylated. The order of deamination and reduction differs by lineage: bacteria deaminate first and then reduce, usually with one bifunctional RibD protein, whereas fungi reduce first and then deaminate, with two separate proteins. The ribulose-5-phosphate branch makes the four-carbon donor 3,4-dihydroxy-2-butanone 4-phosphate. The two branches converge at lumazine synthase, and riboflavin synthase then forms riboflavin by a dismutation of two lumazine molecules. Riboflavin kinase converts riboflavin to FMN and FMN adenylyltransferase converts FMN to FAD. In many bacteria both activation steps are carried out by one bifunctional RibF protein, whereas eukaryotes use a monofunctional riboflavin kinase and a separate FAD synthase. |
Metabolic Pathway | COMPLETE | bacteria eukaryota fungi |
2 | riboflavin biosynthetic process FMN biosynthetic process FAD biosynthetic process |
19 | 12 | 14 | 2 | 4 | 9 | 28/28 | 1 | ✓ | modules/riboflavin_biosynthesis.yaml | |
De novo serine biosynthesis and serine/glycine one-carbon unit generation (PHGDH/PSAT1/PSPH + SHMT1/SHMT2)MODULE:serine_biosynthesis_one_carbon De novo L-serine biosynthesis and its immediate use as a one-carbon donor form a central node of intermediary metabolism, supplying the building... [more...][less]De novo L-serine biosynthesis and its immediate use as a one-carbon donor form a central node of intermediary metabolism, supplying the building blocks and methyl groups for nucleotide synthesis, methylation and redox balance — a pathway on which proliferating and neural cells especially depend. Serine is made from the glycolytic intermediate 3-phospho-D-glycerate by the "phosphorylated pathway": PHGDH (D-3-phosphoglycerate dehydrogenase) oxidises 3-phosphoglycerate to 3-phosphonooxypyruvate using NAD+; PSAT1 (phosphoserine aminotransferase, PLP-dependent) transaminates it with glutamate to O-phospho-L-serine; and PSPH (phosphoserine phosphatase, Mg2+-dependent) hydrolyses the phosphate to release L-serine, the committed final step. The newly made serine then feeds one-carbon (folate) metabolism through serine hydroxymethyltransferase, which reversibly transfers a one-carbon unit from serine to tetrahydrofolate, producing glycine and 5,10-methylenetetrahydrofolate. Humans have two SHMT isozymes running this reaction in parallel compartments: cytosolic SHMT1 (supplying one-carbon units for cytosolic thymidylate/purine synthesis and the methylation cycle, with a nuclear role in the thymidylate-synthesis complex) and mitochondrial SHMT2 (the principal entry to mitochondrial one-carbon metabolism, exporting formate/one-carbon units to the cytosol and supplying glycine). Inherited defects cause serine deficiency: PHGDH — Neu-Laxova syndrome 1 / serine-deficiency with microcephaly and seizures; PSAT1 — Neu-Laxova syndrome 2; PSPH — phosphoserine phosphatase deficiency. |
Metabolic Pathway | DRAFT | 0 | L-serine biosynthetic process tetrahydrofolate interconversion |
3 | 5 | 2 | 0 | 0 | 1 | 5/5 | 0 | ✗ | modules/serine_biosynthesis_one_carbon.yaml | ||
De novo sphingolipid biosynthesis (ceramide core, with fungal inositol-phosphorylceramide head groups)MODULE:sphingolipid_de_novo_synthesis De novo sphingolipid synthesis builds ceramide, the hydrophobic backbone of all complex sphingolipids, from serine and fatty acyl-CoA on the... [more...][less]De novo sphingolipid synthesis builds ceramide, the hydrophobic backbone of all complex sphingolipids, from serine and fatty acyl-CoA on the endoplasmic-reticulum membrane. The committed, rate-limiting first step is catalysed by serine palmitoyltransferase (SPT), a pyridoxal-5'-phosphate-dependent membrane complex built on a heterodimer of two homologous subunits (SPTLC1/LCB1 and SPTLC2/LCB2). A small, lineage-specific activating subunit is also required: SPTSSA/B in animals, which sets acyl-CoA specificity, and the unrelated Tsc3 in fungi. SPT condenses L-serine with palmitoyl-CoA to 3-ketodihydrosphingosine. 3-ketodihydrosphingosine reductase (KDSR, yeast Tsc10) then reduces this, using NADPH, to dihydrosphingosine (sphinganine). Ceramide synthases of the TLC/Lag1 family N-acylate the sphingoid base with a fatty acyl-CoA. Each animal isoform prefers a different acyl chain length: CERS1 makes C18 ceramide (brain/muscle), CERS2 very-long-chain C22-C24 ceramide (broadly expressed), and CERS3 ultra-long-chain C26+ (acyl)ceramides for the skin barrier. Fungal Lag1 and Lac1 act with the accessory subunit Lip1 and use C26-CoA. The sphingoid base is then modified at C4 by one of two related di-iron enzymes. The dihydroceramide desaturase DEGS1 introduces the 4,5-trans double bond, an O2- and iron-dependent oxidation that converts dihydroceramide to ceramide; this is the predominant route in animals. The sphingoid-base C4-hydroxylase (yeast Sur2) instead converts sphinganine or dihydroceramide to the phyto (4-hydroxy) form, which is the predominant route in fungi and plants. Fungal ceramides are also hydroxylated at C2 of the very long acyl chain (Scs7). Fungi then build their characteristic complex sphingolipids in the Golgi. The Aur1-Kei1 inositol phosphorylceramide (IPC) synthase transfers inositol phosphate from phosphatidylinositol to ceramide. IPC is mannosylated by Csg1/Csh1-Csg2 complexes to MIPC, and in budding yeast Ipt1 adds a second inositol phosphate to make M(IP)2C. Animals instead make sphingomyelin and glycosphingolipids, which are covered by separate modules. Inherited defects of the human ceramide core include HSAN1 (SPTLC1/SPTLC2), spastic paraplegia (SPTSSA), erythrokeratodermia/thrombocytopenia (KDSR), progressive myoclonic epilepsy 8 (CERS1), congenital ichthyosis ARCI9 (CERS3) and hypomyelinating leukodystrophy 18 (DEGS1). The fungal IPC synthase is the target of the antifungal aureobasidin A. |
Metabolic Pathway | DRAFT | Fungi |
0 | sphingolipid biosynthetic process ceramide biosynthetic process |
16 | 15 | 9 | 3 | 6 | 7 | 37/37 | 0 | ✗ | modules/sphingolipid_de_novo_synthesis.yaml | |
De novo tetrahydrofolate and folylpolyglutamate biosynthesisMODULE:tetrahydrofolate_biosynthesis De novo synthesis of tetrahydrofolate (THF) and its polyglutamylated forms, as found in bacteria, fungi, plants and many protists but absent from... [more...][less]De novo synthesis of tetrahydrofolate (THF) and its polyglutamylated forms, as found in bacteria, fungi, plants and many protists but absent from animals, which must take up preformed folate. The pathway joins two branches. In the pterin branch, GTP cyclohydrolase I opens the GTP imidazole ring to give 7,8-dihydroneopterin triphosphate; the triphosphate is removed (a Nudix-type pyrophosphatase followed by a phosphatase) to give 7,8-dihydroneopterin; dihydroneopterin aldolase releases glycolaldehyde to give 6-hydroxymethyl-7,8-dihydropterin; and 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase activates it as the diphosphate. In the p-aminobenzoate (pABA) branch, chorismate is aminated by glutamine-dependent aminodeoxychorismate synthase and 4-amino-4-deoxychorismate is cleaved by aminodeoxychorismate lyase to pABA and pyruvate. Dihydropteroate synthase condenses the pterin diphosphate with pABA to 7,8-dihydropteroate, dihydrofolate synthase adds the first L-glutamate to give 7,8-dihydrofolate, and dihydrofolate reductase reduces it with NADPH to THF. Folylpolyglutamate synthase then adds further gamma-linked glutamates, which retain folates in cells and organelles and make them preferred cofactors of folate-dependent enzymes. The reaction chain is conserved, but enzyme architecture varies: dihydroneopterin aldolase, pyrophosphokinase and dihydropteroate synthase are separate proteins in many bacteria and a single trifunctional polypeptide in fungi; aminodeoxychorismate synthase is a two-subunit PabA-PabB enzyme in many bacteria and a fused polypeptide in fungi and plants; and dihydrofolate synthase and folylpolyglutamate synthase are one bifunctional FolC protein in many bacteria but separate proteins in fungi and plants. In eukaryotes the steps are split between compartments (for example, the fungal trifunctional pterin enzyme and plant dihydrofolate synthase are mitochondrial). Chorismate supply, folate salvage and transport, and the interconversion and use of one-carbon-substituted THF are outside the module. |
Metabolic Pathway | DRAFT | 0 | tetrahydrofolate biosynthetic process tetrahydrofolylpolyglutamate biosynthetic process |
20 | 19 | 9 | 5 | 10 | 7 | 14/24 | 0 | ✗ | modules/tetrahydrofolate_biosynthesis.yaml | ||
Death receptor apoptotic signaling pathway moduleMODULE:death_receptor_apoptotic_signaling Death ligands activate death-domain receptors and FADD-containing DISC complexes, bringing initiator caspase-8 into proximity to trigger extrinsic... [more...][less]Death ligands activate death-domain receptors and FADD-containing DISC complexes, bringing initiator caspase-8 into proximity to trigger extrinsic apoptotic protease cascades, exemplified by FASLG-FAS (CD95) signaling. |
Signaling Pathway | DRAFT | metazoa |
6 | extrinsic apoptotic signaling pathway via death domain receptors Fas signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✓ | modules/death_receptor_apoptotic_signaling.yaml | |
Diadenosine tetraphosphate (Ap4A) turnoverMODULE:diadenosine_tetraphosphate_turnover A reusable metabolic module for the production and removal of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A), a dinucleoside polyphosphate that... [more...][less]A reusable metabolic module for the production and removal of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A), a dinucleoside polyphosphate that accumulates under stress and has been proposed to act as an intracellular signal. Ap4A is made as a side reaction of aminoacyl-tRNA synthetases, either by transfer of the aminoacyl-adenylate AMP to ATP (as in lysyl-tRNA synthetase) or by direct condensation of two ATP molecules (as in glycyl-tRNA synthetase). It is removed by one of three unrelated enzyme chemistries: asymmetrical Nudix hydrolases that yield ATP + AMP (animals and other eukaryotes), symmetrical ApaH-type hydrolases that yield two ADP (proteobacteria), and Ap4A phosphorylases that yield ADP + ATP by phosphorolysis (fungi). Downstream Ap4A effectors (for example HINT1 or transcription factors) and the related Ap3A/FHIT system are outside the module boundary. |
Metabolic Pathway | DRAFT | 1 | diadenosine polyphosphate metabolic process |
9 | 6 | 2 | 2 | 6 | 1 | 5/10 | 0 | ✓ | modules/diadenosine_tetraphosphate_turnover.yaml | ||
Dictyostelium DIF-1 (differentiation-inducing factor 1) biosynthesisMODULE:dicty_dif1_biosynthesis Biosynthesis of DIF-1, the chlorinated polyketide morphogen that induces prestalk/stalk cell differentiation in the social amoeba Dictyostelium... [more...][less]Biosynthesis of DIF-1, the chlorinated polyketide morphogen that induces prestalk/stalk cell differentiation in the social amoeba Dictyostelium discoideum. The pathway builds and tailors a hexanoyl-primed acylphloroglucinol in three enzymatic stages: (1) the hybrid type I/type III "steely" polyketide synthase StlB condenses a hexanoyl-CoA starter with malonyl-CoA extender units to make the acylphloroglucinol backbone THPH (1-(3,5-dihydroxy-... phloro- caprophenone); (2) the flavin-dependent halogenase ChlA chlorinates THPH, first to 3-chloro-THPH and then to 3,5-dichloro-THPH (des-methyl-DIF-1); and (3) the O-methyltransferase DmtA methylates des-methyl-DIF-1 to yield mature DIF-1. DIF-1 is then secreted and read out by the prestalk transcriptional machinery (DimA/DimB). This module is Dictyostelium-specific but phrased over enzyme functions and family selectors with D. discoideum representative members rather than a fixed gene list, so a related steely-PKS / halogenase / O-MT route in another dictyostelid could be substituted. OUT OF SCOPE: the DIF-1 RESPONSE (DimA/DimB-driven prestalk/prespore patterning; a separate module), DIF-1 dechlorination/inactivation (the DIF catabolic arm), and the additional O-methylation intermediates upstream of chlorination — only the three named, reviewed enzymes StlB, ChlA and DmtA are grounded here. |
Metabolic Pathway | DRAFT | Dictyostelium discoideum |
0 | DIF-1 biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/dicty_dif1_biosynthesis.yaml | |
Dictyostelium DIF-1 response and prestalk gene activationMODULE:dicty_dif1_response_prestalk_patterning The transcriptional response to the morphogen DIF-1 that specifies prestalk/ stalk cell fate in Dictyostelium discoideum. DIF-1 (the chlorinated... [more...][less]The transcriptional response to the morphogen DIF-1 that specifies prestalk/ stalk cell fate in Dictyostelium discoideum. DIF-1 (the chlorinated acylphloroglucinol produced by the dicty_dif1_biosynthesis module) is perceived by the basic-region leucine-zipper (bZIP) transcription factors DimA and DimB, which translocate to the nucleus and reprogram cell-type gene expression: DimA/DimB activate prestalk/stalk genes (the extracellular-matrix markers ecmA and ecmB) and repress prespore genes, so a cell exposed to DIF-1 commits to the prestalk pathway. The two bZIPs are partly redundant and heterodimerise, with DimB the principal activator of ecmB. This module is the RESPONSE arm; its input is the DIF-1 made by the separate biosynthesis module. OUT OF SCOPE: DIF-1 biosynthesis (dicty_dif1_biosynthesis module), the STATa/CudA culmination circuit (CudA is only indirectly DIF-1-linked), and DIF-1 catabolism. Phrased over transcription-factor functions and family selectors with D. discoideum representatives. |
Developmental Process | DRAFT | Dictyostelium discoideum |
0 | cellular response to differentiation-inducing factor 1 |
3 | 4 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/dicty_dif1_response_prestalk_patterning.yaml | |
Dictyostelium SDF-2 spore-encapsulation relay (AcbA-TagC-DhkA-RegA-PKA)MODULE:dicty_sdf2_encapsulation_relay The non-cell-autonomous signalling relay that triggers rapid, synchronous encapsulation of prespore cells into spores during culmination in... [more...][less]The non-cell-autonomous signalling relay that triggers rapid, synchronous encapsulation of prespore cells into spores during culmination in Dictyostelium discoideum. The acyl-CoA-binding protein AcbA is unconventionally secreted by prespore cells and cleaved at the prestalk cell surface by the ABC-transporter/ serine-protease TagC to release the peptide signal SDF-2. SDF-2 binds the membrane sensor histidine kinase DhkA and INHIBITS its phosphorelay; because DhkA (through the histidine-phosphotransfer protein RdeA) normally keeps the response-regulator cAMP phosphodiesterase RegA active, inhibiting DhkA lowers RegA activity, so intracellular cAMP rises and activates cAMP-dependent protein kinase (PKA-C released from PKA-R), which drives spore encapsulation. The net logic is a double negative — SDF-2 inhibits DhkA, DhkA activates RegA, RegA suppresses cAMP/PKA — so SDF-2 ultimately ACTIVATES encapsulation. The relay is self-amplifying (encapsulating cells release more AcbA). Phrased over functions and family selectors with D. discoideum representatives rather than a fixed gene list. OUT OF SCOPE: the parallel GABA/GrlE input that also triggers AcbA release (a separate module), the ACR/PKA culmination cAMP source, and spore-coat assembly. The histidine-phosphotransfer intermediate RdeA is described in the DhkA->RegA connection but is NOT separately grounded here because it has not yet been reviewed. |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | sporulation (spore encapsulation) triggered by SDF-2 |
6 | 7 | 5 | 0 | 0 | 4 | 7/7 | 0 | ✗ | modules/dicty_sdf2_encapsulation_relay.yaml | |
Dictyostelium cGMP chemotaxis arm (guanylyl cyclases to GbpC to myosin II)MODULE:dicty_cgmp_chemotaxis_arm The cGMP second-messenger branch that controls myosin II and the cell-rear response during chemoattractant (cAMP) chemotaxis in Dictyostelium... [more...][less]The cGMP second-messenger branch that controls myosin II and the cell-rear response during chemoattractant (cAMP) chemotaxis in Dictyostelium discoideum. On stimulation, two guanylyl cyclases — the membrane-bound GCA and the cytosolic soluble guanylyl cyclase sGC (sgcA) — produce a transient cGMP burst (the two are partly redundant; only the gca/sgc double mutant loses all cGMP). cGMP is then read out by GbpC, the large multidomain Roco-family protein that accounts for essentially all high-affinity soluble cGMP binding: cGMP binding to its cyclic-nucleotide-binding domains drives an intramolecular cascade (RasGEF -> Roc GTPase -> MAP3K-like kinase) whose output regulates myosin II heavy-chain phosphorylation and filament assembly at the cell rear, enabling retraction and polarity. Phrased over enzyme/effector functions and family selectors with D. discoideum representatives. OUT OF SCOPE: the parallel cGMP effector GbpD (a Rap1 GEF) and the Ca2+ channel IplA, the upstream chemoattractant relay (dicty_extracellular_camp_relay), and the precise in-vivo myosin-kinase substrate of GbpC (an unresolved question flagged in the gbpC review). |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | cGMP biosynthetic process |
3 | 3 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/dicty_cgmp_chemotaxis_arm.yaml | |
Dictyostelium counting-factor group-size controlMODULE:dicty_counting_factor_size_control The secreted-signal feedback system that sets the number of cells per aggregate (and hence fruiting-body size) in Dictyostelium discoideum.... [more...][less]The secreted-signal feedback system that sets the number of cells per aggregate (and hence fruiting-body size) in Dictyostelium discoideum. Aggregating cells secrete "counting factor" (CF), a large multisubunit complex whose principal component is Countin (CtnA); high CF activity decreases cell-cell adhesion and the size of cAMP-relay streams, breaking large aggregation territories into smaller groups. The cytosolic protein SmlA negatively regulates the secretion of counting factor: smlA-null cells oversecrete CF and form many small aggregates, whereas countin-null cells undersignal and form few large ones. The module is thus a two-element size rheostat — SmlA restrains CF output, CtnA is the secreted size-limiting signal. Phrased over the reviewed D. discoideum proteins. OUT OF SCOPE: the other CF subunits (CF45-1, CF50) which are not yet reviewed, and the downstream glucose/adhesion effectors of CF. |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | regulation of aggregate size involved in sorocarp development |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/dicty_counting_factor_size_control.yaml | |
Dictyostelium developmental cell-cell adhesion and tgr allorecognitionMODULE:dicty_allorecognition_adhesion The developmentally staged cell-cell adhesion systems of Dictyostelium discoideum, culminating in tgr-locus allorecognition. As starving cells... [more...][less]The developmentally staged cell-cell adhesion systems of Dictyostelium discoideum, culminating in tgr-locus allorecognition. As starving cells enter development they deploy successive adhesion molecules: (1) the Ca2+-dependent adhesion molecule ddCAD-1 (cadA), which mediates EDTA-sensitive homophilic adhesion at the loose-aggregate stage; (2) the contact-sites-A glycoprotein csA/gp80 (csaA), which mediates EDTA-resistant (Ca2+-independent) homophilic adhesion during tight aggregation; and (3) the polymorphic Tiger proteins TgrC1 (the ligand) and TgrB1 (the receptor), a heterophilic self-recognition pair required for post-aggregation adhesion and kin discrimination — cells bearing matching tgrB1/tgrC1 alleles cooperate, enabling coordinated multicellular development and excluding non-kin. This is a set of parallel, developmentally ordered adhesion systems rather than a linear pathway, so it is modelled as staged PRECEDES steps. OUT OF SCOPE: the intracellular actin cytoskeleton coupling of adhesion, and the other ~12 tgr paralogs at the tgr locus (only the reviewed tgrB1/tgrC1 pair is grounded). Note tgrC1 = lagC/gp150. |
Developmental Process | DRAFT | Dictyostelium discoideum |
0 | aggregation involved in sorocarp development |
4 | 4 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/dicty_allorecognition_adhesion.yaml | |
Dictyostelium extracellular cAMP relay / aggregation oscillatorMODULE:dicty_extracellular_camp_relay The defining Dictyostelium discoideum aggregation system — a self-organising extracellular cAMP oscillator that propagates chemotactic waves so... [more...][less]The defining Dictyostelium discoideum aggregation system — a self-organising extracellular cAMP oscillator that propagates chemotactic waves so that starving amoebae stream together into a mound. Secreted cAMP is detected by the seven-transmembrane receptor cAR1 (carA), which couples through the heterotrimeric G protein Galpha2 (gpaB); receptor activation recruits the PH-domain adaptor CRAC (dagA) that is required to activate the aggregation adenylyl cyclase ACA (acaA), which synthesises cAMP. The newly made cAMP is secreted and activates cAR1 on neighbouring cells (the RELAY, a positive feedback), while the extracellular phosphodiesterase PdsA degrades secreted cAMP and the intracellular response-regulator phosphodiesterase RegA degrades internal cAMP — the negative feedback / adaptation that lets the system oscillate and produce propagating waves rather than saturate. This is the extracellular-cAMP CHEMOTACTIC oscillator, distinct from the generic intracellular GPCR->cAMP->PKA cassette. OUT OF SCOPE: the downstream PKA-driven developmental gene expression (cAMP effector; see the pkaC review and the SDF-2 relay module), the actin/PI3K chemotaxis motor, and the later adenylyl cyclases ACG/ACR. Phrased over functions and family selectors with D. discoideum representatives. |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | aggregation involved in sorocarp development |
4 | 6 | 3 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/dicty_extracellular_camp_relay.yaml | |
Dictyostelium starvation / growth-to-development initiationMODULE:dicty_starvation_initiation The switch that commits starving Dictyostelium discoideum cells to development. Two inputs converge. (1) Density sensing: growing and... [more...][less]The switch that commits starving Dictyostelium discoideum cells to development. Two inputs converge. (1) Density sensing: growing and early-starving cells secrete conditioned-medium factor (CMF, cmfA); only when CMF accumulates above a threshold (i.e. enough cells are present) can cells respond to cAMP pulses and aggregate, coupling cell density to developmental onset. (2) The growth-to-development kinase: on starvation the DYRK-family dual-specificity kinase YakA arrests the cell cycle and drives developmental initiation, in part by down-regulating the Pumilio-family translational repressor PufA; PufA normally binds the pkaC (PKA catalytic subunit) mRNA and represses its translation, so relieving PufA de-represses PKA-C, and rising PKA activity turns on early developmental gene expression and the cAMP-signalling machinery. The net YakA -| PufA -| pkaC logic is a double negative — YakA activates PKA. OUT OF SCOPE: the downstream cAMP relay (dicty_extracellular_camp_relay) and PKA's many later developmental roles; the CMF receptor CMFR1 (not yet reviewed). Phrased over functions and family selectors with D. discoideum representatives. |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | aggregation involved in sorocarp development |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/dicty_starvation_initiation.yaml | |
Diphthamide biosynthesis on translation elongation factor 2MODULE:diphthamide_biosynthesisABSTRACT Diphthamide is a post-translationally modified histidine residue found only on archaeal and eukaryotic translation elongation factor 2 (EF2), at... [more...][less]Diphthamide is a post-translationally modified histidine residue found only on archaeal and eukaryotic translation elongation factor 2 (EF2), at the tip of domain IV. It is the target of diphtheria toxin and Pseudomonas exotoxin A, which ADP-ribosylate it and so inactivate EF2. The modification is built on the folded EF2 protein in the cytosol in four enzymatic steps. First, a [4Fe-4S]-cluster enzyme cleaves S-adenosyl-L-methionine at the methionine C(gamma)-S bond, unlike canonical radical-SAM enzymes, and transfers the 3-amino-3-carboxypropyl (ACP) group to C2 of the histidine imidazole ring. In archaea this enzyme is a Dph2 homodimer; in eukaryotes it is a Dph1-Dph2 heterodimer that also needs the CSL-zinc-finger protein Dph3, which reduces its iron-sulfur clusters, and the J-domain protein Dph4. Second, the SAM-dependent methyltransferase Dph5 trimethylates the amino group and methylates the carboxylate, giving diphthine methyl ester. Third, the WD40-repeat methylesterase Dph7 hydrolyses the ester to diphthine. Fourth, the ATP-binding diphthine-ammonia ligase Dph6 amidates the carboxylate with ammonium to form diphthamide. Diphthamide is not essential in yeast, but its loss reduces translational fidelity (more -1 ribosomal frameshifting) and confers resistance to diphtheria toxin and the antifungal sordarin. |
Biological Process | DRAFT | Archaea Eukaryota |
0 | protein histidyl modification to diphthamide |
7 | 7 | 4 | 1 | 2 | 3 | 9/15 | 0 | ✗ | modules/diphthamide_biosynthesis.yaml | |
Distal L-leucine catabolismMODULE:leucine_catabolism A reusable four-position pathway that converts leucine-derived 3-methylbutanoyl-CoA (isovaleryl-CoA) to acetoacetate and acetyl-CoA. The pathway... [more...][less]A reusable four-position pathway that converts leucine-derived 3-methylbutanoyl-CoA (isovaleryl-CoA) to acetoacetate and acetyl-CoA. The pathway comprises acyl-CoA dehydrogenation, biotin-dependent carboxylation, methylglutaconyl-CoA hydration, and HMG-CoA cleavage. It separates reaction roles from lineage-specific enzyme families and cellular locations. Upstream leucine transamination and branched-chain 2-oxoacid dehydrogenation are outside the module; the terminal HMG-CoA lyase reaction can also serve other HMG-CoA-generating pathways. |
Metabolic Pathway | DRAFT | 0 | L-leucine catabolic process |
7 | 6 | 4 | 1 | 2 | 3 | 10/10 | 0 | ✗ | modules/leucine_catabolism.yaml | ||
Dolichol / dolichyl-phosphate biosynthesis (cis-PT -> DHRSX -> SRD5A3 -> DHRSX -> DOLK)MODULE:dolichyl_phosphate_biosynthesis Dolichyl phosphate (Dol-P) is the essential polyprenol lipid carrier on which the eukaryotic glycosylation machinery assembles and delivers... [more...][less]Dolichyl phosphate (Dol-P) is the essential polyprenol lipid carrier on which the eukaryotic glycosylation machinery assembles and delivers glycans: it anchors the lipid-linked oligosaccharide for N-linked glycosylation, the mannose/glucose donors (Dol-P-Man, Dol-P-Glc) for N-glycan, O-mannose, GPI-anchor and C/O-mannosylation, and it is regenerated after each transfer cycle. Its biosynthesis begins where the isoprenoid-diphosphate trunk ends: the ER-membrane cis-prenyltransferase (cis-PT) complex — catalytic subunit DHDDS plus the non-catalytic partner NUS1 (NgBR) — elongates (2E,6E)-farnesyl diphosphate (FPP) by many cis (Z)-condensations of isopentenyl diphosphate (IPP) to the long-chain dehydrodolichyl diphosphate (dehydro-Dol-PP). This polyprenyl diphosphate is dephosphorylated to polyprenol by a phosphatase that has not been identified in humans. Polyprenol is then converted to dolichol by a three-step detour rather than by a single reduction. DHRSX oxidizes polyprenol to polyprenal (NAD+), SRD5A3 reduces the alpha-isoprene double bond of polyprenal to give dolichal (NADPH), and DHRSX reduces dolichal to dolichol (NADPH). Dolichol kinase DOLK then phosphorylates dolichol (CTP-dependent) to Dol-P, completing the carrier pool. The dolichyl-diphosphate phosphatase DOLPP1 regenerates Dol-P from the Dol-PP released after oligosaccharyltransferase moves the glycan onto protein. The cis-PT subunits, SRD5A3, DOLK and DOLPP1 are endoplasmic reticulum membrane proteins, whereas DHRSX has been localized to lipid droplets. Defects across this module cause congenital disorders of glycosylation (DHDDS-CDG/RP59, NUS1-CDG/epileptic encephalopathy, DHRSX-CDG, SRD5A3-CDG, DOLK-CDG) and inherited retinal dystrophy. |
Metabolic Pathway | DRAFT | 0 | dolichyl monophosphate biosynthetic process polyprenol biosynthetic process dolichol-linked oligosaccharide biosynthetic process |
7 | 7 | 6 | 0 | 0 | 4 | 5/6 | 0 | ✗ | modules/dolichyl_phosphate_biosynthesis.yaml | ||
Dolichol phosphate and lipid-linked sugar-donor supply for glycosylationMODULE:dolichol_phosphate_sugar_donor_supply Assembly of the dolichol-linked oligosaccharide (and of GPI anchors and protein O- and C-mannosylation) depends on a dolichyl-phosphate (Dol-P)... [more...][less]Assembly of the dolichol-linked oligosaccharide (and of GPI anchors and protein O- and C-mannosylation) depends on a dolichyl-phosphate (Dol-P) lipid carrier, on the cytosolic nucleotide sugars GDP-mannose and UDP-glucose, and on two lipid-linked monosaccharide donors made from them, dolichyl-phosphate-mannose (Dol-P-Man) and dolichyl-phosphate-glucose (Dol-P-Glc). GDP-mannose is made in the cytosol from fructose 6-phosphate by mannose-6-phosphate isomerase, phosphomannomutase and GDP-mannose pyrophosphorylase; UDP-glucose is made from glucose 6-phosphate by phosphoglucomutase and UDP-glucose pyrophosphorylase. Dol-P is made at the endoplasmic-reticulum membrane by a three-step detour from polyprenol: an SDR-family polyprenol dehydrogenase oxidises polyprenol to polyprenal, the steroid-5-alpha-reductase-like polyprenal reductase saturates the alpha-isoprene unit to give dolichal, and the same SDR enzyme reduces dolichal to dolichol, which dolichol kinase phosphorylates with CTP. Dol-P is then charged with mannose from GDP-mannose by Dol-P-Man synthase and with glucose from UDP-glucose by Dol-P-Glc synthase (ALG5). Dol-P-Man synthase exists in two architectures: a single-subunit enzyme with its own C-terminal membrane anchor (budding yeast, Ustilago, trypanosomes) and a soluble catalytic subunit held at the membrane by two small accessory subunits (animals, fission yeast). In mammals a utilisation factor (MPDU1/Lec35) is additionally required for lumenal use of both lipid-linked donors. |
Metabolic Pathway | DRAFT | eukaryotes |
0 | dolichol-linked oligosaccharide biosynthetic process dolichyl monophosphate biosynthetic process GDP-mannose biosynthetic process dolichol phosphate mannose biosynthetic process |
18 | 15 | 15 | 1 | 2 | 12 | 32/35 | 0 | ✗ | modules/dolichol_phosphate_sugar_donor_supply.yaml | |
Dopamine receptor signaling — D1-like Golf/Gs and D2-like Gi/o control of adenylyl cyclase, the cAMP/PKA/DARPP-32/PP1 switch, and GRK/arrestin/RGS termination in striatal neuronsMODULE:dopamine_receptor_signalingCONCRETE Dopamine signals through five G protein-coupled receptors split into two classes with opposite effects on adenylyl cyclase. The D1-like receptors... [more...][less]Dopamine signals through five G protein-coupled receptors split into two classes with opposite effects on adenylyl cyclase. The D1-like receptors (DRD1 and DRD5) couple through the stimulatory G alpha subunits — in the striatum chiefly the Golf variant GNAL rather than ubiquitous Gs — to activate adenylyl cyclase type 5 (ADCY5), raising cAMP and activating cAMP-dependent protein kinase (PKA). The D2-like receptors (DRD2, DRD3 and DRD4) couple through the inhibitory G alpha subunits GNAI2 and GNAO1 to inhibit ADCY5 and lower cAMP. The signal converges on a single bistable integrator, the phosphoprotein DARPP-32 (PPP1R1B). When PKA phosphorylates DARPP-32 at threonine 34 it becomes a potent inhibitor of protein phosphatase 1 (PP1, the PPP1CA/PPP1CB/PPP1CC catalytic subunits), amplifying phosphorylation of PP1 substrates downstream of D1 signalling. The switch is governed by a network of kinases and phosphatases acting on distinct residues: CDK5 phosphorylates threonine 75, converting DARPP-32 into a competitive inhibitor of PKA; a PKA-activated PP2A holoenzyme with the B56-delta regulatory subunit (PPP2R5D) and a Ca2+-activated PP2A holoenzyme with the PR72 subunit (PPP2R3A) dephosphorylate threonine 75; the Ca2+/calmodulin phosphatase calcineurin (PPP3CA/PPP3CB/PPP3CC) dephosphorylates threonine 34; and casein kinase 1 (CSNK1A1) phosphorylates serine 137 to protect phospho-threonine 34 from calcineurin. Receptor output is terminated by G protein-coupled receptor kinases (GRK2, GRK3, GRK5, GRK6), which phosphorylate agonist-occupied receptors so that beta-arrestins (ARRB1, ARRB2) uncouple them from G proteins and drive internalisation, and by regulators of G protein signalling, most prominently the striatal RGS9-2/G-beta-5/R7BP GAP complex (RGS9, GNB5, RGS7BP) that accelerates GTP hydrolysis on the D2-coupled G alpha subunits. Dopamine signalling also reaches the ERK cascade through DARPP-32-dependent control of the striatal tyrosine phosphatase STEP (PTPN5), and D2 receptors engage a G protein-independent arrestin arm in which ARRB2 scaffolds PP2A onto AKT. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | G protein-coupled dopamine receptor signaling pathway |
18 | 26 | 9 | 3 | 8 | 10 | 15/40 | 0 | ✗ | modules/dopamine_receptor_signaling.yaml | |
Dph1-Dph2 diphthamide synthesis complex in Drosophila melanogasterMODULE:dmel_diphthamide_dph1_dph2_complexCONCRETE Diphthamide is a modified histidine residue on translation elongation factor 2 (eEF2) that is required for accurate translation and is the target... [more...][less]Diphthamide is a modified histidine residue on translation elongation factor 2 (eEF2) that is required for accurate translation and is the target of diphtheria toxin. Its first step, transfer of a 3-amino-3-carboxypropyl group from S-adenosylmethionine to the histidine of eEF2, is catalysed by a heterodimer of the iron-sulfur radical SAM-like enzymes Dph1 and Dph2. Later steps are performed by Dph3, Dph4, Dph5, Dph6 and Dph7, which are not part of this complex. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | 2-(3-amino-3-carboxypropyl)histidine synthase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_diphthamide_dph1_dph2_complex.yaml | |
Dystrophin glycoprotein complex in Drosophila melanogasterMODULE:dmel_dystrophin_glycoprotein_complexCONCRETE The dystrophin glycoprotein complex (DGC) links the actin cytoskeleton to the extracellular matrix across the plasma membrane, mainly in muscle.... [more...][less]The dystrophin glycoprotein complex (DGC) links the actin cytoskeleton to the extracellular matrix across the plasma membrane, mainly in muscle. Dystroglycan (Dg) spans the membrane: its extracellular part binds laminin and other matrix proteins and its cytoplasmic tail binds dystrophin, which in turn binds actin. Sarcoglycans form a transmembrane subcomplex that stabilizes the link, and the cytoplasmic adaptors dystrobrevin and syntrophins bind dystrophin and recruit signaling proteins. Drosophila has single dystrophin (Dys) and dystroglycan genes, one dystrobrevin, three sarcoglycans and two syntrophin-like genes. Loss of Dys or Dg causes age-dependent muscle degeneration, and Dg also acts in epithelial polarity and in the oocyte. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | dystrophin-associated glycoprotein complex |
5 | 6 | 4 | 0 | 0 | 1 | 0/8 | 0 | ✗ | modules/dmel_dystrophin_glycoprotein_complex.yaml | |
E. coli HdeA/HdeB periplasmic acid-stress holdasesMODULE:enterobacterial_acid_stress_holdasesCONCRETE A periplasmic acid-stress module in which the ATP-independent chaperones HdeA and HdeB bind acid-unfolding client proteins, suppress irreversible... [more...][less]A periplasmic acid-stress module in which the ATP-independent chaperones HdeA and HdeB bind acid-unfolding client proteins, suppress irreversible aggregation, and preserve them for refolding after neutralization. HdeA is activated under extreme acid through dimer dissociation and disordering, whereas HdeB acts at milder acidic pH through a distinct dynamic folded-dimer mechanism. HdeB also supports client refolding after neutralization, but the direct release step has not yet been separated from potential downstream folding factors. Acid-sensing transcriptional regulation, cytoplasmic pH homeostasis, HdeB-specific post-neutralization handoff, and the post-neutralization cooperation of DegP and SurA are outside this focused in-situ holdase module. |
Biological Process | DRAFT | Escherichia coli K-12 |
0 | cellular stress response to acidic pH protein stabilization |
4 | 3 | 3 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/enterobacterial_acid_stress_holdases.yaml | |
E. coli ManXYZ mannose-family PTSMODULE:bacterial_mannose_ptsCONCRETE A bacterial phosphoenolpyruvate-dependent group-translocation module in which the soluble/peripheral ManX EIIAB subunit relays phosphate from HPr... [more...][less]A bacterial phosphoenolpyruvate-dependent group-translocation module in which the soluble/peripheral ManX EIIAB subunit relays phosphate from HPr through its EIIA and EIIB histidines to sugar entering through the inner-membrane ManY/ManZ channel. ManY and ManZ form the EIIC/EIID membrane translocation subcomplex, while all three subunits are required for efficient transport and concomitant phosphorylation of mannose-family substrates. Upstream enzyme I and HPr, dedicated fructose PTS systems, nitrogen-regulatory PTS signaling, sugar chemotaxis, and bacteriophage lambda DNA penetration are neighboring processes outside this transport module. |
Transport Step | DRAFT | Escherichia coli |
0 | phosphoenolpyruvate-dependent sugar phosphotransferase system mannose transmembrane transport |
3 | 2 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/bacterial_mannose_pts.yaml | |
E. coli periplasmic organophosphate scavengingMODULE:bacterial_periplasmic_phosphate_scavengingCONCRETE A phosphate-starvation effector module in which E. coli periplasmic phosphatases liberate inorganic phosphate from extracellular-facing... [more...][less]A phosphate-starvation effector module in which E. coli periplasmic phosphatases liberate inorganic phosphate from extracellular-facing organophosphate substrates. PhoA hydrolyzes phosphate monoesters through its alkaline phosphatase activity, while AppA contributes a phytase/acid phosphatase branch under phosphate limitation. Sec export, PhoB/PhoR transcriptional induction, and Pst phosphate import are adjacent processes outside this mature periplasmic scavenging boundary. |
Biological Process | COMPLETE | Escherichia coli K-12 |
0 | dephosphorylation |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/bacterial_periplasmic_phosphate_scavenging.yaml | |
EF-P translation stall rescueMODULE:efp_translation_stall_rescueCONCRETE Species-neutral bacterial module for elongation factor P-dependent rescue of cytosolic ribosomes that stall while translating consecutive proline... [more...][less]Species-neutral bacterial module for elongation factor P-dependent rescue of cytosolic ribosomes that stall while translating consecutive proline residues. EF-P is universal in bacteria and is the ortholog of archaeal aIF5A and eukaryotic eIF5A, whose hypusine-activated stall rescue is the same biology in another domain of life and is modelled separately. The module has three roles: lineage-specific activation of EF-P by post-translational modification of its loop-1 tip residue, engagement of the stalled ribosome, and stimulation of peptide-bond formation so elongation resumes. The activating chemistry differs by lineage and is modelled as a variant set over three characterized routes: EpmA/EpmB/EpmC (R)-beta-lysylation and hydroxylation of Lys34 in Escherichia coli and Salmonella, EarP rhamnosylation of Arg32 in Pseudomonas and Shewanella, and 5-aminopentanolylation of Lys32 in Bacillus subtilis. |
Biological Process | COMPLETE | Bacteria |
1 | rescue of stalled cytosolic ribosome translational elongation |
7 | 7 | 3 | 1 | 3 | 2 | 8/8 | 0 | ✓ | modules/efp_translation_stall_rescue.yaml | |
EGFR signaling pathway in Drosophila melanogasterMODULE:dmel_egfr_signalingCONCRETE Drosophila has a single EGF receptor (Egfr), a receptor tyrosine kinase activated by the TGF-alpha-like ligands Spitz, Keren and Gurken and the... [more...][less]Drosophila has a single EGF receptor (Egfr), a receptor tyrosine kinase activated by the TGF-alpha-like ligands Spitz, Keren and Gurken and the neuregulin-like ligand Vein. Spitz, Keren and Gurken are made as inactive membrane-bound precursors; the chaperone Star carries them from the endoplasmic reticulum to the Golgi, where rhomboid intramembrane proteases cleave them to release the secreted ligand. Ligand-bound Egfr recruits the adaptor Drk (Grb2) and the guanine nucleotide exchange factor Son of sevenless, which activates Ras85D. Ras triggers the Raf, Dsor1 (MEK) and Rolled (ERK) kinase cascade, assisted by the scaffolds KSR, CNK and Aveugle. ERK changes nuclear gene expression by activating the ETS factor Pointed and promoting the degradation or export of the repressors Yan (Aop) and Capicua. The pathway acts in oogenesis axis formation, photoreceptor recruitment, wing vein formation, and cell survival and proliferation in many tissues. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | epidermal growth factor receptor signaling pathway |
8 | 31 | 7 | 0 | 0 | 6 | 10/31 | 0 | ✗ | modules/dmel_egfr_signaling.yaml | |
EGFR signaling pathway moduleMODULE:egfr_signaling Bilaterian EGFR signaling couples an EGF-family ligand to an EGFR/ERBB-family receptor tyrosine kinase, creates phosphotyrosine docking sites for... [more...][less]Bilaterian EGFR signaling couples an EGF-family ligand to an EGFR/ERBB-family receptor tyrosine kinase, creates phosphotyrosine docking sites for GRB2/drk/Sem-5 adaptors and SOS Ras GEFs, and routes the signal through Ras-RAF-MEK-ERK. The conserved invertebrate and vertebrate core is represented with fly and worm variants, while vertebrate ERBB heterodimer and PI3K branches are kept as optional extensions. |
Signaling Pathway | DRAFT | bilaterians C. elegans Drosophila melanogaster human vertebrates |
4 | epidermal growth factor receptor signaling pathway |
18 | 16 | 14 | 1 | 3 | 10 | 26/26 | 0 | ✓ | modules/egfr_signaling.yaml | |
ER membrane protein complex (EMC) in Drosophila melanogasterMODULE:dmel_er_membrane_protein_complexCONCRETE The ER membrane protein complex (EMC) is a multisubunit membrane protein insertase in the endoplasmic reticulum. It inserts tail-anchored proteins... [more...][less]The ER membrane protein complex (EMC) is a multisubunit membrane protein insertase in the endoplasmic reticulum. It inserts tail-anchored proteins with moderately hydrophobic transmembrane segments and the first transmembrane segment of many multipass membrane proteins in the N-terminus out orientation, and it supports biogenesis of other multipass proteins. The conserved hydrophilic vestibule formed by EMC3 and EMC6 in the membrane carries out insertion, while the cytosolic EMC2 and EMC8/9 and the large lumenal EMC1, EMC7 and EMC10 subunits shape the complex. In Drosophila the EMC is required in photoreceptors for the biogenesis of rhodopsin and other multipass membrane proteins. Drosophila has two EMC2 paralogs, EMC2A and EMC2B, which FlyBase treats as alternative subunits. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | EMC complex |
5 | 3 | 2 | 1 | 2 | 0 | 0/10 | 0 | ✗ | modules/dmel_er_membrane_protein_complex.yaml | |
ERBB2 signaling pathway moduleMODULE:erbb2_signaling ERBB2/HER2 acts as a ligandless preferred dimerization partner for ERBB receptors, especially ERBB3 after neuregulin binding, producing potent... [more...][less]ERBB2/HER2 acts as a ligandless preferred dimerization partner for ERBB receptors, especially ERBB3 after neuregulin binding, producing potent PI3K-AKT and MAPK output. |
Signaling Pathway | DRAFT | metazoa |
5 | ERBB2 signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 3/5 | 0 | ✓ | modules/erbb2_signaling.yaml | |
ERK1/2 (Ras-RAF-MEK-ERK) MAPK cascade moduleMODULE:erk_cascade A taxon-neutral decomposition of the canonical Ras-RAF-MEK-ERK mitogen-activated protein kinase cascade, the concrete ERK1/2 realization of the... [more...][less]A taxon-neutral decomposition of the canonical Ras-RAF-MEK-ERK mitogen-activated protein kinase cascade, the concrete ERK1/2 realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). The cascade converts receptor-proximal tyrosine-phosphorylation events into ERK1/ERK2 activity and a proliferative/differentiation transcriptional program, and is deployed downstream of many distinct receptor systems: receptor tyrosine kinases (EGFR, FGFR, PDGFR, insulin/IGF), cytokine receptors signaling through JAKs, G-protein-coupled receptors, and integrins. The module captures six parts, numbered as in `parts`: (1) recruitment of SH2/SH3 adaptors (GRB2, SHC) to a receptor phosphotyrosine, with GRB2-mediated recruitment of the Ras guanine nucleotide exchange factor SOS; (2) the Ras nucleotide switch (SOS GEF -> Ras GTPase -> RasGAP), declared as an inner bundle that `conforms_to` gtpase_switch; (3) the conforming ERK kinase relay - Ras-driven RAF(MAP3K) -> MEK1/2(MAP2K) -> ERK1/2(MAPK) on the TEY motif - declared as an inner bundle that `conforms_to` mapk_relay; (4) ERK action on nuclear (ELK1/Ets, RSK, MSK) and cytoplasmic substrates to drive transcription, proliferation, and differentiation; (5) DUSP/MKP negative feedback on ERK; and (6) optional Sprouty/SPRED feedback inhibition at the SOS-Ras-RAF level. Grounded in GO:0000165 (MAPK cascade) / GO:0070371 (ERK1 and ERK2 cascade). |
Signaling Pathway | DRAFT | metazoa |
7 | MAPK cascade ERK1 and ERK2 cascade |
16 | 13 | 12 | 1 | 3 | 15 | 18/20 | 1 | ✗ | Boolean | modules/erk_cascade.yaml |
ERK5 (MEKK2/3-MEK5-ERK5) MAPK cascade moduleMODULE:erk5_cascade A taxon-neutral decomposition of the ERK5 (big MAP kinase 1, BMK1) cascade, the MEF2-driven concrete realization of the generic three-tier MAP... [more...][less]A taxon-neutral decomposition of the ERK5 (big MAP kinase 1, BMK1) cascade, the MEF2-driven concrete realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Growth factors, and oxidative and osmotic stress, signal through the MAP3Ks MEKK2 (MAP3K2) and MEKK3 (MAP3K3) to the dedicated dual-specificity MAP2K MEK5 (MAP2K5), which dually phosphorylates the MAPK ERK5 (MAPK7) on its TEY activation-loop motif. ERK5 is distinctive in carrying a large C-terminal transcriptional-activation domain in addition to its kinase domain, and its principal output is activation of MEF2-family transcription factors controlling proliferation, survival, and endothelial/cardiovascular development. The kinase relay - MEKK2/3 -> MEK5 -> ERK5 - is declared as an inner bundle that `conforms_to` mapk_relay, while the upstream input and the ERK5/MEF2 output are this cascade's free extensions around the conforming core. Grounded in GO:0070375 (ERK5 cascade). |
Signaling Pathway | DRAFT | 1 | ERK5 cascade |
7 | 5 | 6 | 0 | 0 | 4 | 4/4 | 2 | ✗ | modules/erk5_cascade.yaml | ||
ESCRT machinery in Drosophila melanogasterMODULE:dmel_escrt_machineryCONCRETE The endosomal sorting complexes required for transport (ESCRTs) sort ubiquitylated membrane proteins into intralumenal vesicles of multivesicular... [more...][less]The endosomal sorting complexes required for transport (ESCRTs) sort ubiquitylated membrane proteins into intralumenal vesicles of multivesicular bodies and drive membrane scission that buds away from the cytoplasm. ESCRT-0 (Hrs, Stam) binds ubiquitylated cargo on endosomes; ESCRT-I and ESCRT-II bind cargo and membrane and nucleate ESCRT-III, whose subunits polymerize into spirals that constrict the bud neck. The AAA ATPase Vps4, with its cofactor Vta1, disassembles ESCRT-III and recycles it. The same ESCRT-III and Vps4 machinery acts in cytokinetic abscission, nuclear envelope sealing and membrane repair. In Drosophila, loss of ESCRT function causes accumulation of signalling receptors such as Notch on endosomes and neoplastic overgrowth in epithelia. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | endosome transport via multivesicular body sorting pathway |
8 | 6 | 5 | 1 | 2 | 4 | 0/20 | 0 | ✗ | modules/dmel_escrt_machinery.yaml | |
ESCRT-III and Vps4 intralumenal vesicle formationMODULE:escrt_iii_intralumenal_vesicle_formationCONCRETE Multivesicular endosomes form when patches of the limiting endosomal membrane, loaded with ubiquitinated cargo, bud into the lumen and are cut off... [more...][less]Multivesicular endosomes form when patches of the limiting endosomal membrane, loaded with ubiquitinated cargo, bud into the lumen and are cut off as intralumenal vesicles, which the lysosome or lytic vacuole later degrades. The scission is done by ESCRT-III: Vps20/CHMP6 nucleates spirals of Snf7/CHMP4, Vps24/CHMP3 and Vps2/CHMP2 cap them, and the Vps4 AAA ATPase remodels and disassembles the polymer. This module is the eukaryote-wide ESCRT-III core, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
4 | intralumenal vesicle formation multivesicular body assembly |
3 | 4 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/escrt_iii_intralumenal_vesicle_formation.yaml | |
Early metazoan development moduleMODULE:early_metazoan_development A top-level developmental module that organises the conserved early events of animal (metazoan) embryogenesis into an ordered set of sub-programs,... [more...][less]A top-level developmental module that organises the conserved early events of animal (metazoan) embryogenesis into an ordered set of sub-programs, from the fertilised egg to a patterned, three-germ-layer embryo with a segregated germline. The trunk is a temporal sequence of four sub-programs, each detailed in its own dedicated module document: (1) the maternal-to-zygotic transition, which hands control from maternal factors to the embryo's own genome; (2) body axis specification, which converts graded morphogens into the AP, DV, and LR body axes; (3) germ layer specification during gastrulation, which partitions the embryo into endoderm, mesoderm, and ectoderm; and (4) primordial germ cell specification, which sets aside the gamete lineage. All four are wired by a small, deeply conserved "developmental toolkit" of signalling pathways - Wnt, TGF-beta/Nodal/BMP, Hedgehog, Notch, and RTK/FGF - captured here as a cross-cutting variant set that points to the existing signalling module documents. Grounded in GO:0009790 (embryo development). |
Developmental Process | DRAFT | metazoa |
0 | embryo development |
11 | 4 | 4 | 1 | 6 | 3 | 1/4 | 6 | ✗ | modules/early_metazoan_development.yaml | |
Efferocytosis-induced anti-inflammatory programmeMODULE:efferocytosis_induced_anti_inflammatory_programmeABSTRACT A macrophage that has engulfed apoptotic cells suppresses inflammation and makes pro-resolving signals such as IL-10, TGF-beta1 and prostaglandin... [more...][less]A macrophage that has engulfed apoptotic cells suppresses inflammation and makes pro-resolving signals such as IL-10, TGF-beta1 and prostaglandin E2. Several parallel routes read components of the digested cell: sterols activate the liver X receptors, lipids activate PPAR-delta, fatty acids fuel mitochondrial oxidation that raises NAD+ and activates SIRT1 and PBX1, tryptophan feeds IDO1 and the aryl hydrocarbon receptor, DNA signals through TLR9 to the same receptor, and methionine supplies the methyl groups DNMT3A uses to keep ERK signalling on. Chloride sensing through SLC12A2 decides whether the corpse is read as anti-inflammatory. Each route has cargo-specificity controls: engulfing beads, necrotic cells or cargo-free phosphatidylserine beads does not trigger it. |
Signaling Pathway | DRAFT | Mammalia |
0 | negative regulation of inflammatory response |
9 | 18 | 2 | 1 | 6 | 11 | 7/34 | 0 | ✗ | modules/efferocytosis_induced_anti_inflammatory_programme.yaml | |
Efferocytosis-induced macrophage primingMODULE:efferocytosis_induced_macrophage_primingABSTRACT Engulfing an apoptotic cell changes how a macrophage responds to later challenges. In Drosophila embryos, each engulfed corpse triggers a brief... [more...][less]Engulfing an apoptotic cell changes how a macrophage responds to later challenges. In Drosophila embryos, each engulfed corpse triggers a brief rise in cytosolic calcium in the macrophage, which activates JNK. JNK signalling raises expression of the engulfment receptor Draper. Macrophages primed in this way migrate to wounds and take up bacteria; naive macrophages that have never met a corpse do neither. Beads of the same size are engulfed without causing the calcium rise or priming, so the trigger is the corpse itself. Priming is a switch rather than a dial: extra JNK or Draper does not make primed macrophages respond more strongly. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
1 | macrophage activation |
3 | 2 | 2 | 0 | 0 | 1 | 3/4 | 0 | ✗ | modules/efferocytosis_induced_macrophage_priming.yaml | |
Efferocytosis-induced macrophage proliferationMODULE:efferocytosis_induced_macrophage_proliferationABSTRACT After a macrophage engulfs an apoptotic cell, it can divide. Two signals converge to make it do so. Lysosomal DNase II digests the engulfed cell's... [more...][less]After a macrophage engulfs an apoptotic cell, it can divide. Two signals converge to make it do so. Lysosomal DNase II digests the engulfed cell's DNA in the phagolysosome, and the resulting oligonucleotides activate DNA-PKcs, then mTORC2 and AKT. Separately, GAS6 bound to the apoptotic cell activates the MERTK receptor tyrosine kinase and ERK1/2. Both routes raise MYC, which induces the transcription factor BHLHE40. BHLHE40 represses the anti-proliferative factor c-MAF, and the macrophage enters the cell cycle. The daughter cells keep clearing apoptotic cells, so the programme expands the pool of pro-resolving macrophages at sites of injury. |
Signaling Pathway | DRAFT | Mammalia |
4 | macrophage proliferation |
5 | 10 | 4 | 0 | 0 | 9 | 11/22 | 0 | ✗ | modules/efferocytosis_induced_macrophage_proliferation.yaml | |
Eggshell structural proteins in Drosophila melanogasterMODULE:dmel_eggshell_structural_proteinsCONCRETE The Drosophila eggshell is secreted by the somatic follicle cells that surround the oocyte during late oogenesis. The vitelline membrane, the... [more...][less]The Drosophila eggshell is secreted by the somatic follicle cells that surround the oocyte during late oogenesis. The vitelline membrane, the innermost layer, is laid down first from vitelline membrane proteins (Vm26Aa, Vm26Ab, Vm26Ac, Vm32E, Vm34Ca and Vml) that are cross-linked into an insoluble layer. The chorion is secreted afterwards and is built from chorion proteins encoded mainly by two clusters: an X-linked cluster at 7F (Cp36, Cp38 and Cp7Fa-c) and an autosomal cluster at 66D (Cp15, Cp16, Cp18 and Cp19). The chorion gene clusters are amplified in follicle cells by developmentally regulated DNA re-replication, which allows the large and rapid synthesis of chorion proteins. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | chorion-containing eggshell formation |
5 | 15 | 4 | 0 | 0 | 1 | 0/15 | 0 | ✗ | modules/dmel_eggshell_structural_proteins.yaml | |
Ehrlich pathway (amino acid catabolism to fusel alcohols and fusel acids)MODULE:ehrlich_pathwayCONCRETE Catabolic route by which yeasts and other fungi degrade the branched-chain amino acids (leucine, isoleucine, valine), the aromatic amino acids... [more...][less]Catabolic route by which yeasts and other fungi degrade the branched-chain amino acids (leucine, isoleucine, valine), the aromatic amino acids (phenylalanine, tyrosine, tryptophan) and methionine when these are used as nitrogen sources. Only the amino group is retained by the cell; the carbon skeleton is excreted. The pathway has three steps. A pyridoxal-phosphate aminotransferase first transfers the amino group to an acceptor 2-oxo acid (2-oxoglutarate for the branched-chain aminotransferases; pyruvate or phenylpyruvate for the inducible aromatic aminotransferase), giving the corresponding 2-oxo acid. A thiamine-diphosphate-dependent 2-oxo-acid decarboxylase then irreversibly converts the 2-oxo acid to an aldehyde with one carbon fewer; this is the first step specific to the pathway. Finally, depending on the redox state of the cell, the aldehyde is reduced by NADH alcohol dehydrogenases to a fusel alcohol (isoamyl alcohol, 2-methylbutanol, isobutanol, 2-phenylethanol, tyrosol, tryptophol) or oxidized by aldehyde dehydrogenases to a fusel acid. All three steps are carried out by sets of overlapping isozymes whose use depends on the amino acid, the carbon source and the growth stage. In budding yeast the aminotransferase and decarboxylase of the aromatic branch are co-induced by aromatic amino acids. Oxidative degradation of the 2-oxo acids by the mitochondrial branched-chain 2-oxo acid dehydrogenase complex, the catabolic route that dominates in animals, is outside this module. |
Metabolic Pathway | DRAFT | fungi |
0 | branched-chain amino acid catabolic process aromatic amino acid catabolic process |
10 | 13 | 3 | 3 | 6 | 2 | 15/15 | 0 | ✗ | modules/ehrlich_pathway.yaml | |
Eiger (TNF) signaling pathway in Drosophila melanogasterMODULE:dmel_eiger_tnf_signalingCONCRETE Eiger is the single Drosophila member of the tumor necrosis factor superfamily. It is a type II transmembrane protein that can be released as a... [more...][less]Eiger is the single Drosophila member of the tumor necrosis factor superfamily. It is a type II transmembrane protein that can be released as a soluble ligand by the metalloprotease Tace. Eiger binds the TNF receptors Grindelwald and Wengen, which signal through Traf proteins and the Tak1-Tab2 kinase complex to the JNK kinase kinases Hemipterous and Mkk4 and the JNK Basket. The Ste20-family kinase Misshapen acts upstream in the JNK cascade. JNK activation by Eiger induces apoptosis and cell elimination in development and tumour suppression, and also contributes to tissue growth, regeneration, pain sensitization and immune responses. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | tumor necrosis factor-mediated signaling pathway |
7 | 12 | 6 | 0 | 0 | 5 | 1/12 | 0 | ✗ | modules/dmel_eiger_tnf_signaling.yaml | |
Elba early boundary factor complex in Drosophila melanogasterMODULE:dmel_elba_boundary_complexCONCRETE Elba is a heterotrimeric chromatin boundary (insulator) factor active in the early embryo. It binds a specific DNA sequence in the Fab-7 boundary... [more...][less]Elba is a heterotrimeric chromatin boundary (insulator) factor active in the early embryo. It binds a specific DNA sequence in the Fab-7 boundary of the Bithorax complex and gives the boundary its early insulating activity. Elba1 and Elba2 are BEN-domain DNA-binding proteins, and Elba3 bridges them; Elba3 is expressed only in early embryos, which restricts the complex to that stage. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | transcription regulator complex |
4 | 4 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_elba_boundary_complex.yaml | |
Electron-transfer flavoprotein (ETF) system — electron sink for mitochondrial FAD dehydrogenasesMODULE:electron_transfer_flavoprotein_system The electron-transfer flavoprotein (ETF) system is the shared electron-relay that couples a large set of mitochondrial matrix FAD-dependent... [more...][less]The electron-transfer flavoprotein (ETF) system is the shared electron-relay that couples a large set of mitochondrial matrix FAD-dependent dehydrogenases to the respiratory chain. At least a dozen matrix flavoenzymes — the acyl-CoA dehydrogenases of fatty-acid beta-oxidation (ACADVL, ACADM, ACADS, ACAD9, etc.), the branched-chain and other acyl-CoA dehydrogenases of amino-acid catabolism (IVD, GCDH, etc.), sarcosine and dimethylglycine dehydrogenases, and others — do not pass their electrons directly to the respiratory chain. Instead they reduce a common, soluble matrix heterodimeric flavoprotein, ETF (the ETFA alpha subunit, which carries the FAD, plus the ETFB beta subunit, which carries AMP and provides the docking surface for the partner dehydrogenases). Reduced ETF then diffuses to the inner-membrane iron-sulfur flavoprotein ETF-ubiquinone oxidoreductase (ETFDH / ETF-QO), which reoxidises ETF and transfers the electrons to ubiquinone (CoQ) in the respiratory chain, linking these oxidations to oxidative phosphorylation. Because ETF/ETFDH is the common electron sink for so many dehydrogenases, its inherited deficiency (ETFA, ETFB or ETFDH) causes multiple acyl-CoA dehydrogenase deficiency (MADD / glutaric acidemia type 2), a severe fatty-acid-oxidation and amino-acid-oxidation disorder; the ETFDH form is frequently riboflavin-responsive and can present as a myopathy with secondary coenzyme-Q10 deficiency. |
Metabolic Pathway | DRAFT | 0 | respiratory electron transport chain |
3 | 3 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/electron_transfer_flavoprotein_system.yaml | ||
Elg1 RFC-like complex in Drosophila melanogasterMODULE:dmel_elg1_rfc_like_complexCONCRETE Replication factor C (RFC) is a pentameric AAA+ clamp loader made of one large subunit and four small subunits. In the Elg1 RFC-like complex the... [more...][less]Replication factor C (RFC) is a pentameric AAA+ clamp loader made of one large subunit and four small subunits. In the Elg1 RFC-like complex the large subunit Rfc1 is replaced by Elg1 (ATAD5 in mammals), while the four small RFC subunits are shared. In yeast and human cells this complex unloads the PCNA sliding clamp from DNA after Okazaki fragment ligation, and its loss raises genome instability. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Elg1 RFC-like complex |
3 | 3 | 2 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/dmel_elg1_rfc_like_complex.yaml | |
Elongator complex in Drosophila melanogasterMODULE:dmel_elongator_complexCONCRETE Elongator is a conserved six-subunit complex that modifies uridines at the wobble position (U34) of tRNAs by adding a carboxymethyl group, the... [more...][less]Elongator is a conserved six-subunit complex that modifies uridines at the wobble position (U34) of tRNAs by adding a carboxymethyl group, the first step towards mcm5U and mcm5s2U, which are needed for efficient and accurate decoding. It is formed by two subcomplexes. Elp1, Elp2 and Elp3 form the core subcomplex; Elp3 is the catalytic subunit, a radical SAM enzyme with an acetyltransferase domain, and Elp1 is the scaffold. Elp4, Elp5 and Elp6 form a hetero-hexameric RecA-like ring (two copies of each) that binds tRNA and ATP. In Drosophila, Elp3 is required for larval development and neuronal function. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | elongator holoenzyme complex |
3 | 2 | 2 | 0 | 0 | 0 | 0/6 | 0 | ✗ | modules/dmel_elongator_complex.yaml | |
Embryonic body axis specification moduleMODULE:body_axis_specification An early-metazoan patterning module in which the embryo converts spatially graded maternal and zygotic signals into the three body axes:... [more...][less]An early-metazoan patterning module in which the embryo converts spatially graded maternal and zygotic signals into the three body axes: anterior/posterior (AP), dorsal/ventral (DV), and left/right (LR). The three axes are modelled as a variant set along the "axis" dimension because they are laid down by distinct but conserved morphogen systems: a posteriorising Wnt/beta-catenin gradient (with FGF and retinoic acid) reading out AP; a BMP activity gradient antagonised by organizer-secreted BMP inhibitors (Chordin, Noggin) reading out DV; and Nodal/Lefty reaction-diffusion breaking LR symmetry. The transcriptional readouts (Brachyury/TBXT, OTX2, CDX2, Goosecoid) partition the embryo into territories that the germ-layer and organ-forming programs subsequently elaborate. Grounded in GO:0009880 (embryonic pattern specification). See modules/germ_layer_specification.yaml for the fate decisions these axes feed, and the wnt_signaling, bmp_signaling, and nodal_signaling modules for the signalling machinery. |
Developmental Process | DRAFT | metazoa |
2 | embryonic pattern specification |
4 | 9 | 0 | 1 | 3 | 7 | 2/8 | 0 | ✗ | modules/body_axis_specification.yaml | |
Endogenous protein lipoylationMODULE:endogenous_protein_lipoylation Endogenous protein lipoylation builds a lipoyl cofactor directly on conserved lysine residues in lipoyl domains. All characterized routes transfer... [more...][less]Endogenous protein lipoylation builds a lipoyl cofactor directly on conserved lysine residues in lipoyl domains. All characterized routes transfer an octanoyl group from octanoyl-acyl carrier protein to a protein carrier and use a radical-SAM lipoate synthase to insert sulfur atoms at C6 and C8. In the modeled routes, the topology varies by lineage: some organisms modify client lipoyl domains directly, whereas others use GcvH as an obligatory relay carrier and an amidotransferase to deliver the modified acyl group to client proteins. This module models the direct bacterial route, the characterized Bacillus relay, and the characterized human mitochondrial relay as alternatives. Exogenous lipoate salvage by ATP-dependent lipoate-protein ligases and the downstream lipoate-dependent enzyme complexes are outside the boundary. |
Metabolic Pathway | DRAFT | 2 | protein lipoylation |
12 | 8 | 8 | 1 | 3 | 5 | 5/10 | 0 | ✓ | modules/endogenous_protein_lipoylation.yaml | ||
Endoplasmic reticulum lifecycleMODULE:endoplasmic_reticulum_lifecycleCONCRETE The endoplasmic reticulum is never made de novo: it grows from existing membrane, is shaped into sheets and tubules, imports the proteins of the... [more...][less]The endoplasmic reticulum is never made de novo: it grows from existing membrane, is shaped into sheets and tubules, imports the proteins of the secretory pathway as they are made, folds and modifies them, removes those that fail to fold, adjusts its capacity through the unfolded protein response, and is turned over by ER-phagy. This umbrella module composes the modules for those stages by reference. Co-translational protein import and oxidative folding are required in every eukaryote; the other stages are optional because the modelled pathways are lineage-specific or are not yet written as eukaryote-wide rules. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | endoplasmic reticulum organization endoplasmic reticulum |
5 | 0 | 4 | 0 | 0 | 3 | 0/0 | 0 | ✗ | modules/endoplasmic_reticulum_lifecycle.yaml | |
Endoplasmic reticulum unfolded protein responseMODULE:er_unfolded_protein_responseCONCRETE The endoplasmic reticulum unfolded protein response (UPR-ER) matches the folding capacity of the ER to the load of client proteins entering it. In... [more...][less]The endoplasmic reticulum unfolded protein response (UPR-ER) matches the folding capacity of the ER to the load of client proteins entering it. In animals ER stress is sensed by three ER-membrane transducers. The kinase-endoribonuclease IRE1 removes a small intron from the XBP1 mRNA, and the spliced mRNA encodes the active bZIP transcription factor XBP1s, which induces chaperone, folding and ER-associated degradation genes, including the BiP gene. The eIF2alpha kinase PERK phosphorylates eIF2alpha to attenuate general translation and so reduce client load; reduced ternary complex favours translation of the uORF-containing ATF4 mRNA, and ATF4 then activates cytoprotective genes. ATF6 is an ER-membrane-anchored bZIP factor that is released by intramembrane proteolysis and enters the nucleus. The ER HSP70 BiP is both a luminal folding chaperone and a UPR target, and its binding to the luminal domains of the transducers keeps them inactive until misfolded proteins compete it away. The IRE1 arm is the ancestral eukaryotic core: budding yeast has only Ire1 and its spliced-mRNA target Hac1, an unrelated bZIP factor that plays the XBP1 role, while the PERK and ATF6 arms are animal additions. The arms are partly redundant; in C. elegans, loss of the IRE1-XBP1 arm together with PERK or ATF6 causes larval arrest, and neuronal XBP1s can activate the UPR-ER in distant tissues. |
Signaling Pathway | DRAFT | Metazoa Saccharomyces cerevisiae |
5 | endoplasmic reticulum unfolded protein response |
7 | 10 | 4 | 1 | 2 | 11 | 16/16 | 0 | ✗ | modules/er_unfolded_protein_response.yaml | |
Endothelin receptor signaling pathway moduleMODULE:endothelin_receptor_signaling The endothelin receptor signaling pathway (GO:0086100) and its canonical phospholipase C-activating branch (GO:0160135) are initiated when the... [more...][less]The endothelin receptor signaling pathway (GO:0086100) and its canonical phospholipase C-activating branch (GO:0160135) are initiated when the secreted 21-amino-acid bicyclic peptide hormones endothelin-1 (EDN1, PANTHER:PTHR13874:SF10), endothelin-2 (EDN2, PANTHER:PTHR13874:SF9), and endothelin-3 (EDN3, PANTHER:PTHR13874:SF11) bind and activate their cognate seven-transmembrane G protein-coupled receptors EDNRA (ETA, PANTHER:PTHR46099:SF2; selective for EDN1 and EDN2 over EDN3) and EDNRB (ETB, PANTHER:PTHR46099:SF3; equipotent for EDN1, EDN2, and EDN3) at the plasma membrane of vascular smooth-muscle cells, endothelial cells, neural crest derivatives, and renal/cardiac tissues. Agonist-bound EDNRA and EDNRB couple primarily to heterotrimeric Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to stimulate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) to mobilize intracellular Ca2+ and regulate vascular tone, systemic arterial blood pressure, and enteric/melanocytic neural crest development. |
Signaling Pathway | DRAFT | Euteleostomi |
1 | endothelin receptor signaling pathway phospholipase C-activating endothelin receptor signaling pathway |
3 | 7 | 2 | 0 | 0 | 1 | 3/7 | 0 | ✗ | modules/endothelin_receptor_signaling.yaml | |
Enok histone acetyltransferase complex in Drosophila melanogasterMODULE:dmel_enok_complexCONCRETE Enok (Enoki mushroom) is the Drosophila MOZ/MORF (KAT6) family MYST histone acetyltransferase. It forms a complex with the bromodomain-PHD scaffold... [more...][less]Enok (Enoki mushroom) is the Drosophila MOZ/MORF (KAT6) family MYST histone acetyltransferase. It forms a complex with the bromodomain-PHD scaffold Br140 (BRPF homolog), the ING-family protein Ing5 and Eaf6, the same subunit composition as the mammalian MOZ/MORF complexes. Enok acetylates histone H3 and was first identified through its requirement for mushroom body neuroblast proliferation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | MOZ/MORF histone acetyltransferase complex |
5 | 4 | 4 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/dmel_enok_complex.yaml | |
Enterocyte apical sterol uptake and efflux — NPC1L1 uptake opposed by ABCG5/ABCG8 exportMODULE:intestinal_sterol_absorption_and_efflux Net absorption of dietary and biliary sterols across the small intestine is set at the enterocyte brush-border membrane by two opposing transport... [more...][less]Net absorption of dietary and biliary sterols across the small intestine is set at the enterocyte brush-border membrane by two opposing transport activities. Niemann-Pick C1-like 1 (NPC1L1) binds free cholesterol through its luminal N-terminal domain and takes it up into the cell by sterol-induced, clathrin/AP2-dependent endocytosis of NPC1L1 with cholesterol-enriched membrane; NPC1L1 favours cholesterol over plant sterols and is the target of the absorption inhibitor ezetimibe. The ATP-binding cassette heterodimer ABCG5/ABCG8 exports neutral sterols, especially plant sterols such as sitosterol and part of the absorbed cholesterol, from the apical membrane back into the lumen; the same transporter on the hepatocyte canalicular membrane secretes sterols into bile. The balance of uptake and efflux limits net sterol absorption and keeps plant sterols out of the circulation. NPC1L1 loss-of-function variants lower LDL cholesterol, whereas biallelic loss of ABCG5 or ABCG8 causes sitosterolaemia, with plant-sterol accumulation and premature atherosclerosis. |
Transport Step | DRAFT | Homo sapiens |
0 | intestinal cholesterol absorption |
3 | 2 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/intestinal_sterol_absorption_and_efflux.yaml | |
Enterohepatic bile salt cycling transport relay; BSEP/ASBT/FABP6/OSTalpha-beta/NTCPMODULE:enterohepatic_bile_salt_cyclingCONCRETE Conjugated bile salts are not consumed by the digestion they enable: they are secreted into bile, act as detergents in the intestinal lumen, and... [more...][less]Conjugated bile salts are not consumed by the digestion they enable: they are secreted into bile, act as detergents in the intestinal lumen, and are then reclaimed and returned to the liver, so that the whole bile salt pool recirculates many times a day and only a small fraction is lost in faeces. The relay is carried out by a small set of membrane transporters acting in a fixed order around a closed loop, each at a defined pole of a polarised epithelium: ATP-driven export across the hepatocyte canalicular (apical) membrane into bile (BSEP/ABCB11); sodium-coupled uptake across the apical brush border of the terminal ileal enterocyte (ASBT/SLC10A2); cytosolic shuttling across the enterocyte by a soluble bile acid binding protein (FABP6); basolateral efflux into portal blood by an obligate heteromeric facilitative transporter (OSTalpha/OSTbeta, SLC51A/SLC51B); and sodium-coupled reuptake across the hepatocyte basolateral (sinusoidal) membrane (NTCP/SLC10A1), closing the cycle. The hepatic uptake step has two parallel implementations - the sodium-dependent SLC10A1 route for conjugated bile salts and the sodium-independent OATP route for unconjugated and some conjugated species - which is modelled here as a variant set. Two paralogous members of one family (PANTHER:PTHR10361) supply the two sodium-coupled steps at opposite epithelial poles, and PAINT resolves this as a sub-branch split: the apical ileal node and the basolateral hepatic node are distinct ancestral nodes within the family. Loss of any single step produces a recognisable human disorder, which is the clearest evidence that the steps are required parts rather than redundant routes. |
Metabolic Pathway | DRAFT | Mammalia |
3 | bile acid and bile salt transport bile acid metabolic process |
8 | 7 | 5 | 1 | 2 | 5 | 4/8 | 0 | ✗ | modules/enterohepatic_bile_salt_cycling.yaml | |
Entner-Doudoroff glycolysis and gluconeogenesis moduleMODULE:entner_doudoroff_and_gluconeogenesis A taxon-neutral module for bacterial hexose-phosphate central carbon metabolism in organisms that route glucose through the Entner-Doudoroff... [more...][less]A taxon-neutral module for bacterial hexose-phosphate central carbon metabolism in organisms that route glucose through the Entner-Doudoroff pathway rather than relying on a complete forward Embden-Meyerhof-Parnas glycolytic route. The module separates the upper Entner-Doudoroff branch from shared lower glycolytic reactions and from gluconeogenic bypass reactions that regenerate hexose phosphate from pyruvate, phosphoenolpyruvate, or triose phosphate precursors. |
Metabolic Pathway | DRAFT | 0 | glycolytic process via Entner-Doudoroff Pathway gluconeogenesis |
25 | 17 | 20 | 2 | 4 | 4 | 0/0 | 17 | ✓ | modules/entner_doudoroff_and_gluconeogenesis.yaml | ||
Enveloped segmented dsRNA bacteriophage (Cystoviridae) procapsid packaging, replication, and envelope morphogenesisMODULE:phage_dsrna_cystovirus_lifecycleCONCRETE A reusable module representing the intracellular assembly, sequential plus-strand RNA packaging, intra-capsid double-stranded RNA synthesis, and... [more...][less]A reusable module representing the intracellular assembly, sequential plus-strand RNA packaging, intra-capsid double-stranded RNA synthesis, and intracellular lipid envelope acquisition of enveloped trisegmented dsRNA bacteriophages (family Cystoviridae, exemplified by Pseudomonas phage phi6). Unlike DNA phages, cystoviruses never expose naked genomic dsRNA to the host cytoplasm. Instead, a dodecahedral polymerase complex (procapsid) is pre-assembled from 120 copies of major inner shell protein P1, 12 copies of the RNA-directed RNA polymerase P2, 12 hexamers of the packaging NTPase turret P4 at the five-fold vertices, and the assembly/packaging cofactor P7. The empty procapsid sequentially packages single-stranded (+)-sense precursor transcripts s+, m+, and l+ in strict order via P4 NTPase translocation, synthesizes complementary (-)-strands inside the expanded core via P2 RdRP to yield the S, M, and L dsRNA segments, and transcribes late mRNAs by semi-conservative strand displacement. The dsRNA-filled core is subsequently enclosed by the T=13 icosahedral outer shell protein P8 (forming the nucleocapsid), enveloped inside the host cytoplasm by host-derived lipid vesicles containing viral membrane proteins P9, P6, P10, and P13 through the action of the nonstructural membrane morphogenetic factor P12, decorated with the pilus-attachment spike P3 anchored to P6, and released by P5 muralytic endopeptidase and P10 holin-like membrane lysis. |
Biological Process | COMPLETE | Cystoviridae |
0 | viral genome packaging viral RNA genome replication virion assembly |
7 | 11 | 6 | 0 | 0 | 5 | 11/11 | 0 | ✗ | modules/phage_dsrna_cystovirus_lifecycle.yaml | |
Ephrin receptor signaling pathway moduleMODULE:ephrin_receptor_signaling Membrane-tethered ephrin ligands activate Eph receptor tyrosine kinases across cell-cell contacts, producing bidirectional signals that pattern... [more...][less]Membrane-tethered ephrin ligands activate Eph receptor tyrosine kinases across cell-cell contacts, producing bidirectional signals that pattern adhesion, repulsion, migration, and vascular organization. |
Signaling Pathway | DRAFT | metazoa |
7 | ephrin receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 4/7 | 0 | ✓ | modules/ephrin_receptor_signaling.yaml | |
Ergosterol biosynthesis (squalene -> lanosterol -> ergosterol)MODULE:ergosterol_biosynthesisCONCRETE Fungal sterol synthesis converts farnesyl diphosphate from the isoprenoid trunk into ergosterol, the principal sterol of fungal membranes, through... [more...][less]Fungal sterol synthesis converts farnesyl diphosphate from the isoprenoid trunk into ergosterol, the principal sterol of fungal membranes, through about twenty reactions on the endoplasmic-reticulum membrane. The first half is shared with animal cholesterol synthesis. Squalene synthase reductively joins two farnesyl diphosphates into squalene, squalene epoxidase oxidises it to 2,3-oxidosqualene, and lanosterol synthase cyclises that to lanosterol. The cytochrome P450 sterol 14alpha-demethylase (CYP51) then removes the C-14 methyl, a Delta14-reductase saturates the resulting double bond, and a C-4 demethylation complex removes both C-4 methyls in two rounds: a C-4 methylsterol oxidase oxidises the methyl to a carboxylate, a 3beta-hydroxysteroid dehydrogenase/C-4 decarboxylase releases it as CO2, and a 3-ketosteroid reductase restores the 3beta-hydroxyl. A membrane scaffold (Erg28) tethers the three C-4 demethylation enzymes, yielding zymosterol. The ergosterol-specific tail follows. A sterol C-24 methyltransferase adds the C-28 methyl group that animals lack. A C-8 sterol isomerase that is unrelated to the animal EBP isomerase moves the Delta8 bond to Delta7. A C-5 desaturase homologous to animal SC5D adds the Delta5 bond, a cytochrome P450 C-22 desaturase (CYP61) adds the side-chain Delta22 bond, and a C-24(28) reductase completes ergosterol. The P450 steps take electrons from NADPH-cytochrome P450 reductase, and the C-4 oxidase and C-5 desaturase use cytochrome b5, which can also support CYP51. The pathway is the target of the main antifungal drug classes: azoles (CYP51), allylamines such as terbinafine (squalene epoxidase) and morpholines (Delta14-reductase and C-8 isomerase). |
Metabolic Pathway | DRAFT | Fungi |
0 | ergosterol biosynthetic process |
17 | 16 | 16 | 0 | 0 | 18 | 34/34 | 0 | ✗ | modules/ergosterol_biosynthesis.yaml | |
Erythromycin A biosynthesis (Saccharopolyspora erythraea)MODULE:erythromycin_biosynthesis Representative-species module for biosynthesis of the macrolide antibiotic erythromycin A in Saccharopolyspora erythraea, encoded by the ery... [more...][less]Representative-species module for biosynthesis of the macrolide antibiotic erythromycin A in Saccharopolyspora erythraea, encoded by the ery cluster (MIBiG BGC0000055). It is grounded to the concrete S. erythraea gene set reviewed under genes/SACEN/. The module combines a modular type I polyketide synthase (DEBS) that builds the macrolactone, post-PKS cytochrome-P450 oxidations, two TDP-deoxysugar pathways feeding two glycosyltransferases, final O-methylation, and rRNA-methylation self-resistance. Companion prose/MIBiG-alignment notes are in terms/erythromycin_biosynthesis/. |
Metabolic Pathway | DRAFT | Saccharopolyspora erythraea NRRL 2338 |
0 | erythromycin biosynthetic process |
9 | 20 | 8 | 0 | 0 | 6 | 20/20 | 0 | ✓ | modules/erythromycin_biosynthesis.yaml | |
Estrogen receptor signaling pathway moduleMODULE:estrogen_receptor_signaling Estrogen receptors act as ligand-regulated nuclear receptors and signaling scaffolds, recruiting co-regulators to control chromatin, transcription,... [more...][less]Estrogen receptors act as ligand-regulated nuclear receptors and signaling scaffolds, recruiting co-regulators to control chromatin, transcription, and cell-type-specific hormone responses. |
Signaling Pathway | DRAFT | metazoa |
0 | estrogen receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 3/5 | 0 | ✓ | modules/estrogen_receptor_signaling.yaml | |
Ether lipid / plasmalogen biosynthesis (FAR1/2 -> GNPAT -> AGPS -> PexRAP -> ER assembly -> PEDS1)MODULE:ether_lipid_plasmalogen_biosynthesis Ether phospholipids, and especially the plasmalogens (1-O-alk-1'-enyl-2-acyl glycerophospholipids), are major membrane lipids - abundant in brain,... [more...][less]Ether phospholipids, and especially the plasmalogens (1-O-alk-1'-enyl-2-acyl glycerophospholipids), are major membrane lipids - abundant in brain, heart and immune cells - that serve in membrane structure, vesicular trafficking, signalling and as endogenous antioxidants. Unlike ester glycerolipids their synthesis begins in the peroxisome. Fatty acyl-CoA reductase (FAR1, the rate-limiting and plasmalogen-feedback- regulated isoform; FAR2 a paralog) reduces long-chain fatty acyl-CoA to the fatty alcohol that will form the ether-linked sn-1 chain. In parallel, glyceronephosphate O-acyltransferase (GNPAT/DHAPAT) acylates dihydroxyacetone phosphate (DHAP) to acyl-DHAP - the first committed step. Alkyldihydroxyacetone-phosphate synthase (AGPS), an FAD enzyme that forms a complex with GNPAT, then exchanges the acyl group of acyl-DHAP for the FAR-derived fatty alcohol, creating the defining O-alkyl ether bond and yielding alkyl-DHAP. After further steps (reduction to alkyl-glycerol-3-phosphate, acylation, and headgroup addition, largely at the ER) the resulting plasmanylethanolamine is converted to the vinyl-ether plasmalogen plasmenylethanolamine by the ER desaturase PEDS1 (plasmanylethanolamine desaturase, formerly TMEM189), which introduces the characteristic 1-O-alk-1'-enyl double bond. Loss-of-function across the peroxisomal steps causes rhizomelic chondrodysplasia punctata (PEX7/RCDP1, GNPAT/RCDP2, AGPS/RCDP3, FAR1/RCDP4) and related plasmalogen- deficiency disorders. |
Metabolic Pathway | DRAFT | 0 | ether lipid biosynthetic process fatty alcohol biosynthetic process glycerophospholipid biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 6/8 | 0 | ✗ | modules/ether_lipid_plasmalogen_biosynthesis.yaml | ||
Ethylene signaling (ETR/ERS receptor-CTR1-EIN2-EBF-EIN3/EIL1 module)MODULE:ethylene_signalingABSTRACT Ethylene signaling in land plants is a double-negative relay from the endoplasmic reticulum to the nucleus. Ethylene is perceived by a family of... [more...][less]Ethylene signaling in land plants is a double-negative relay from the endoplasmic reticulum to the nucleus. Ethylene is perceived by a family of ER-membrane receptors related to bacterial two-component histidine kinases (in Arabidopsis ETR1 and ERS1 of subfamily 1 and ETR2, ERS2 and EIN4 of subfamily 2), which bind the gas through a copper cofactor in their N-terminal transmembrane domain. In the absence of ethylene the receptors keep the associated Raf-like protein kinase CTR1 active; CTR1 phosphorylates the cytosolic C-terminal domain of the NRAMP-like ER membrane protein EIN2, preventing its signalling. Ethylene binding inactivates the receptors and CTR1, so EIN2 is dephosphorylated and proteolytically cleaved; the released C-terminal fragment (EIN2-CEND) moves to the nucleus and also binds the 3' UTRs of EBF1 and EBF2 mRNAs, repressing their translation in cytoplasmic P-bodies. EBF1 and EBF2 are F-box substrate adaptors of SCF E3 ubiquitin ligases that continuously target the transcription factors EIN3 and EIL1 for proteasomal degradation; their inhibition, together with ethylene-induced turnover of the EBF proteins, stabilizes EIN3/EIL1 in the nucleus. EIN3/EIL1 bind EIN3-binding sites in target promoters and activate the ethylene transcriptional cascade (e.g. ERF1), including EBF2 and receptor genes as negative feedback. Ethylene biosynthesis (ACC synthase and ACC oxidase), receptor-associated regulators such as RTE1, and downstream ERF-family transcription factors are outside this module. |
Signaling Pathway | DRAFT | land plants |
0 | ethylene-activated signaling pathway |
6 | 6 | 5 | 0 | 0 | 5 | 8/8 | 0 | ✗ | modules/ethylene_signaling.yaml | |
Eukaryotic (THI4/THI5-type) de novo thiamine diphosphate biosynthesisMODULE:eukaryotic_thiamine_biosynthesis De novo synthesis of thiamine diphosphate (ThDP), the active vitamin B1 cofactor, by the route used in fungi. The thiazole and pyrimidine halves of... [more...][less]De novo synthesis of thiamine diphosphate (ThDP), the active vitamin B1 cofactor, by the route used in fungi. The thiazole and pyrimidine halves of thiamine are made separately and then joined. Both halves are made by single-turnover ("suicide") enzymes that donate part of their own structure to the product. The thiazole synthase THI4 builds an adenylated thiazole (ADP-5-ethyl-4-methylthiazole-2-carboxylate, ADT) from NAD+ and glycine, using the sulfur of one of its own active-site cysteines, which is left as a dehydroalanine; THI4 orthologues do the same in plants. The pyrimidine synthase THI5 (NMT1 in fission yeast) makes 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMP-P) from pyridoxal 5'-phosphate and the side chain of one of its own histidine residues, in an iron-dependent reaction. ADT is converted to the thiazole phosphate by steps whose enzymes are still unknown, and HMP-P is phosphorylated to the diphosphate (HMP-PP) by HMP-P kinases of the ThiD family, which are fused to a TenA-like domain in budding yeast. The bifunctional THI6 protein joins the thiazole phosphate and HMP-PP to thiamine monophosphate; its second domain is a hydroxyethylthiazole kinase that can bring free thiazole into the pathway. Thiamine monophosphate is dephosphorylated to thiamine by a phosphatase that has not been identified, and thiamine pyrophosphokinase converts thiamine to ThDP. The enzymes are cytosolic. This route differs from the bacterial ThiC/ThiG pathway, and plants combine a THI4-type thiazole synthase with a bacterial-type ThiC pyrimidine synthase. |
Metabolic Pathway | DRAFT | fungi |
2 | thiamine biosynthetic process thiamine diphosphate biosynthetic process |
12 | 9 | 11 | 0 | 0 | 8 | 17/19 | 2 | ✗ | modules/eukaryotic_thiamine_biosynthesis.yaml | |
Eukaryotic cytosolic de novo fatty acid synthesis (type I FAS)MODULE:fatty_acid_de_novo_synthesis Cytosolic de novo fatty acid synthesis builds long-chain saturated fatty acids (mainly C16:0 and C18:0) from acetyl-CoA in eukaryotes, supplying... [more...][less]Cytosolic de novo fatty acid synthesis builds long-chain saturated fatty acids (mainly C16:0 and C18:0) from acetyl-CoA in eukaryotes, supplying membrane phospholipids, sphingolipids, storage triacylglycerol and acylated proteins. Cytosolic acetyl-CoA is supplied either by ATP-citrate lyase, which cleaves citrate exported from mitochondria (animals, plants and many fungi such as fission yeast), or, in yeasts without ATP-citrate lyase, by acetyl-CoA synthetase acting on acetate. A biotin-dependent multidomain acetyl-CoA carboxylase then carboxylates acetyl-CoA to malonyl-CoA in the committed, highly regulated step. The chain is assembled by a type I fatty acid synthase (FAS), a multifunctional megasynthase that carries all the acyl-transfer, condensation, reduction, dehydration and acyl-carrier activities on large polypeptides and iteratively adds two-carbon units from malonyl-CoA using NADPH. Two unrelated architectures carry out this step: the animal FAS is a homodimer of a single polypeptide that releases free palmitate through a thioesterase, whereas the fungal FAS is a 2.6 MDa alpha6-beta6 barrel built from two polypeptides that releases the product as acyl-CoA (mostly palmitoyl- and stearoyl-CoA) through a malonyl/palmitoyl-transferase domain. In animals an auxiliary thioesterase can release medium-chain fatty acids early. Saturated acyl-CoAs are commonly desaturated by an endoplasmic-reticulum delta-9 stearoyl-CoA desaturase to palmitoleoyl- and oleoyl-CoA. Chain extension beyond C16-C18 is carried out by the separate microsomal elongation cycle, and the mitochondrial dissociated (type II) FAS that makes the octanoyl precursor of lipoic acid is a distinct pathway. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | fatty acid biosynthetic process malonyl-CoA biosynthetic process |
10 | 7 | 5 | 2 | 4 | 4 | 15/16 | 0 | ✗ | modules/fatty_acid_de_novo_synthesis.yaml | |
Eukaryotic hexosamine biosynthesis and GlcNAc salvageMODULE:hexosamine_biosynthesisCONCRETE A reusable eukaryotic pathway that converts fructose 6-phosphate to UDP-N-acetylglucosamine through glutamine-dependent amination, acetyl-CoA-... [more...][less]A reusable eukaryotic pathway that converts fructose 6-phosphate to UDP-N-acetylglucosamine through glutamine-dependent amination, acetyl-CoA- dependent N-acetylation, phosphomutase conversion, and UTP-dependent uridylyl transfer, all catalysed by soluble cytosolic enzymes. The eukaryotic order (N-acetylation of glucosamine 6-phosphate before the 6-phosphate to 1-phosphate mutase step) differs from the bacterial route, in which glucosamine 6-phosphate is first isomerised to the 1-phosphate and then acetylated and uridylylated by a bifunctional enzyme. In animals and some other eukaryotes a GlcNAc-kinase salvage branch enters at the N-acetylglucosamine 6-phosphate intermediate. Feedback inhibition of the first, glutamine-dependent amidotransferase by UDP-GlcNAc couples pathway flux to nutrient availability and glycosylation demand. The product supplies protein N-glycosylation, GPI-anchor synthesis, chitin synthesis in fungi, proteoglycan synthesis and O-GlcNAcylation in animals, and the sialic-acid route. |
Metabolic Pathway | DRAFT | eukaryotes |
0 | UDP-N-acetylglucosamine biosynthetic process |
6 | 5 | 5 | 0 | 0 | 4 | 15/15 | 0 | ✗ | modules/hexosamine_biosynthesis.yaml | |
Eukaryotic polyamine metabolism (biosynthesis, back-conversion and antizyme feedback)MODULE:polyamine_metabolism The polyamines putrescine, spermidine and spermine are small polycations needed for eukaryotic cell growth. They stabilise nucleic acids and... [more...][less]The polyamines putrescine, spermidine and spermine are small polycations needed for eukaryotic cell growth. They stabilise nucleic acids and chromatin, regulate ion channels and act in translation. Spermidine is also the precursor of the hypusine modification of eIF5A, which is why it is essential in yeast. Biosynthesis begins with ornithine decarboxylase (ODC), a short-lived PLP-dependent enzyme that decarboxylates L-ornithine to putrescine and is the main control point. Some lineages also make putrescine by hydrolysing agmatine with agmatinase. In parallel, a pyruvoyl-dependent S-adenosylmethionine decarboxylase makes decarboxylated SAM (dcSAM), the only aminopropyl donor. Spermidine synthase transfers an aminopropyl group from dcSAM to putrescine to make spermidine. Where spermine is made, a spermine synthase adds a second aminopropyl group. Animals use a dedicated SMS family for this, and budding yeasts use the SPE3 paralogue SPE4. Each transfer releases 5'-methylthioadenosine (MTA), which the methionine salvage cycle recycles. Back-conversion catabolism oxidises spermine or N1-acetylated polyamines with FAD-dependent polyamine oxidases to give shorter polyamines plus an aminoaldehyde and H2O2. In animals, SAT1 N1-acetylates polyamines and peroxisomal PAOX then oxidises them, while SMOX oxidises free spermine. In budding yeast a single oxidase, Fms1, oxidises both spermine and N1-acetylpolyamines, and its 3-aminopropanal product is the source of beta-alanine for pantothenate and coenzyme A synthesis. ODC is controlled by antizyme, a protein whose synthesis needs a +1 ribosomal frameshift that polyamines stimulate. Antizyme binds ODC and targets it for ubiquitin-independent proteasomal degradation. In vertebrates, antizyme inhibitors (catalytically dead ODC paralogues) bind antizyme and release ODC. |
Metabolic Pathway | DRAFT | 0 | polyamine biosynthetic process polyamine catabolic process |
18 | 14 | 8 | 4 | 9 | 10 | 23/24 | 0 | ✗ | modules/polyamine_metabolism.yaml | ||
Exocyst complex in Drosophila melanogasterMODULE:dmel_exocystCONCRETE The exocyst is an octameric tethering complex that captures secretory and recycling vesicles at sites of exocytosis on the plasma membrane before... [more...][less]The exocyst is an octameric tethering complex that captures secretory and recycling vesicles at sites of exocytosis on the plasma membrane before SNARE-mediated fusion. Its eight subunits (Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84) are long helical-bundle proteins; Sec3 and Exo70 bind plasma membrane phosphoinositides and small GTPases, while Sec15 binds Rab11 on the vesicle. Structural studies divide the complex into two four-subunit modules, Sec3-Sec5-Sec6-Sec8 and Sec10-Sec15-Exo70-Exo84. In Drosophila the exocyst is required for polarized membrane delivery, for example to the rhabdomere of photoreceptors, to growing neurites and for epithelial junction protein trafficking. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | exocyst |
3 | 3 | 2 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_exocyst.yaml | |
F-actin capping protein (CapZ) in Drosophila melanogasterMODULE:dmel_f_actin_capping_proteinCONCRETE Capping protein is an alpha/beta heterodimer that binds the barbed (plus) end of actin filaments with high affinity and blocks the addition and... [more...][less]Capping protein is an alpha/beta heterodimer that binds the barbed (plus) end of actin filaments with high affinity and blocks the addition and loss of actin subunits there. It limits filament elongation, which shapes branched actin networks and controls the length of actin structures. In Drosophila the alpha (cpa) and beta (cpb) subunits are each required to restrict actin filament growth, for example in bristle development and in the germline, and loss of either subunit destabilizes the other. The same heterodimer also caps the barbed end of the Arp1 filament of dynactin. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | F-actin capping protein complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_f_actin_capping_protein.yaml | |
FGF23-alpha-Klotho endocrine axis in phosphate and vitamin D homeostasisMODULE:fgf23_klotho_phosphate_homeostasis The bone-kidney endocrine axis through which the hormone FGF23 lowers serum phosphate and active vitamin D. In osteocytes and osteoblasts FGF23 is... [more...][less]The bone-kidney endocrine axis through which the hormone FGF23 lowers serum phosphate and active vitamin D. In osteocytes and osteoblasts FGF23 is synthesised as a secreted proprotein whose activity is set post-translationally at a proprotein-convertase site (R176XXR179): the Golgi polypeptide GalNAc-transferase GALNT3 O-glycosylates Thr178, which shields the site from furin-type cleavage and permits secretion of intact, active hormone, whereas FAM20C phosphorylation of Ser180 opposes that glycosylation and favours cleavage into inactive N- and C-terminal fragments. Circulating intact FGF23 acts on kidney (and parathyroid) cells that express the single-pass transmembrane co-receptor alpha-Klotho, which tethers the FGF23 C-terminal tail to the FGFR1c ectodomain and converts the canonical receptor tyrosine kinase into a high-affinity FGF23 receptor. Signalling through the Klotho-FGFR1c complex reduces proximal-tubule sodium-phosphate cotransport (NaPi-2a/SLC34A1 and NaPi-2c/SLC34A3), causing phosphaturia, and lowers 1,25-dihydroxyvitamin D by suppressing the 25-hydroxyvitamin D 1-alpha-hydroxylase CYP27B1 and inducing the 24-hydroxylase CYP24A1. Loss of function at the hormone, glycosylation or co-receptor step causes hyperphosphatemic familial tumoral calcinosis, and cleavage-resistant FGF23 or excess osteocytic FGF23 production causes hypophosphatemic rickets. |
Signaling Pathway | DRAFT | 0 | phosphate ion homeostasis |
5 | 5 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/fgf23_klotho_phosphate_homeostasis.yaml | ||
FGFR signaling pathway in Drosophila melanogasterMODULE:dmel_fgfr_signalingCONCRETE Drosophila has two FGF receptor tyrosine kinases with distinct ligands. Breathless (Btl) is activated by Branchless (Bnl) and guides tracheal... [more...][less]Drosophila has two FGF receptor tyrosine kinases with distinct ligands. Breathless (Btl) is activated by Branchless (Bnl) and guides tracheal branch migration, and Heartless (Htl) is activated by Pyramus and Thisbe and directs the spreading and migration of mesoderm and glial cells. Both receptors use the FGFR-specific cytoplasmic adaptor Stumps (Downstream of FGFR, Dof). Signaling proceeds through Drk, Sos, Ras85D and the Raf-Dsor1-Rolled MAP kinase cascade, ending in ETS factor output (Pointed activation, Yan/Aop relief). Pebble, a Rho exchange factor, acts in Heartless-dependent mesoderm migration. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | fibroblast growth factor receptor signaling pathway |
9 | 22 | 6 | 1 | 2 | 5 | 8/22 | 0 | ✗ | modules/dmel_fgfr_signaling.yaml | |
FGFR signaling pathway moduleMODULE:fgfr_signaling Secreted FGF ligands, presented by heparan sulfate (paracrine FGFs) or by alpha/beta-Klotho co-receptors (endocrine FGFs), activate one or more... [more...][less]Secreted FGF ligands, presented by heparan sulfate (paracrine FGFs) or by alpha/beta-Klotho co-receptors (endocrine FGFs), activate one or more FGFR receptor tyrosine kinase paralogs. The activated receptor phosphorylates the FRS2-family docking protein, which recruits GRB2-SOS to drive Ras-MAPK signalling and GRB2-GAB1-p85 to engage PI3K, while PLC-gamma binds the receptor directly and hydrolyses PIP2. The kinase-less paralog-like FGFRL1 attenuates signalling by sequestering ligand. |
Signaling Pathway | DRAFT | metazoa |
11 | fibroblast growth factor receptor signaling pathway |
20 | 18 | 8 | 4 | 11 | 8 | 25/27 | 0 | ✓ | modules/fgfr_signaling.yaml | |
FRIGIDA-dependent FLC activation and vernalization-induced Polycomb silencing of FLCMODULE:vernalization_flc_silencingCONCRETE In winter-annual Arabidopsis thaliana accessions, the plant-specific scaffold protein FRIGIDA (FRI) assembles the FRI-C transcription activator... [more...][less]In winter-annual Arabidopsis thaliana accessions, the plant-specific scaffold protein FRIGIDA (FRI) assembles the FRI-C transcription activator complex (with SUF4, FLX, FES1 and FRL1) at the FLOWERING LOCUS C (FLC) promoter. FRI-C recruits H3K4 and H3K36 methyltransferase and H2A.Z exchange activities and the nuclear cap-binding complex, raising expression of the MADS-box floral repressor FLC. FLC, with its partner SVP, represses the floral integrators FT (in leaves) and SOC1 (in the meristem), so flowering is blocked before winter. Prolonged cold (vernalization) overcomes this block in two mechanistically separate phases. (1) Nucleation: the slow, quantitative cold induction of the VEL protein VIN3 is the molecular readout of the length of winter. VIN3 heterodimerizes through its VEL domain with the constitutively expressed VRN5 (VIL1), which bridges it to a VRN2-containing PRC2 core (SWN/CLF, FIE, MSI1). The resulting PHD-PRC2 is targeted to a three-nucleosome nucleation region near the first exon-intron boundary of FLC, where the sequence-specific repressor VAL1 also binds. VIN3 VEL-domain head-to-tail polymerization builds multivalent assemblies that nucleate H3K27me3, switching individual FLC alleles digitally into a metastable silenced state. (2) Spreading and maintenance: after return to warmth, H3K27me3 spreads over the whole FLC locus in a step that needs CLF-PRC2 and LHP1, and the chromatin-associated, sequence-nonspecific DNA-binding B3 protein VRN1 is needed to keep FLC stably silenced through later development. Silencing of FLC de-represses FT and SOC1, so flowering follows in spring. The autonomous pathway (FCA, FPA, FLD, FVE, FY, LD), which represses FLC independently of cold, COOLAIR antisense transcription, and resetting of FLC in each generation are outside this module. |
Biological Process | DRAFT | Arabidopsis thaliana |
0 | vernalization response negative regulation of gene expression, epigenetic |
6 | 12 | 5 | 0 | 0 | 5 | 15/15 | 0 | ✗ | modules/vernalization_flc_silencing.yaml | |
Fc-epsilon receptor signaling pathway moduleMODULE:fc_epsilon_receptor_signaling High-affinity IgE receptor signaling couples FCER1 antigen crosslinking to ITAM phosphorylation, SYK activation, BTK/PLC-gamma signaling, calcium... [more...][less]High-affinity IgE receptor signaling couples FCER1 antigen crosslinking to ITAM phosphorylation, SYK activation, BTK/PLC-gamma signaling, calcium mobilization, and mast-cell effector responses. |
Signaling Pathway | DRAFT | jawed vertebrates |
8 | Fc-epsilon receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 5/7 | 0 | ✓ | modules/fc_epsilon_receptor_signaling.yaml | |
Fc-gamma receptor signaling pathway moduleMODULE:fc_gamma_receptor_signaling Fc-gamma receptor signaling couples immune-complex binding to ITAM-containing receptor chains, SYK/BTK activation, PLC-gamma and PI3K branches,... [more...][less]Fc-gamma receptor signaling couples immune-complex binding to ITAM-containing receptor chains, SYK/BTK activation, PLC-gamma and PI3K branches, phagocytosis, and inflammatory effector functions. |
Signaling Pathway | DRAFT | jawed vertebrates |
8 | Fc-gamma receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 5/7 | 0 | ✓ | modules/fc_gamma_receptor_signaling.yaml | |
Ferritin complexes in Drosophila melanogasterMODULE:dmel_ferritin_complexCONCRETE Insect ferritins store and transport iron. The main Drosophila ferritin is a 24-subunit shell made of equal numbers of heavy-chain homolog... [more...][less]Insect ferritins store and transport iron. The main Drosophila ferritin is a 24-subunit shell made of equal numbers of heavy-chain homolog (Fer1HCH) and light-chain homolog (Fer2LCH) subunits; unlike mammalian ferritin it is largely made in the secretory pathway and is present in the hemolymph. The heavy-chain subunit carries the ferroxidase centre that oxidises Fe(II) for storage as Fe(III) in the mineral core. Ferritin in the midgut iron cell region takes up dietary iron and is needed for iron export to the rest of the body. A third gene, Fer3HCH, encodes a mitochondrial ferritin expressed mainly in the testis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ferritin complex |
3 | 2 | 2 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_ferritin_complex.yaml | |
Ferroptosis (iron-dependent lipid-peroxidation cell death) moduleMODULE:ferroptosis A decomposition of ferroptosis: the iron-dependent form of regulated cell death in which polyunsaturated-fatty-acid (PUFA) phospholipids in... [more...][less]A decomposition of ferroptosis: the iron-dependent form of regulated cell death in which polyunsaturated-fatty-acid (PUFA) phospholipids in cellular membranes undergo iron-catalysed peroxidation to lipid hydroperoxides, ultimately rupturing the membrane. Ferroptosis is morphologically and biochemically distinct from apoptosis, necroptosis, and pyroptosis: there is no caspase cascade and no dedicated executioner enzyme. Instead the program is defined by the balance between (a) a driver arm that supplies the oxidisable substrate (PUFA phospholipids) and the redox-active iron that catalyses peroxidation, and (b) several biochemically independent defense arms that detoxify lipid hydroperoxides or quench the propagating radicals. Death occurs when the defenses are overwhelmed, so ferroptosis is best modelled as one execution node negatively regulated, in parallel and redundantly, by multiple suppressor systems. Design intent: the module is organized as a driver layer (PUFA-phospholipid supply and labile-iron supply) that provides input to a central execution node (GO:0097707 ferroptosis), opposed by four independent suppressor sub-modules that each NEGATIVELY_REGULATE the execution node: the canonical GPX4-glutathione axis, the FSP1-CoQ10 axis, the mitochondrial DHODH-CoQ10 axis, and the GCH1-BH4 (tetrahydrobiopterin) axis. A transcriptional/regulatory sub-module (NRF2/KEAP1, ATF4, p53) tunes the set point of these defenses and is kept optional. The module is framed for the mammalian in-vivo implementation, using human gene products as concrete representatives. The core chemistry (iron + O2 + PUFA membranes) and the principal defenses (GPX4, the CoQ system) are deeply conserved across eukaryotes, with ferroptosis-like death reported in plants, fungi, and protozoa. Genes are grounded to UniProt and GO ids taken from the matching per-gene reviews under genes/human/; GO ids are used only in their correct aspect (MF in function, BP in processes/concepts, CC in locations). |
Biological Process | DRAFT | Mammalia |
0 | ferroptosis |
18 | 27 | 17 | 0 | 0 | 14 | 22/24 | 1 | ✗ | modules/ferroptosis.yaml | |
Fibrinolysis — plasminogen activation by tPA on fibrin and uPA/uPAR on cells, plasmin degradation of fibrin, and its serpin and TAFI brakes; PLG/PLAT/PLAU/PLAUR/SERPINE1/SERPINB2/SERPINF2/CPB2MODULE:fibrinolysisCONCRETE Fibrinolysis dissolves fibrin clots. Its effector is plasmin, the active serine protease formed from the zymogen plasminogen (PLG). Plasminogen... [more...][less]Fibrinolysis dissolves fibrin clots. Its effector is plasmin, the active serine protease formed from the zymogen plasminogen (PLG). Plasminogen activation is catalysed by two serine proteases. Tissue-type plasminogen activator (tPA, PLAT) is a poor enzyme in solution, but on a fibrin surface it binds fibrin and then plasminogen to form a ternary complex, which lowers its Michaelis constant by orders of magnitude. This restricts plasmin formation to the clot. Fibrin is therefore both the substrate of fibrinolysis and the template for its activation step. Urokinase-type plasminogen activator (uPA, PLAU) works mainly on cell surfaces, bound to its GPI-anchored receptor uPAR (PLAUR), which focuses plasminogen activation at the pericellular surface. Plasmin cleaves fibrin into soluble degradation products. Partial digestion exposes C-terminal lysine residues that bind the kringle lysine-binding sites of plasminogen and tPA, a positive feedback that accelerates further activation. The system is held in check at three points. Plasminogen activator inhibitor-1 (PAI-1, SERPINE1) is the main fast-acting serpin inhibitor of tPA and uPA. PAI-2 (SERPINB2), protease nexin-1 (SERPINE2) and protein C inhibitor (SERPINA5) are tissue- or context-restricted plasminogen activator inhibitors. Alpha2-antiplasmin (SERPINF2) inhibits free plasmin almost instantly. Thrombin-activatable fibrinolysis inhibitor (TAFI, CPB2), once activated by the thrombin-thrombomodulin complex, is a basic carboxypeptidase that removes the C-terminal lysines from partly degraded fibrin and so removes fibrin's cofactor function. |
Biological Process | DRAFT | 0 | fibrinolysis |
7 | 11 | 6 | 0 | 0 | 8 | 3/13 | 0 | ✗ | modules/fibrinolysis.yaml | ||
Filamentous bacteriophage non-lytic virion assembly and trans-envelope extrusionMODULE:phage_filamentous_extrusionCONCRETE A reusable module representing the chronic, non-lytic virion assembly and trans-envelope extrusion pathway of filamentous single-stranded DNA... [more...][less]A reusable module representing the chronic, non-lytic virion assembly and trans-envelope extrusion pathway of filamentous single-stranded DNA bacteriophages (Inoviridae, exemplified by Ff coliphages M13, fd, and f1). Unlike lytic phages that assemble capsids in the cytoplasm and lyse the host, filamentous phages package progeny circular (+)ssDNA into a left-handed helical nucleoprotein complex with the dimeric ssDNA-binding protein pV in the cytoplasm, store all five structural coat proteins (pVIII, pIII, pVI, pVII, pIX) as integral inner-membrane proteins, and continuously extrude mature filaments across both bacterial membranes without killing the host cell (GO:0099045 viral extrusion). Extrusion is driven by a trans-envelope assembly nanomachine comprising the inner-membrane ATPase motor complex pI/pXI (encoded by gene I via full-length translation and internal initiation) coupled across the periplasm to the gated outer-membrane secretin channel pIV. Assembly initiates when the packaging hairpin of the pV-ssDNA complex is recognized at the pI/pXI motor and capped by the distal tip proteins pVII and pIX, proceeds via ATP- and proton-motive-force-driven replacement of cytoplasmic pV dimers by ~2,700 membrane-embedded major coat subunits pVIII, and terminates when the proximal tip complex pVI-pIII caps the trailing end and releases the virion through the pIV secretin pore. |
Biological Process | COMPLETE | Inoviridae |
0 | viral extrusion virion assembly |
6 | 8 | 5 | 0 | 0 | 5 | 8/8 | 0 | ✗ | modules/phage_filamentous_extrusion.yaml | |
Flavin cofactor biosynthesis (riboflavin -> FMN -> FAD; RFK + FLAD1)MODULE:flavin_cofactor_biosynthesis Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are the redox cofactors of the flavoproteins — respiratory Complex I and II, the... [more...][less]Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are the redox cofactors of the flavoproteins — respiratory Complex I and II, the acyl-CoA dehydrogenases of fatty-acid oxidation, MTHFR, PNPO, kynurenine 3-monooxygenase and hundreds of others. Because humans cannot make the riboflavin (vitamin B2) ring de novo, dietary riboflavin is converted intracellularly to its active cofactor forms in two committed steps. Riboflavin kinase (RFK) first phosphorylates riboflavin with ATP (and a divalent metal) to FMN. FAD synthase (FLAD1, an FMN adenylyltransferase) then adenylylates FMN with ATP to FAD; human FLAD1 has isoforms differing in an N-terminal molybdopterin-binding/KH region and additionally shows FAD-diphosphatase (FAD-hydrolysing) activity that reverses the last step and can act as a flavin chaperone for apo-flavoproteins. The pathway is the sole supply of flavin cofactors: inherited FLAD1 deficiency causes a lipid-storage myopathy with combined respiratory-chain / multiple-acyl-CoA-dehydrogenase deficiency, part of which is riboflavin-responsive. |
Metabolic Pathway | DRAFT | 0 | FAD biosynthetic process FMN biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/flavin_cofactor_biosynthesis.yaml | ||
Folate one-carbon carrier-state interconversionMODULE:folate_one_carbon_interconversionCONCRETE A taxon-neutral module for interconversion of the substituted tetrahydrofolate carrier states 5,10-methylene-THF, 5,10-methenyl-THF, 10-formyl-THF,... [more...][less]A taxon-neutral module for interconversion of the substituted tetrahydrofolate carrier states 5,10-methylene-THF, 5,10-methenyl-THF, 10-formyl-THF, 5-methyl-THF, and the salvaged 5-formyl-THF pool. The module separates four chemically distinct transformations: pyridine-nucleotide-linked oxidation of 5,10-methylene-THF to 5,10-methenyl-THF, hydrolysis of 5,10-methenyl-THF to 10-formyl-THF, reduction of 5,10-methylene-THF to 5-methyl-THF, and ATP-dependent salvage of 5-formyl-THF to 5,10-methenyl-THF. Fused FolD/MTHFD architectures and NAD(H)- versus NADP(H)-linked variants are represented as alternative implementations of the same carrier-state conversions; eukaryotes such as yeasts add trifunctional C1-tetrahydrofolate synthases in the cytosol and mitochondria and, in some fungi, a monofunctional NAD-specific dehydrogenase that lacks cyclohydrolase activity. The dehydrogenase and cyclohydrolase operations form the required coupled core; MTHFR reduction and 5-formyl-THF salvage are independent optional branches. Upstream one-carbon loading by serine hydroxymethyltransferase, glycine cleavage, or formate-tetrahydrofolate ligase and downstream use by purine, thymidylate, or methionine synthesis are outside this module. |
Metabolic Pathway | DRAFT | bacteria Euteleostomi |
5 | tetrahydrofolate interconversion |
18 | 15 | 4 | 3 | 13 | 2 | 14/19 | 0 | ✓ | modules/folate_one_carbon_interconversion.yaml | |
Fructolysis (hepatic dietary fructose catabolism; hereditary fructose intolerance)MODULE:fructolysis Fructolysis is the liver (and kidney/intestine) pathway that catabolises dietary fructose, feeding its carbon into glycolysis/gluconeogenesis while... [more...][less]Fructolysis is the liver (and kidney/intestine) pathway that catabolises dietary fructose, feeding its carbon into glycolysis/gluconeogenesis while bypassing the main phosphofructokinase regulatory step of glycolysis. Three cytosolic steps: ketohexokinase (KHK, fructokinase) phosphorylates fructose to fructose-1-phosphate at the expense of ATP; the liver-type fructose-bisphosphate aldolase (ALDOB) cleaves fructose-1-phosphate to dihydroxyacetone phosphate (DHAP) + D-glyceraldehyde; and triokinase (TKFC) phosphorylates the D-glyceraldehyde to D-glyceraldehyde-3- phosphate. The DHAP and glyceraldehyde-3-phosphate then enter the glycolytic / gluconeogenic triose-phosphate pool. Because KHK is not feedback-regulated, hepatic fructose uptake and phosphorylation are rapid and unregulated, transiently trapping phosphate as fructose-1-phosphate. Inherited defects: KHK deficiency causes benign essential fructosuria; ALDOB deficiency causes hereditary fructose intolerance (HFI) — toxic accumulation of fructose-1-phosphate with ATP/phosphate depletion, hypoglycemia and hepatic/renal injury on fructose or sucrose ingestion; and TKFC deficiency causes a rare multisystem disorder (cataracts, developmental problems). ALDOB (like the other aldolases) also participates in the aldol cleavage of fructose-1,6-bisphosphate in glycolysis/gluconeogenesis, and TKFC additionally has an FMN-cyclase (FAD-AMP lyase) activity in riboflavin metabolism. |
Metabolic Pathway | DRAFT | 0 | fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/fructolysis.yaml | ||
Fungal NAD+ biosynthesis from tryptophan and pyridine salvageMODULE:nad_de_novo_and_salvage_fungal NAD+ supply network of yeasts and other fungi, in which several precursor routes converge on nicotinate mononucleotide (NaMN) or nicotinamide... [more...][less]NAD+ supply network of yeasts and other fungi, in which several precursor routes converge on nicotinate mononucleotide (NaMN) or nicotinamide mononucleotide (NMN) and then share the final adenylylation and amidation steps. De novo synthesis uses the kynurenine pathway: an indoleamine 2,3-dioxygenase-family enzyme opens L-tryptophan to N-formylkynurenine, a kynurenine formamidase releases kynurenine, kynurenine 3-monooxygenase and kynureninase give 3-hydroxyanthranilate, 3-hydroxyanthranilate 3,4-dioxygenase opens the ring to 2-amino-3-carboxymuconate semialdehyde, which cyclizes non-enzymatically to quinolinate, and quinolinate phosphoribosyltransferase makes NaMN. Fungi lack the aspartate-derived (NadA/NadB) de novo route. In the Preiss-Handler salvage route, nicotinamide released by NAD+-consuming enzymes is deamidated by a nicotinamidase and the resulting nicotinate is converted to NaMN by nicotinate phosphoribosyltransferase. Nicotinamide riboside and nicotinic acid riboside are either phosphorylated by nicotinamide riboside kinase (to NMN or NaMN) or cleaved to the free bases by nucleosidases and nucleoside phosphorylases, which then enter the Preiss-Handler route. NaMN is adenylylated to nicotinate adenine dinucleotide (NaAD) by NMN/NaMN adenylyltransferases and amidated to NAD+ by a glutamine-dependent NAD+ synthetase, whereas NMN is adenylylated directly to NAD+. The de novo route requires oxygen, so fermenting yeasts depend on salvage under anaerobic conditions. Precursor uptake, NAD+-consuming reactions such as sirtuin deacetylation, and NADP+ formation are outside the module. |
Metabolic Pathway | DRAFT | 0 | NAD+ biosynthetic process 'de novo' NAD+ biosynthetic process from L-tryptophan NAD+ biosynthetic process via the salvage pathway |
19 | 16 | 12 | 2 | 6 | 12 | 24/24 | 0 | ✗ | modules/nad_de_novo_and_salvage_fungal.yaml | ||
Fungal ammonium assimilation into glutamate and glutamine, and glutamate deaminationMODULE:nitrogen_assimilation_glutamate_glutamine Assimilation of ammonium into the amino group of L-glutamate and the amide group of L-glutamine, and the reverse release of ammonium from... [more...][less]Assimilation of ammonium into the amino group of L-glutamate and the amide group of L-glutamine, and the reverse release of ammonium from glutamate, as organised in fungi and other eukaryotic microbes. Glutamate and glutamine are the nitrogen donors for nearly all other nitrogenous compounds, so these reactions sit between nitrogen-source catabolism and biosynthesis. Glutamine synthetase ligates ammonium to L-glutamate with ATP to give L-glutamine; it is the only route to glutamine and is required in every growth condition. Ammonium reaches glutamate by two alternative routes. In the first, NADP-dependent glutamate dehydrogenase reductively aminates 2-oxoglutarate with NADPH; in budding yeast this is the main route when glucose is plentiful and is carried by two isozymes, one constitutive and one induced on non-fermentable carbon sources. In the second, the glutamine synthetase-glutamate synthase (GS-GOGAT) cycle, an NADH-dependent glutamate synthase transfers the glutamine amide nitrogen to 2-oxoglutarate, giving two molecules of L-glutamate, one of which replaces the glutamate consumed by glutamine synthetase. Fungal glutamate synthase is a single large polypeptide that combines the domains carried by the separate large and small subunits of bacterial NADPH-dependent glutamate synthase. The GS-GOGAT cycle has higher affinity for 2-oxoglutarate and uses NADH rather than NADPH, and it becomes required for glutamate synthesis when the NADP-dependent dehydrogenases are absent or when glutamine is the nitrogen source. Loss of both routes causes glutamate auxotrophy. An NAD-dependent glutamate dehydrogenase runs the reaction in the catabolic direction, oxidatively deaminating L-glutamate to 2-oxoglutarate and ammonium; it supplies the ammonium for glutamine synthesis when glutamate is the nitrogen source. 2-Oxoglutarate itself comes from isocitrate dehydrogenases of central carbon metabolism. |
Metabolic Pathway | DRAFT | 0 | L-glutamate biosynthetic process L-glutamine biosynthetic process |
6 | 4 | 3 | 1 | 2 | 3 | 9/9 | 0 | ✗ | modules/nitrogen_assimilation_glutamate_glutamine.yaml | ||
Fungal beta-1,3-glucan synthesis at the plasma membraneMODULE:fungal_beta_1_3_glucan_synthesisCONCRETE Beta-1,3-glucan is the main structural polysaccharide of most fungal cell walls and septa. It is made at the plasma membrane by glucan synthase, a... [more...][less]Beta-1,3-glucan is the main structural polysaccharide of most fungal cell walls and septa. It is made at the plasma membrane by glucan synthase, a multi-pass GT48 (FKS family) glycosyltransferase. The synthase transfers glucose from cytosolic UDP-glucose to the growing chain at an active site on the cytosolic face and threads the chain through a transmembrane channel into the wall. The small GTPase Rho1 is the regulatory subunit: GTP-bound Rho1 binds the synthase and is needed for its activity. Many fungi have several synthase paralogs with distinct jobs. Saccharomyces cerevisiae has Fks1 and Gsc2/Fks2. Schizosaccharomyces pombe has four: Bgs1 makes the linear beta-1,3-glucan of the primary septum, Bgs4 makes the major branched beta-1,3-glucan of the wall and secondary septum, Bgs2 acts in the spore wall, and Bgs3 is essential but its product is less well defined. Bgs3 works with Ghs2, a Kre6-related membrane protein with an extracellular GH16 domain. In the current model Ghs2 adds beta-1,6-linked branches to the chain Bgs3 extrudes, but that reaction has not been assayed. UDP-glucose supply, synthase trafficking and localization factors, Rho1 GEFs and GAPs, and later cross-linking and remodeling of wall glucan by GH72/GH16/GH17 enzymes are outside the module. |
Metabolic Pathway | DRAFT | fungi |
1 | fungal-type cell wall (1->3)-beta-D-glucan biosynthetic process |
8 | 6 | 3 | 1 | 4 | 2 | 4/8 | 0 | ✗ | modules/fungal_beta_1_3_glucan_synthesis.yaml | |
Fungal cell wall alpha-1,3-glucan synthesis and remodelingMODULE:fungal_alpha_1_3_glucan_synthesisCONCRETE Alpha-1,3-glucan is a major cell wall polysaccharide in many ascomycetes and basidiomycetes. It is absent from Saccharomyces cerevisiae, but in... [more...][less]Alpha-1,3-glucan is a major cell wall polysaccharide in many ascomycetes and basidiomycetes. It is absent from Saccharomyces cerevisiae, but in Schizosaccharomyces pombe it is about a third of the wall glucan and is essential. It is made at the plasma membrane by Ags1-family synthases, very large multi-pass proteins with two probable catalytic regions. An intracellular GT5 (glycogen synthase-like) domain makes a short alpha-1,4-glucan primer. An extracellular GH13 (alpha-amylase-like) domain is proposed to join or remodel chains. The mature S. pombe polymer is two alpha-1,3-glucan chains of about 120 residues each, coupled through short alpha-1,4-linked segments. Separate GPI-anchored GH13 enzymes on the cell surface (Aah1 and Aah3 in S. pombe) are needed for normal chain assembly. By analogy to characterised Aspergillus homologs they are thought to be 4-alpha-glucanotransferases, not hydrolases. In S. pombe, Ags1 makes alpha-glucan at growing tips and in the primary septum, alongside the beta-glucan synthase Bgs1, while sporulation-specific paralogs (Mok12, Mok13, Mok14) make the spore-envelope alpha-glucans. UDP-glucose supply, the Rho2-Pck2 signalling that controls Ags1, synthase trafficking, and alpha-glucan degradation (e.g. Agn1 during cell separation) are outside the module. |
Metabolic Pathway | DRAFT | fungi |
0 | fungal-type cell wall (1->3)-alpha-glucan biosynthetic process |
7 | 4 | 2 | 2 | 4 | 1 | 3/4 | 0 | ✗ | modules/fungal_alpha_1_3_glucan_synthesis.yaml | |
Fungal chitin synthesis and deacetylation to chitosanMODULE:fungal_chitin_chitosan_synthesisCONCRETE Chitin, a linear beta-1,4-linked polymer of N-acetylglucosamine, is a minor but essential structural polysaccharide of the fungal cell wall, septa... [more...][less]Chitin, a linear beta-1,4-linked polymer of N-acetylglucosamine, is a minor but essential structural polysaccharide of the fungal cell wall, septa and spore walls. It is made at the plasma membrane by chitin synthases, processive multi-pass membrane GT-2 glycosyltransferases that transfer N-acetylglucosamine from cytosolic UDP-N-acetylglucosamine to the growing chain and extrude the chain through a transmembrane channel to the cell surface. Fungi have several chitin synthase classes with different cellular jobs. In budding yeast, chitin synthase II (Chs2) makes the primary septum at the bud neck, chitin synthase III (catalytic Chs3 activated by the Chs4 or, in sporulation, Shc1 subunit) makes most cell-wall chitin, the chitin ring at bud emergence and the chitin of the spore wall, and chitin synthase I (Chs1) repairs the birth scar after cell separation. Loss of all three is lethal. Some nascent chitin is then deacetylated by secreted or membrane-anchored CE4-family chitin deacetylases to give chitosan, a beta-1,4-glucosamine polymer. In budding yeast this happens only in the ascospore wall, where the sporulation-specific deacetylases Cda1 and Cda2 convert Chs3-made chitin into the chitosan layer; in other fungi, such as Cryptococcus neoformans, deacetylases also make chitosan in the vegetative wall. The supply of UDP-N-acetylglucosamine (hexosamine pathway), chitin synthase trafficking and localisation factors, and chitin cross-linking or degradation are outside the module. |
Metabolic Pathway | DRAFT | fungi |
0 | chitin biosynthetic process |
6 | 5 | 2 | 1 | 3 | 2 | 7/7 | 0 | ✗ | modules/fungal_chitin_chitosan_synthesis.yaml | |
Fungal glycogen synthesis and mobilisationMODULE:glycogen_metabolism_fungalCONCRETE Fungi store glucose as glycogen, a branched alpha-1,4/alpha-1,6 glucan, through a UDP-glucose-dependent pathway like that of animals and unlike the... [more...][less]Fungi store glucose as glycogen, a branched alpha-1,4/alpha-1,6 glucan, through a UDP-glucose-dependent pathway like that of animals and unlike the ADP-glucose pathway of bacteria. Glucose 1-phosphate is activated with UTP to UDP-glucose by UDP-glucose pyrophosphorylase. Synthesis starts on glycogenin, a self-glucosylating GT-8 glucosyltransferase that attaches glucose to its own tyrosine residue(s) and extends a short alpha-1,4 oligosaccharide primer. Glycogen synthase (GT-3) elongates the primer by adding glucose from UDP-glucose to non-reducing ends, and the GH13 branching enzyme moves segments of chain to alpha-1,6 positions to create branches. Mobilisation has two routes. In the cytosol, glycogen phosphorylase releases glucose 1-phosphate from chain ends until it stops near a branch, and the bifunctional debranching enzyme transfers the remaining short branch to another chain (4-alpha-glucanotransferase) and hydrolyses the single alpha-1,6-linked glucose (amylo-alpha-1,6-glucosidase). Alternatively, glycogen delivered to the vacuole by autophagy is hydrolysed to free glucose by a vacuolar GH15 glucoamylase. Phosphoglucomutase interconverts glucose 1-phosphate and glucose 6-phosphate, linking both arms to glycolysis. Both arms are induced by nutrient limitation and stress and are controlled post-translationally (for example by phosphorylation of glycogen synthase and phosphorylase); these regulatory inputs are outside the module. |
Metabolic Pathway | DRAFT | fungi |
0 | glycogen metabolic process |
12 | 9 | 9 | 1 | 2 | 8 | 18/18 | 0 | ✗ | modules/glycogen_metabolism_fungal.yaml | |
Fused-Smurf ubiquitin ligase complex in Drosophila melanogasterMODULE:dmel_fused_smurf_complexCONCRETE The serine/threonine kinase Fused, best known as a Hedgehog pathway component, also forms a complex with the HECT-domain E3 ubiquitin ligase Smurf.... [more...][less]The serine/threonine kinase Fused, best known as a Hedgehog pathway component, also forms a complex with the HECT-domain E3 ubiquitin ligase Smurf. In the Drosophila ovary germline stem cell niche, the Fused-Smurf complex promotes ubiquitylation and degradation of the BMP type I receptor Thickveins in cells displaced from the niche, sharpening the BMP response and allowing stem cell daughters to differentiate. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ubiquitin ligase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_fused_smurf_complex.yaml | |
G protein-coupled opioid receptor signaling pathway moduleMODULE:opioid_receptor_signaling The G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635) are... [more...][less]The G protein-coupled opioid receptor signaling pathway (GO:0038003) and its canonical adenylate cyclase-inhibiting branch (GO:0031635) are initiated when endogenous opioid and opioid-like neuropeptide precursors — proenkephalin-A (PENK, PANTHER:PTHR11438:SF3; cleaved into Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Phe, and Met-enkephalin-Arg-Gly-Leu), proenkephalin-B / prodynorphin (PDYN, PANTHER:PTHR11438:SF4; cleaved into dynorphin A, dynorphin B, alpha-/beta-neoendorphin, and Leu-enkephalin), and prepronociceptin (PNOC, PANTHER:PTHR11438:SF2; cleaved into nociceptin / orphanin FQ), together with pro-opiomelanocortin-derived beta-endorphin — are secreted from neuronal dense-core vesicles and bind the seven-transmembrane opioid receptor family GPCRs OPRM1 (mu-type opioid receptor, PANTHER:PTHR24229:SF7), OPRD1 (delta-type opioid receptor, PANTHER:PTHR24229:SF2), OPRK1 (kappa-type opioid receptor, PANTHER:PTHR24229:SF1), and OPRL1 (nociceptin/NOP receptor, PANTHER:PTHR24229:SF11) at the plasma membrane and synaptic membrane. Agonist-bound opioid receptors couple to pertussis-toxin-sensitive inhibitory heterotrimeric Gi/o proteins (exemplified by GNAI1, PANTHER:PTHR10218:SF359), inhibiting adenylate cyclase (exemplified by ADCY5, PANTHER:PTHR45627:SF7) to lower intracellular cAMP while released Gbeta-gamma dimers activate GIRK potassium channels and inhibit voltage-gated Ca2+ channels to suppress presynaptic neurotransmitter release and nociceptive transmission. |
Signaling Pathway | DRAFT | Euteleostomi |
1 | G protein-coupled opioid receptor signaling pathway adenylate cyclase-inhibiting opioid receptor signaling pathway |
3 | 9 | 2 | 0 | 0 | 1 | 4/9 | 0 | ✗ | modules/opioid_receptor_signaling.yaml | |
G1/S transition of the mitotic cell cycle (Start / restriction point)MODULE:g1_s_transitionCONCRETE A taxon-neutral decomposition of the G1/S transition: the commitment step ("Start" in yeasts, the "restriction point" in metazoa) at which a cell... [more...][less]A taxon-neutral decomposition of the G1/S transition: the commitment step ("Start" in yeasts, the "restriction point" in metazoa) at which a cell irreversibly enters a new division cycle. Four steps are modeled: (1) a G1 cyclin-CDK (cyclin D-CDK4/6 in metazoa, Cln3-Cdc28 in budding yeast, Puc1/Cig-Cdc2 in fission yeast) accumulates with growth and phosphorylates the transcriptional corepressor of the G1/S program; (2) the G1/S transcription factor is released from its corepressor (Rb from E2F-DP in metazoa, Whi5 from SBF/MBF in budding yeast; fission yeast MBF has no Rb/Whi5-type corepressor and is modeled as its own variant); (3) the G1/S cyclins transcribed by that program (cyclin E, Cln1/2 and Clb5/6, Cig2) activate the G1/S CDK; and (4) the G1/S CDK phosphorylates the stoichiometric CDK inhibitor (p27/Kip1, Sic1, Rum1), marking it for SCF-dependent ubiquitination and proteasomal destruction, which releases S-phase CDK activity in a switch-like positive feedback loop. The module ends with active S-phase cyclin-CDK; DNA replication licensing and initiation are downstream and are not part of this module. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0000082 (G1/S transition of mitotic cell cycle). |
Biological Process | DRAFT | Eukaryota Metazoa Saccharomyces cerevisiae Schizosaccharomyces pombe |
4 | G1/S transition of mitotic cell cycle |
8 | 11 | 4 | 1 | 3 | 8 | 36/36 | 0 | ✗ | modules/g1_s_transition.yaml | |
G2/M transition of the mitotic cell cycle (mitotic entry)MODULE:g2_m_transitionCONCRETE A taxon-neutral decomposition of mitotic entry, the switch-like activation of cyclin B-CDK1 (Cdc2/Cdc28-Clb2/Cdc13) at the G2/M transition. Five... [more...][less]A taxon-neutral decomposition of mitotic entry, the switch-like activation of cyclin B-CDK1 (Cdc2/Cdc28-Clb2/Cdc13) at the G2/M transition. Five steps are modeled: (1) assembly of the cyclin B-CDK1 holoenzyme and activating T-loop phosphorylation by the CDK-activating kinase (CDK7-cyclin H-MAT1 in metazoa and Mcs6-Mcs2 in fission yeast; the unrelated single-subunit Cak1 in budding yeast); (2) inhibitory phosphorylation of CDK1 Tyr15 (and Thr14) by the Wee1/Mik1/Swe1 and Myt1 kinases, which holds the complex inactive through G2; (3) activating dephosphorylation by the Cdc25 (Mih1) phosphatase, which triggers mitotic entry; (4) the Polo-like kinase (PLK1, Cdc5, Plo1), which reinforces the transition by activating Cdc25 and priming Wee1 for destruction; and (5) the Greatwall-endosulfine axis (MASTL/Rim15/Ppk18 -> ENSA-ARPP19/Igo1-2/Igo1 -| PP2A-B55), which suppresses the CDK-counteracting phosphatase so that CDK substrate phosphorylation can accumulate. Mutual antagonism between CDK1 and Wee1, and positive feedback between CDK1 and Cdc25, make the transition bistable and irreversible. Checkpoint kinases that restrain Cdc25 and activate Wee1 after DNA damage are modeled as an optional regulatory part. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0000086 (G2/M transition of mitotic cell cycle). |
Biological Process | DRAFT | Eukaryota Saccharomyces cerevisiae |
12 | G2/M transition of mitotic cell cycle |
9 | 11 | 6 | 1 | 2 | 13 | 36/36 | 0 | ✗ | modules/g2_m_transition.yaml | |
GABA shunt (glutamate to GABA to succinate)MODULE:gaba_shuntCONCRETE Three-step pathway, found in animals, plants and fungi, that converts L-glutamate to succinate through gamma-aminobutyrate (GABA) and succinate... [more...][less]Three-step pathway, found in animals, plants and fungi, that converts L-glutamate to succinate through gamma-aminobutyrate (GABA) and succinate semialdehyde. It bypasses the 2-oxoglutarate-to-succinate segment of the TCA cycle. A pyridoxal-phosphate glutamate decarboxylase first converts L-glutamate to GABA and CO2 in the cytosol. A pyridoxal-phosphate GABA transaminase then transfers the amino group of GABA to an acceptor 2-oxo acid, giving succinate semialdehyde. Finally, succinate-semialdehyde dehydrogenase oxidizes succinate semialdehyde to succinate with NAD+ or NADP+. The chemistry is conserved, but the implementations differ between lineages. Animal glutamate decarboxylases form a family separate from the calmodulin-binding decarboxylases of plants and fungi. Animal and fungal GABA transaminases use 2-oxoglutarate and so regenerate glutamate, whereas the main plant enzyme uses pyruvate or glyoxylate. GABA catabolism takes place in the mitochondrial matrix of animals and plants but in the cytosol of budding yeast. In animals the shunt makes and clears the inhibitory neurotransmitter GABA. In plants it responds to stress and makes the GABA gradient that guides pollen tubes. In yeasts it lets GABA serve as a nitrogen source and helps cells tolerate oxidative stress. Organisms that lack glutamate decarboxylase, such as fission yeast, can still degrade GABA taken up from outside. |
Metabolic Pathway | DRAFT | animals fungi green plants |
0 | GABA shunt |
8 | 5 | 3 | 2 | 4 | 2 | 9/13 | 0 | ✗ | modules/gaba_shunt.yaml | |
GARP and EARP tethering complexes in Drosophila melanogasterMODULE:dmel_garp_complexCONCRETE The Golgi-associated retrograde protein (GARP) complex and the endosome-associated recycling protein (EARP) complex are related multisubunit... [more...][less]The Golgi-associated retrograde protein (GARP) complex and the endosome-associated recycling protein (EARP) complex are related multisubunit tethering complexes that share Vps51, Vps52 and Vps53. GARP contains Vps54 (scattered, scat, in Drosophila) and tethers endosome-derived vesicles at the trans-Golgi network, supporting retrograde transport of cargo such as lysosomal hydrolase receptors. EARP contains Vps50 in place of Vps54 and acts in recycling from endosomes to the plasma membrane. Drosophila scat mutants are male sterile, with defects in spermatid differentiation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | GARP complex EARP complex |
3 | 2 | 0 | 1 | 2 | 0 | 5/5 | 0 | ✗ | modules/dmel_garp_complex.yaml | |
GDP-mannose biosynthesis in Drosophila melanogasterMODULE:dmel_gdp_mannose_biosynthesisCONCRETE GDP-mannose is the mannose donor for N-glycan precursor assembly, GPI anchors and protein O-mannosylation (through dolichol-phosphate-mannose), and... [more...][less]GDP-mannose is the mannose donor for N-glycan precursor assembly, GPI anchors and protein O-mannosylation (through dolichol-phosphate-mannose), and the precursor of GDP-fucose. It is made in the cytosol from hexose 6-phosphates. Hexokinases phosphorylate glucose or mannose; glucose 6-phosphate is isomerized to fructose 6-phosphate by glucose-6-phosphate isomerase (Pgi), and mannose-6-phosphate isomerase (Mpi) interconverts fructose 6-phosphate and mannose 6-phosphate. Phosphomannomutase (Pmm2) converts mannose 6-phosphate to mannose 1-phosphate, and GDP-mannose pyrophosphorylase, formed by the catalytic subunit Gmppb and the regulatory subunit Gmppa, condenses mannose 1-phosphate with GTP to make GDP-mannose. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | GDP-mannose biosynthetic process |
6 | 6 | 5 | 0 | 0 | 5 | 0/7 | 0 | ✗ | modules/dmel_gdp_mannose_biosynthesis.yaml | |
GPCR-PLC-calcium-PKC signaling pathway moduleMODULE:gpcr_plc_calcium_pkc_signaling A compact Gq/11-coupled GPCR signaling module. Agonist-bound GPCR activates G alpha q/11, which stimulates phospholipase C beta to cleave PIP2 into... [more...][less]A compact Gq/11-coupled GPCR signaling module. Agonist-bound GPCR activates G alpha q/11, which stimulates phospholipase C beta to cleave PIP2 into IP3 and DAG. IP3 releases calcium from intracellular stores, calcium/calmodulin activates calcium-sensitive effectors, and DAG plus calcium activates conventional PKC isoforms such as PRKCA. The pathway is grounded in GO:0007200 and includes PAINT ancestry where local seed rows support PRKCA and calmodulin roles. |
Signaling Pathway | DRAFT | eukaryotes |
3 | phospholipase C-activating G protein-coupled receptor signaling pathway |
5 | 6 | 4 | 0 | 0 | 3 | 4/6 | 0 | ✗ | modules/gpcr_plc_calcium_pkc_signaling.yaml | |
GPCR-cAMP-PKA signaling pathway moduleMODULE:gpcr_camp_pka_signaling A compact Gs-coupled GPCR signaling module. An agonist-occupied GPCR activates heterotrimeric Gs, G alpha s stimulates adenylyl cyclase, cAMP... [more...][less]A compact Gs-coupled GPCR signaling module. An agonist-occupied GPCR activates heterotrimeric Gs, G alpha s stimulates adenylyl cyclase, cAMP accumulates and activates PKA, and PKA phosphorylates cytosolic and nuclear substrates including CREB. The module is grounded in GO:0007188. ADRB2 is anchored to PAINT GPCR nodes; downstream GNAS, ADCY5, PRKACA, and CREB1 are curated UniProt exemplars without PTN ancestry claims in this first pass. |
Signaling Pathway | DRAFT | eukaryotes |
2 | adenylate cyclase-modulating G protein-coupled receptor signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 2/5 | 0 | ✗ | modules/gpcr_camp_pka_signaling.yaml | |
GPI anchor biosynthesis I — GlcNAc transferase (GPI-GnT) complex; PIGA/PIGC/PIGH/PIGP/PIGQ/PIGYMODULE:gpi_anchor_glcnac_transferase Glycosylphosphatidylinositol (GPI) anchor biosynthesis begins on the cytoplasmic face of the endoplasmic-reticulum membrane with the transfer of... [more...][less]Glycosylphosphatidylinositol (GPI) anchor biosynthesis begins on the cytoplasmic face of the endoplasmic-reticulum membrane with the transfer of N-acetylglucosamine from UDP-GlcNAc onto phosphatidylinositol (PI) to form GlcNAc-PI, the first and committed step. This reaction is carried out by the multi-subunit GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex, in which PIGA is the catalytic phosphatidylinositol N-acetylglucosaminyltransferase and PIGC, PIGH, PIGP, PIGQ (GPI1) and PIGY are required non-catalytic subunits (the Dol-P-Man synthase subunit DPM2 also associates with and regulates the complex). GPI anchors ultimately tether ~150 human proteins to the cell surface; the GlcNAc-PI product is subsequently de-N-acetylated and elaborated by the downstream Pig/Pgap enzymes. Defects in this first step cause GPI-deficiency disease: acquired somatic PIGA mutations in haematopoietic stem cells cause paroxysmal nocturnal haemoglobinuria (PNH), germline PIGA hypomorphs cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2), and biallelic PIGC/PIGH/PIGP/PIGQ/PIGY defects cause inherited GPI-deficiency developmental and epileptic encephalopathies (GPIBD). |
Metabolic Pathway | DRAFT | 0 | GPI anchor biosynthetic process |
2 | 6 | 1 | 0 | 0 | 0 | 6/6 | 0 | ✗ | modules/gpi_anchor_glcnac_transferase.yaml | ||
GPI anchor biosynthesis II — de-N-acetylation, inositol acylation and mannosylation; PIGL/PIGW/PIGM/PIGX/PIGV/PIGBMODULE:gpi_anchor_core_glycan_assembly After the GPI-GlcNAc transferase complex makes GlcNAc-PI, the glycosylphosphatidylinositol (GPI) precursor is elaborated by de-N-acetylation,... [more...][less]After the GPI-GlcNAc transferase complex makes GlcNAc-PI, the glycosylphosphatidylinositol (GPI) precursor is elaborated by de-N-acetylation, inositol acylation and the sequential addition of three mannoses, on the endoplasmic-reticulum membrane. PIGL de-N-acetylates GlcNAc-PI to glucosaminyl-phosphatidylinositol (GlcN-PI); the intermediate is then flipped to the ER lumen and PIGW acylates the inositol ring (from acyl-CoA) to GlcN-(acyl)PI, a form required for later transamidase recognition. Three dolichyl-phosphate-mannose (Dol-P-Man)- dependent mannosyltransferases then build the trimannosyl core: GPI mannosyltransferase I (the catalytic PIGM with its stabilising subunit PIGX) adds the first mannose (alpha-1,4); PIGV (GPI-MT-II) adds the second (alpha-1,6); and PIGB (GPI-MT-III) adds the third (alpha-1,2), the mannose that later receives the bridging ethanolamine-phosphate for protein attachment. Defects across this segment cause GPI-deficiency disease: PIGL (CHIME syndrome), PIGW and PIGM/PIGV (hyperphosphatasia with mental retardation / Mabry syndrome and related inherited GPI-deficiency encephalopathies), and PIGB (a developmental and epileptic encephalopathy, GPIBD). |
Metabolic Pathway | DRAFT | 0 | GPI anchor biosynthetic process |
6 | 6 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/gpi_anchor_core_glycan_assembly.yaml | ||
GPI anchor biosynthesis III — ethanolamine-phosphate additions; PIGN/PIGG/PIGF/PIGOMODULE:gpi_anchor_ethanolamine_phosphate As the trimannosyl core of the glycosylphosphatidylinositol (GPI) anchor is built, three ethanolamine-phosphate (EtNP) groups are transferred from... [more...][less]As the trimannosyl core of the glycosylphosphatidylinositol (GPI) anchor is built, three ethanolamine-phosphate (EtNP) groups are transferred from phosphatidylethanolamine onto the mannoses by three ER-membrane EtNP transferases. PIGN (GPI-ET-I) adds EtNP to the first mannose; PIGG (GPI-ET-II), together with its accessory subunit PIGF, adds EtNP to the second mannose (a side-branch EtNP removed after the anchor is attached to protein); and PIGO (GPI-ET-III), also partnered by PIGF, adds the bridging EtNP to the third mannose — the ethanolamine-phosphate whose amino group forms the amide bond to the protein C-terminus at the transamidation step. PIGF is a non-catalytic accessory subunit shared by PIGO and PIGG, required to stabilise both. Defects cause GPI-deficiency disease: PIGN (multiple congenital anomalies-hypotonia-seizures syndrome 1, MCAHS1), PIGO (hyperphosphatasia with mental retardation syndrome 2, HPMRS2), PIGG (an intellectual-disability/seizure GPIBD) and PIGF (inherited GPI deficiency). |
Metabolic Pathway | DRAFT | 0 | GPI anchor biosynthetic process |
4 | 5 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/gpi_anchor_ethanolamine_phosphate.yaml | ||
GPI anchor biosynthesis IV — transamidase complex (attachment to protein); PIGK/PIGS/PIGT/PIGU/GPAA1MODULE:gpi_anchor_transamidase The final step that commits a protein to a GPI anchor is transamidation: in the ER lumen the five-subunit GPI transamidase (GPI-T) complex... [more...][less]The final step that commits a protein to a GPI anchor is transamidation: in the ER lumen the five-subunit GPI transamidase (GPI-T) complex recognises the C-terminal GPI-attachment signal peptide of a nascent protein, cleaves it, and forms an amide bond between the new C-terminus and the amino group of the bridging ethanolamine-phosphate on the third mannose of the completed GPI precursor. PIGK (GPI8) is the catalytic subunit, a cysteine-protease-like enzyme that forms the carbonyl(acyl-enzyme) intermediate; PIGT disulfide-links to and stabilises PIGK and holds the complex together; GPAA1 helps present the GPI substrate and stabilise the intermediate for amide-bond formation; PIGU assists GPI-substrate recognition; and PIGS is an indispensable but non-catalytic subunit. The product is a mature GPI-anchored protein that is then exported and remodelled. Defects across the complex cause GPI-deficiency disease with overlapping developmental/epileptic-encephalopathy, cerebellar-atrophy and hyperphosphatasia phenotypes: PIGK, PIGS, PIGT (MCAHS3 / a PNH-like phenotype), PIGU and GPAA1. |
Metabolic Pathway | DRAFT | 0 | attachment of GPI anchor to protein GPI anchor biosynthetic process |
2 | 5 | 1 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/gpi_anchor_transamidase.yaml | ||
GPI anchor biosynthesis V — post-attachment lipid remodeling; PGAP1/PGAP3/PGAP2MODULE:gpi_anchor_remodeling After a protein has been GPI-anchored by the transamidase, the anchor's lipid moiety is remodeled so the mature GPI-anchored protein can exit the... [more...][less]After a protein has been GPI-anchored by the transamidase, the anchor's lipid moiety is remodeled so the mature GPI-anchored protein can exit the ER, traffic through the Golgi and partition into membrane microdomains (lipid rafts). Three post-GPI-attachment factors carry out the remodeling. In the endoplasmic reticulum, PGAP1 is a GPI inositol-deacylase that removes the acyl chain from the inositol ring of the anchor (the acyl group added earlier by PIGW); this inositol-deacylation is required for efficient ER-to-Golgi transport of GPI-anchored proteins. In the Golgi, fatty-acid remodeling then exchanges the unsaturated sn-2 chain of the phosphatidylinositol for a saturated one: the GPI-specific phospholipase A2 PGAP3 first removes the sn-2 unsaturated fatty acid, and PGAP2 is required to reacylate the resulting lyso-GPI intermediate with a saturated (stearoyl) chain, generating the mature, raft-associating anchor needed for stable cell-surface expression. Inherited defects cause GPI-deficiency disease: PGAP1 (intellectual disability / encephalopathy), PGAP3 (hyperphosphatasia with mental retardation syndrome 4, HPMRS4) and PGAP2 (HPMRS3). |
Metabolic Pathway | DRAFT | 0 | GPI anchor remodelling GPI anchor biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/gpi_anchor_remodeling.yaml | ||
GTPBP3-MTO1 mitochondrial tRNA modification complex in Drosophila melanogasterMODULE:dmel_gtpbp3_mto1_complexCONCRETE GTPBP3 and MTO1, the mitochondrial orthologs of bacterial MnmE and MnmG, act together to install a taurinomethyl group at the wobble uridine (U34)... [more...][less]GTPBP3 and MTO1, the mitochondrial orthologs of bacterial MnmE and MnmG, act together to install a taurinomethyl group at the wobble uridine (U34) of several mitochondrial tRNAs, forming taurinomethyluridine (taum5U). This modification supports accurate decoding during mitochondrial translation. GTPBP3 is a GTPase that binds the methylene donor, and MTO1 is an FAD-dependent enzyme. In Drosophila the orthologs are CG18528 (GTPBP3) and CG4610 (MTO1). |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | GTPBP3-MTO1 complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_gtpbp3_mto1_complex.yaml | |
Galactose catabolism (Leloir pathway)MODULE:galactose_leloir_pathwayCONCRETE The Leloir pathway converts D-galactose to glucose 6-phosphate. A galactose mutarotase supplies alpha-D-galactose, galactokinase phosphorylates it... [more...][less]The Leloir pathway converts D-galactose to glucose 6-phosphate. A galactose mutarotase supplies alpha-D-galactose, galactokinase phosphorylates it to alpha-D-galactose 1-phosphate, and galactose-1-phosphate uridylyltransferase exchanges UMP with UDP-glucose to give glucose 1-phosphate and UDP-galactose. UDP-glucose 4-epimerase regenerates UDP-glucose from UDP-galactose, so the pathway is catalytic in its UDP-sugar co-substrate, and phosphoglucomutase converts glucose 1-phosphate to glucose 6-phosphate for glycolysis. In bacteria and animals the mutarotase and the epimerase are separate proteins; in yeasts a single bifunctional protein carries an N-terminal UDP-glucose 4-epimerase domain and a C-terminal mutarotase domain. The pathway is distinct from nucleotide-sugar biosynthesis or isolated UDP-galactose epimerization in organisms that lack the galactokinase and uridylyltransferase reactions. |
Metabolic Pathway | DRAFT | 3 | Leloir pathway |
8 | 6 | 5 | 1 | 2 | 5 | 16/19 | 0 | ✗ | modules/galactose_leloir_pathway.yaml | ||
Galanin-activated signaling pathway moduleMODULE:galanin_signaling The galanin-activated signaling pathway (GO:0090663) is initiated when the secreted neuropeptide hormones galanin (GAL, PANTHER:PTHR16839:SF1; a... [more...][less]The galanin-activated signaling pathway (GO:0090663) is initiated when the secreted neuropeptide hormones galanin (GAL, PANTHER:PTHR16839:SF1; a 29- to 30-residue peptide sharing a strictly conserved N-terminal Trp2-Asn5-Tyr9 pharmacophore) and galanin-like peptide (GALP, PANTHER:PTHR20950:SF1; a 60-residue hypothalamic neuropeptide whose residues 9-21 are identical to galanin residues 1-13) bind and activate the seven-transmembrane G protein-coupled galanin receptors GALR1 (PANTHER:PTHR24230:SF31), GALR2 (PANTHER:PTHR24230:SF13), and GALR3 (PANTHER:PTHR24230:SF17) at the plasma membrane of central and peripheral neurons, pituitary cells, and pancreatic islet cells. Agonist-bound GALR1 and GALR3 couple primarily to pertussis-toxin-sensitive Gi/o heterotrimeric G proteins (exemplified by GNAI1, PANTHER:PTHR10218:SF359) to inhibit adenylate cyclase and open GIRK channels, whereas GALR2 couples primarily to Gq/11 proteins (exemplified by GNAQ, PANTHER:PTHR10218:SF329) to activate phospholipase C-beta (PLCB1, PANTHER:PTHR10336:SF12), mobilize IP3-sensitive intracellular Ca2+ stores, and modulate nociception, feeding, neuroendocrine secretion, and neuronal excitability. |
Signaling Pathway | DRAFT | Euteleostomi |
1 | galanin-activated signaling pathway |
3 | 8 | 2 | 0 | 0 | 1 | 4/8 | 0 | ✗ | modules/galanin_signaling.yaml | |
Gamma-glutamyl putrescine catabolism to 4-aminobutanoateMODULE:gamma_glutamyl_putrescine_catabolismCONCRETE A four-reaction route in which putrescine is activated by ATP-dependent gamma-glutamylation, oxidized to a gamma-glutamyl aminoaldehyde, oxidized... [more...][less]A four-reaction route in which putrescine is activated by ATP-dependent gamma-glutamylation, oxidized to a gamma-glutamyl aminoaldehyde, oxidized again to gamma-glutamyl-4-aminobutanoate, and hydrolyzed to release 4-aminobutanoate (GABA) and glutamate. Putrescine supply and import, the parallel non-glutamylated transaminase route, and the downstream GABA shunt are separate modules. |
Metabolic Pathway | DRAFT | 1 | putrescine catabolic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/11 | 0 | ✗ | modules/gamma_glutamyl_putrescine_catabolism.yaml | ||
Gamma-secretase complex in Drosophila melanogasterMODULE:dmel_gamma_secretase_complexCONCRETE Gamma-secretase is an intramembrane aspartyl protease that cleaves type I membrane proteins within their transmembrane domains after their... [more...][less]Gamma-secretase is an intramembrane aspartyl protease that cleaves type I membrane proteins within their transmembrane domains after their ectodomains have been shed. Presenilin (Psn) is the catalytic subunit and carries the two catalytic aspartates; nicastrin (Nct), Aph-1 and Pen-2 are required for assembly, maturation and activity. In Drosophila the complex performs the S3 cleavage of Notch that releases the Notch intracellular domain, so loss of its subunits causes Notch-like phenotypes. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | gamma-secretase complex |
3 | 2 | 2 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/dmel_gamma_secretase_complex.yaml | |
Gamma-tubulin complexes in Drosophila melanogasterMODULE:dmel_gamma_tubulin_complexesCONCRETE Gamma-tubulin complexes nucleate microtubules at centrosomes, spindles and other microtubule-organizing centres. The basic unit is the... [more...][less]Gamma-tubulin complexes nucleate microtubules at centrosomes, spindles and other microtubule-organizing centres. The basic unit is the gamma-tubulin small complex (gamma-TuSC), two gamma-tubulin molecules bound to Grip84 (GCP2) and Grip91 (GCP3). In the larger gamma-tubulin ring complex (gamma-TuRC), several gamma-TuSCs assemble with additional GCP-family proteins (Grip75, Grip128, Grip163) and Grip71 into a ring that templates the 13-protofilament microtubule. Drosophila has two gamma-tubulins: gammaTub23C, used in most tissues, and gammaTub37C, which is maternally supplied and acts in the female germline and early embryo. In the testis a separate gamma-TuRC built from testis-specific t-Grip84, t-Grip91 and t-Grip128 paralogs acts in spermatogenesis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | gamma-tubulin complex |
5 | 3 | 2 | 1 | 2 | 0 | 0/11 | 0 | ✗ | modules/dmel_gamma_tubulin_complexes.yaml | |
Gammaproteobacterial RNase E-centered RNA degradationMODULE:bacterial_rna_degradationCONCRETE Reusable gammaproteobacterial RNA-degradation module in which the membrane-associated endoribonuclease RNase E initiates decay by 5'-end- dependent... [more...][less]Reusable gammaproteobacterial RNA-degradation module in which the membrane-associated endoribonuclease RNase E initiates decay by 5'-end- dependent internal cleavage and its disordered C-terminal scaffold recruits a DEAD-box helicase and a processive 3'-to-5' exoribonuclease. The helicase unwinds structured decay intermediates so that the exonuclease can complete degradation. The canonical Escherichia coli degradosome uses RhlB and the phosphorolytic PNPase; RhlE and the hydrolytic RNase R are alternative partners in Pseudomonas, so helicase and exonuclease identity are modeled as lineage-variable implementations. |
Biological Process | COMPLETE | Gammaproteobacteria |
0 | mRNA catabolic process |
8 | 5 | 3 | 2 | 4 | 3 | 10/10 | 0 | ✗ | modules/bacterial_rna_degradation.yaml | |
Gcn5-containing histone acetyltransferase complexes in Drosophila melanogasterMODULE:dmel_gcn5_acetyltransferase_complexesCONCRETE The histone acetyltransferase Gcn5 acetylates histone H3 as the catalytic subunit of several coactivator complexes. Gcn5 always sits in a HAT... [more...][less]The histone acetyltransferase Gcn5 acetylates histone H3 as the catalytic subunit of several coactivator complexes. Gcn5 always sits in a HAT module with Ada3, Sgf29 and an Ada2 paralog. With Ada2b it forms part of SAGA, a large coactivator that also contains a TBP-interacting core, the Tra1 homolog Nipped-A, and a deubiquitinase module that removes ubiquitin from histone H2B through the protease Nonstop. With Ada2a it forms ATAC, which also contains the Atac1-3 subunits. Smaller ADA and CHAT (Chiffon-containing) complexes contain only the HAT module, with Chiffon in CHAT. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | histone acetyltransferase complex |
10 | 8 | 5 | 1 | 4 | 0 | 0/32 | 0 | ✗ | modules/dmel_gcn5_acetyltransferase_complexes.yaml | |
Generic E1-E2-E3 ubiquitin transfer relay motifMODULE:ubiquitin_transfer_relay The minimal, reusable ubiquitin-conjugation relay: an E1 ubiquitin-activating enzyme adenylates ubiquitin and forms a thioester with it in an... [more...][less]The minimal, reusable ubiquitin-conjugation relay: an E1 ubiquitin-activating enzyme adenylates ubiquitin and forms a thioester with it in an ATP-dependent reaction; the activated ubiquitin is passed to the active-site cysteine of an E2 conjugating enzyme; and an E3 ligase brings the E2~ubiquitin together with a selected substrate to transfer ubiquitin onto a substrate lysine. Iteration builds polyubiquitin chains that mark substrates for proteasomal degradation or other fates. The same relay (with cognate activating/conjugating/ligase enzymes) is reused by the ubiquitin-like modifiers SUMO, NEDD8, and ISG15. The motif is gene-free and taxon-neutral, fixing only the E1/E2/E3 roles by molecular-function term and the activating transfer topology. Grounded in GO:0016567 (protein ubiquitination). |
Biological Process | DRAFT | 0 | protein ubiquitination |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/ubiquitin_transfer_relay.yaml | ||
Generic Embden-Meyerhof-Parnas (EMP) glycolysis moduleMODULE:generic_emp_glycolysisABSTRACT A generic, taxon-neutral decomposition of Embden-Meyerhof-Parnas glycolysis as a module: the catabolism of a hexose phosphate to pyruvate through... [more...][less]A generic, taxon-neutral decomposition of Embden-Meyerhof-Parnas glycolysis as a module: the catabolism of a hexose phosphate to pyruvate through the fructose-6-phosphate and fructose-1,6-bisphosphate intermediates, with net production of ATP and reduced pyridine nucleotide. The module is deliberately phrased as an ordered chain of reaction steps with abstract function selectors rather than a fixed list of genes, so that it can represent bacterial, archaeal, fungal, plant, and animal implementations of the same route. Its defining feature is the passage through fructose-6-phosphate, which is what separates EMP from the Entner-Doudoroff route (which passes through 6-phosphogluconate and 2-keto-3-deoxy-6-phosphogluconate) and from the phosphoketolase routes. Three axes of genuine cross-taxon variation are modelled explicitly as variant sets: how hexose carbon enters the hexose-phosphate pool (ATP-dependent kinase, ADP-dependent kinase, phosphotransferase-system transport coupling, glucose-1-phosphate from a glucan, or fructose and mannose phosphorylated and delivered straight to the fructose 6-phosphate pool), which phosphoryl donor drives the committed 6-phosphofructokinase step (ATP, diphosphate, or ADP), and whether the glyceraldehyde-3-phosphate oxidation step is phosphorylating (conserving the oxidation energy as 1,3-bisphosphoglycerate and then ATP) or non-phosphorylating (running straight to 3-phosphoglycerate and forgoing that ATP). A concrete organism module specialises these selectors with genes, isozymes, compartments, and regulation; see the human investment-phase and payoff-phase modules for a worked concrete instantiation. The steps used by fungi are oriented by representative enzyme families with budding-yeast and fission-yeast members, including the paralogous isozymes that share a step. |
Metabolic Pathway | DRAFT | 0 | glycolytic process through fructose-6-phosphate |
29 | 21 | 13 | 5 | 15 | 13 | 35/36 | 0 | ✗ | modules/emp_glycolysis.yaml | ||
Generic GTPase nucleotide switch motif (GEF / GTP / GAP)MODULE:gtpase_switchABSTRACT The minimal, reusable nucleotide-switch motif shared by regulatory GTPases: a guanine-nucleotide exchange factor (GEF) loads GTP to flip the GTPase... [more...][less]The minimal, reusable nucleotide-switch motif shared by regulatory GTPases: a guanine-nucleotide exchange factor (GEF) loads GTP to flip the GTPase into its active conformation, where it engages downstream effectors; a GTPase-activating protein (GAP) then stimulates GTP hydrolysis to return the switch to its inactive GDP-bound state. The motif is deliberately gene-free and taxon-neutral: it fixes only the GEF/GTPase/GAP roles (by molecular-function term) and the load/hydrolyze topology. Concrete switches - the Ras, Rho/Rac/Cdc42, Rab, Arf, Ran, and heterotrimeric-Galpha families - embed this motif as an inner bundle through `conforms_to`, substituting their own GEF/GTPase/GAP and the specific effectors they activate. Grounded in GO:0007264 (small GTPase-mediated signal transduction). |
Signaling Pathway | DRAFT | 0 | small GTPase-mediated signal transduction |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 0 | ✗ | modules/gtpase_switch.yaml | ||
Generic PI3K-AKT-mTOR signaling moduleMODULE:pi3k_akt_mtor A taxon-neutral decomposition of the class I PI3K-AKT-mTOR signaling axis, the reusable survival/growth/metabolism arm deployed downstream of many... [more...][less]A taxon-neutral decomposition of the class I PI3K-AKT-mTOR signaling axis, the reusable survival/growth/metabolism arm deployed downstream of many receptor systems. Like the Ras-MAPK cascade it is a "sidecar" module: the same PI3K->PIP3->AKT->mTOR core is engaged by receptor tyrosine kinases (insulin/IGF, EGFR, PDGFR), by insulin-receptor-substrate (IRS) adaptors, by cytokine receptors signaling through JAKs, by GPCRs (class IB PI3K-gamma), and by active Ras. The module captures: (1) recruitment and activation of class I PI3K (p110 catalytic + p85 regulatory subunits) at a receptor phosphotyrosine, via IRS, or by Ras; (2) PI3K conversion of PIP2 to the second messenger PIP3; (3) PIP3-dependent membrane recruitment of PH-domain proteins PDK1 and AKT; (4) AKT activation by dual phosphorylation (PDK1 on Thr308, mTORC2 on Ser473); (5) AKT-driven activation of mTORC1 via inhibition of the TSC1/2 GAP and consequent Rheb-GTP accumulation; (6) downstream outputs - mTORC1 activation of S6K and 4E-BP1 (translation/growth) and AKT inhibition of FOXO and GSK3 (survival, metabolism); and (7) negative regulation, principally the lipid phosphatase PTEN (which removes the 3-phosphate from PIP3), plus PHLPP (AKT dephosphorylation) and the TSC complex. Grounded in GO:0043491 (phosphatidylinositol 3-kinase/protein kinase B signal transduction) and GO:0031929 (TOR signaling). |
Signaling Pathway | DRAFT | metazoa |
0 | phosphatidylinositol 3-kinase/protein kinase B signal transduction TOR signaling |
7 | 7 | 6 | 0 | 0 | 5 | 2/2 | 4 | ✗ | modules/pi3k_akt_mtor.yaml | |
Generic SNARE-mediated membrane fusion cycle motifMODULE:snare_fusion_cycle The minimal, reusable membrane-fusion motif: cognate vesicle (v-/R-) and target (t-/Q-) SNAREs zipper into a four-helix trans-SNARE complex that... [more...][less]The minimal, reusable membrane-fusion motif: cognate vesicle (v-/R-) and target (t-/Q-) SNAREs zipper into a four-helix trans-SNARE complex that pulls the two bilayers together; the resulting force drives membrane fusion and cargo delivery; and the ATPase NSF, with its SNAP cofactors, then disassembles the cis-SNARE complex to recycle the SNAREs for another round. This cycle underlies essentially all intracellular vesicular fusion (ER-Golgi, endosomal, synaptic-vesicle, etc.). The motif is gene-free and taxon-neutral, fixing only the SNARE-pairing and fusion roles and the pair -> fuse -> recycle topology. Grounded in GO:0006906 (vesicle fusion). |
Transport Step | DRAFT | 0 | vesicle fusion |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/snare_fusion_cycle.yaml | ||
Generic Wnt signaling pathway moduleMODULE:generic_wnt_signaling A generic, taxon-neutral decomposition of Wnt signaling as a module. Wnt signaling is an ancient metazoan cell-cell communication system in which... [more...][less]A generic, taxon-neutral decomposition of Wnt signaling as a module. Wnt signaling is an ancient metazoan cell-cell communication system in which secreted, lipid-modified Wnt glycoproteins act on neighboring cells to control proliferation, cell-fate specification, polarity, and stem-cell maintenance. The module is phrased as a set of conserved functions and pathway segments rather than a fixed gene list, so it can represent invertebrate and vertebrate implementations and the multiple paralogous family members at each step. It captures the shared upstream events (Wnt acylation, secretion, and receptor engagement) and then branches into the canonical beta-catenin-dependent pathway and the beta-catenin-independent (planar-cell-polarity and calcium) pathways. The canonical branch is modeled with both its ligand-off state (the beta-catenin destruction complex driving beta-catenin turnover) and its ligand-on state (signalosome assembly, destruction-complex inhibition, beta-catenin stabilization, nuclear entry, and TCF/LEF-dependent transcription). |
Signaling Pathway | DRAFT | metazoa |
0 | Wnt signaling pathway |
14 | 18 | 8 | 2 | 5 | 9 | 5/13 | 5 | ✗ | modules/wnt_signaling.yaml | |
Generic coat-mediated vesicle budding motifMODULE:vesicle_coat_budding The minimal, reusable vesicle-budding motif: a membrane-associated small GTPase (Arf or Sar1, switched on by its GEF) nucleates assembly of a... [more...][less]The minimal, reusable vesicle-budding motif: a membrane-associated small GTPase (Arf or Sar1, switched on by its GEF) nucleates assembly of a protein coat on the donor membrane; coat adaptors capture transmembrane cargo and concentrate it into the forming bud; polymerization of the coat deforms the membrane and drives scission of a coated vesicle; and the coat is then shed (uncoating, often on GTP hydrolysis) to yield a transport-competent vesicle. The same motif is reused by the COPII (ER exit), COPI (Golgi-to-ER), and clathrin (post-Golgi/ endocytic) systems. The motif is gene-free and taxon-neutral, fixing only the coat, adaptor, and budding roles and the recruit -> capture -> bud -> uncoat topology. Grounded in GO:0006900 (vesicle budding from membrane). |
Transport Step | DRAFT | 0 | vesicle budding from membrane |
5 | 4 | 4 | 0 | 0 | 3 | 0/0 | 4 | ✗ | modules/vesicle_coat_budding.yaml | ||
Generic ferroptosis-defense-factor abundance/activity switch motifMODULE:ferroptosis_defense_factor_switch The minimal, reusable motif for set-point control of a ferroptosis-defense factor: a defense node - a suppressor whose activity is part_of negative... [more...][less]The minimal, reusable motif for set-point control of a ferroptosis-defense factor: a defense node - a suppressor whose activity is part_of negative regulation of ferroptosis (GO:0110076) - is held between two opposed arms. A destabilizer arm lowers the suppressor's abundance or activity (it directly negatively regulates the defense node and is itself part_of positive regulation of ferroptosis, GO:0160020), and a stabilizer arm preserves or restores it (it directly positively regulates the defense node and is part_of negative regulation of ferroptosis). The net ferroptosis set-point is the balance of the two arms acting on the shared defense node. Unlike molecular-function-tiered motifs (e.g. the MAPK relay, where every realization shares the MAP3K/MAP2K/MAPK function terms), the tiers of THIS motif are unified by causal role and topology, NOT by a shared molecular function. Two curated GO-CAM realizations make this explicit with completely different machinery: SLC7A11 is destabilized by a CRL3 ubiquitin ligase (CUL3-KCTD10-RBX1) and rescued by a deubiquitinase (USP18); GPX4 is destabilized by chaperone-mediated autophagy (HSPA8-LAMP2) and stabilized by EGLN3/PHD3 prolyl hydroxylation. Concrete realizations therefore embed this motif through `conforms_to` with status WITH_DEVIATIONS - matching the destabilizer/stabilizer topology while substituting instance-specific tier functions - rather than the EXACT status used by shared-function cascades. |
Regulatory Step | DRAFT | 0 | negative regulation of ferroptosis positive regulation of ferroptosis |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/ferroptosis_defense_factor_switch.yaml | ||
Generic gluconeogenesis moduleMODULE:generic_gluconeogenesisABSTRACT A generic, taxon-neutral decomposition of gluconeogenesis: the synthesis of a hexose phosphate (and, in some lineages, free glucose) from three-... [more...][less]A generic, taxon-neutral decomposition of gluconeogenesis: the synthesis of a hexose phosphate (and, in some lineages, free glucose) from three- and four-carbon precursors such as pyruvate, lactate, glycerol, amino-acid skeletons, or the malate and oxaloacetate made by the glyoxylate cycle from two-carbon substrates. Seven near-equilibrium reactions are shared with Embden-Meyerhof-Parnas glycolysis and run in reverse. The three effectively irreversible glycolytic steps are bypassed by dedicated enzymes. Pyruvate kinase is bypassed either in two steps through oxaloacetate (a pyruvate carboxylase or a malate dehydrogenase makes oxaloacetate, and a phosphoenolpyruvate carboxykinase decarboxylates and phosphorylates it) or in one step by a pyruvate dikinase. Phosphofructokinase is bypassed by fructose-1,6-bisphosphatase. Hexokinase is bypassed only where free glucose is released, by glucose-6-phosphatase. Organisms that keep the product as glucose 6-phosphate for storage polysaccharides and cell-wall glucans stop one step earlier. The module is written as function selectors grounded by representative enzyme families, so that it can represent bacterial, fungal, plant and animal implementations. |
Metabolic Pathway | DRAFT | 0 | gluconeogenesis |
27 | 17 | 13 | 6 | 13 | 11 | 16/17 | 0 | ✗ | modules/gluconeogenesis.yaml | ||
Generic kinase / phosphatase reversible-phosphorylation toggle motifMODULE:kinase_phosphatase_toggle The minimal, reusable reversible-phosphorylation switch: a protein kinase phosphorylates a substrate to set one functional state, and an opposing... [more...][less]The minimal, reusable reversible-phosphorylation switch: a protein kinase phosphorylates a substrate to set one functional state, and an opposing protein phosphatase removes the phosphate to reset it. This antagonistic kinase/ phosphatase pair acting on a shared substrate is the most pervasive regulatory toggle in biology (cell-cycle CDK/phosphatase pairs, the DUSP/MKP feedback in MAPK cascades, receptor kinase/phosphatase balance, etc.). The motif is gene-free and taxon-neutral: it fixes only the kinase and phosphatase roles by molecular-function term and their opposing action on one substrate state. Concrete switches embed it through `conforms_to`, substituting their own kinase, phosphatase, and substrate. Grounded in GO:0006468 (protein phosphorylation) and GO:0006470 (protein dephosphorylation). |
Regulatory Step | DRAFT | 0 | protein phosphorylation protein dephosphorylation |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/kinase_phosphatase_toggle.yaml | ||
Generic phosphotyrosine-adaptor recruitment motifMODULE:phosphotyrosine_adaptor_recruitment The minimal, reusable receptor-proximal recruitment motif: an activated receptor (or receptor-associated kinase) presents a phosphotyrosine docking... [more...][less]The minimal, reusable receptor-proximal recruitment motif: an activated receptor (or receptor-associated kinase) presents a phosphotyrosine docking site; an SH2- or PTB-domain adaptor recognizes that phosphotyrosine; and the adaptor, through a second interaction surface (e.g. an SH3 domain), recruits a downstream effector to the membrane. This pTyr -> adaptor -> effector wiring is the generic interface by which receptor tyrosine kinases, cytokine-receptor- associated JAKs, and other tyrosine-phosphorylation events launch downstream pathways - it is the recruitment step that precedes the Ras switch in MODULE:erk_cascade. The motif is gene-free and taxon-neutral, fixing only the phosphotyrosine-binding and adaptor roles and the recruitment topology. Grounded in GO:0007169 (cell surface receptor protein tyrosine kinase signaling pathway). |
Signaling Pathway | DRAFT | 0 | cell surface receptor protein tyrosine kinase signaling pathway |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/phosphotyrosine_adaptor_recruitment.yaml | ||
Generic three-tier MAP kinase relay (MAP3K -> MAP2K -> MAPK)MODULE:mapk_relayABSTRACT The minimal, reusable core motif shared by all mitogen-activated protein kinase cascades: a three-tier protein kinase relay in which a MAP kinase... [more...][less]The minimal, reusable core motif shared by all mitogen-activated protein kinase cascades: a three-tier protein kinase relay in which a MAP kinase kinase kinase (MAP3K) phosphorylates and activates a MAP kinase kinase (MAP2K), which in turn dually phosphorylates the activation loop of a MAP kinase (MAPK). The motif is deliberately gene-free and taxon-neutral: it fixes only the three tier identities (by molecular-function term) and the activating phosphotransfer topology that connects them. Concrete cascades - ERK1/2, p38, JNK, ERK5, the fungal Fus3/Kss1/Hog1 pathways, and plant MPK cascades - embed this motif as an inner bundle through `conforms_to`, substituting their own kinase families and adding their own upstream activation and downstream effector steps before and after the relay. Grounded in GO:0000165 (MAPK cascade). |
Signaling Pathway | DRAFT | 0 | MAPK cascade |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 0 | ✗ | modules/mapk_relay.yaml | ||
Generic two-component / phosphorelay signal transduction motifMODULE:two_component_relay The minimal, reusable phosphorelay motif of two-component signal transduction: a sensor histidine kinase autophosphorylates on a conserved... [more...][less]The minimal, reusable phosphorelay motif of two-component signal transduction: a sensor histidine kinase autophosphorylates on a conserved histidine in response to a stimulus, then transfers the phosphoryl group to a conserved aspartate on a cognate response regulator, which effects the output (often transcriptional). An optional histidine-phosphotransfer (Hpt) step inserts a His->Asp->His->Asp multistep relay between the sensor and the terminal response regulator. The motif is gene-free and taxon-neutral: it fixes the sensor-kinase / (phosphotransfer) / response-regulator roles by molecular-function term and the His->Asp phosphotransfer topology. Bacterial, archaeal, plant, and fungal two-component systems embed it through `conforms_to` (e.g. the Sln1->Ypd1->Ssk1 phosphorelay upstream of MODULE:scer_hog1_cascade). Grounded in GO:0000160 (phosphorelay signal transduction system). |
Signaling Pathway | DRAFT | 0 | phosphorelay signal transduction system |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/two_component_relay.yaml | ||
Generic zymogen protease-activation cascade motifMODULE:protease_activation_cascade The minimal, reusable proteolytic-activation motif: an active protease cleaves an inactive zymogen at a specific site, converting it into the next... [more...][less]The minimal, reusable proteolytic-activation motif: an active protease cleaves an inactive zymogen at a specific site, converting it into the next active protease, which in turn activates the following zymogen (and acts on effector substrates). Iterating this step builds the self-amplifying proteolytic cascades of the caspase apoptosis pathway, the complement system, and the coagulation cascade. The motif is gene-free and taxon-neutral: it fixes only the protease and zymogen-substrate roles and the cleavage-activates-the-next topology. Concrete cascades embed it through `conforms_to`, substituting their own protease family and zymogen substrates. Grounded in GO:0031638 (zymogen activation). |
Biological Process | DRAFT | 0 | zymogen activation |
4 | 3 | 3 | 0 | 0 | 2 | 0/0 | 3 | ✗ | modules/protease_activation_cascade.yaml | ||
Germ layer specification moduleMODULE:germ_layer_specification The early-metazoan program that, during gastrulation, partitions the pluripotent epiblast/blastula into the three primary germ layers - endoderm,... [more...][less]The early-metazoan program that, during gastrulation, partitions the pluripotent epiblast/blastula into the three primary germ layers - endoderm, mesoderm, and ectoderm - each of which is grounded in a distinct GO "formation of primary germ layer" child term and driven by a conserved signalling logic. High Nodal/TGF-beta (with Wnt and FGF) induces endoderm and mesoderm and their master transcription factors (SOX17, FOXA2, GATA4/6 for endoderm; Brachyury/TBXT, EOMES, MIXL1 for mesoderm), while the ectoderm arises where these signals are low, splitting into BMP-high epidermal and BMP-low (organizer-antagonised) neural ectoderm. The three layers are modelled as a variant set along the "germ layer" axis. Grounded in GO:0001704 (formation of primary germ layer) within GO:0007369 (gastrulation). The upstream morphogen gradients are supplied by modules/body_axis_specification.yaml; the signalling machinery is detailed in the nodal_signaling, wnt_signaling, bmp_signaling, and fgfr_signaling modules. |
Developmental Process | DRAFT | metazoa |
2 | formation of primary germ layer gastrulation |
4 | 8 | 0 | 1 | 3 | 2 | 5/9 | 0 | ✗ | modules/germ_layer_specification.yaml | |
Gibberellin perception and DELLA derepression (GID1-DELLA-SCF(SLY1) module)MODULE:gibberellin_della_signalingABSTRACT Gibberellin (GA) signaling in vascular plants works by de-repression. In the absence of GA, nuclear DELLA proteins (GRAS-family transcriptional... [more...][less]Gibberellin (GA) signaling in vascular plants works by de-repression. In the absence of GA, nuclear DELLA proteins (GRAS-family transcriptional regulators without a DNA-binding domain) restrain growth in part by binding and inactivating growth-promoting transcription factors such as the bHLH PHYTOCHROME-INTERACTING FACTORS (PIF3, PIF4). Bioactive GA (mainly GA4 and GA1) binds the soluble receptor GID1, a non-catalytic member of the hormone-sensitive-lipase alpha/beta-hydrolase family, in a deep pocket that is then capped by the receptor's N-terminal lid. The lid creates a surface that captures the N-terminal DELLA domain (DELLA, VHYNP and LExLE motifs), forming a GA-GID1-DELLA complex in which the DELLA GRAS domain is also contacted by the receptor. The DELLA GRAS domain in this complex is bound with higher affinity by the F-box protein SLEEPY1 (SLY1; GID2 in rice), the substrate adaptor of an SCF E3 ubiquitin ligase (SLY1-ASK1/ASK2-CUL1-RBX1). SCF(SLY1) polyubiquitinates the DELLA, which is then degraded by the 26S proteasome, releasing PIFs and other DELLA-sequestered regulators to drive growth programs such as hypocotyl and stem elongation, seed germination and floral development. GA-GID1 binding also inhibits DELLA activity without proteolysis, apparently by occluding DELLA surfaces needed for partner binding. In Arabidopsis the receptor step is carried out redundantly by GID1A, GID1B and GID1C, and the DELLA step by five paralogs (GAI and RGA, which dominate vegetative growth, and RGL1, RGL2 and RGL3, which act mainly in germination and flower development). Gibberellin biosynthesis and catabolism, which set the GA level, and transcriptional feedback of DELLAs on GA metabolism and receptor genes, are outside this module. |
Signaling Pathway | DRAFT | vascular plants |
0 | gibberellin mediated signaling pathway |
5 | 4 | 4 | 0 | 0 | 4 | 8/8 | 0 | ✗ | modules/gibberellin_della_signaling.yaml | |
Glucagon receptor signaling — glucagon acting through GCGR, Gs, adenylyl cyclase 5/6 and cAMP/PKA, with GRK/beta-arrestin desensitizationMODULE:glucagon_receptor_signalingCONCRETE Glucagon is the counter-regulatory hormone to insulin: released from pancreatic alpha cells when blood glucose falls, it acts chiefly on liver and... [more...][less]Glucagon is the counter-regulatory hormone to insulin: released from pancreatic alpha cells when blood glucose falls, it acts chiefly on liver and kidney through the glucagon receptor (GCGR), a class B G protein-coupled receptor. Agonist-occupied GCGR acts as a guanine nucleotide exchange factor for the stimulatory G protein; GTP-bound G alpha s (GNAS) activates the membrane adenylyl cyclases ADCY5 and ADCY6, raising cAMP and activating protein kinase A (PKA). PKA then drives the hepatic glucose-output programme — activation of glycogenolysis, inhibition of glycogen synthesis and glycolysis, and promotion of gluconeogenesis — which lies downstream of this module. Glucagon itself is one of several peptides cut from the preproglucagon precursor encoded by GCG; the convertase that makes glucagon in alpha cells is part of hormone processing rather than of receptor signalling. As for the other Gs-coupled hormone receptors, signalling is limited by G protein-coupled receptor kinase phosphorylation of the occupied receptor and subsequent beta-arrestin binding. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cellular response to glucagon stimulus |
9 | 7 | 6 | 1 | 2 | 5 | 3/8 | 0 | ✗ | modules/glucagon_receptor_signaling.yaml | |
Glucarate and galactarate catabolism to 2-oxoglutarateMODULE:glucarate_galactarate_catabolismCONCRETE A reusable three-stage aldarate catabolic route in which substrate-specific dehydratases convert D-glucarate or D-galactarate to the common... [more...][less]A reusable three-stage aldarate catabolic route in which substrate-specific dehydratases convert D-glucarate or D-galactarate to the common intermediate 5-dehydro-4-deoxy-D-glucarate. A second dehydratase then forms 2,5-dioxopentanoate, which an aldehyde dehydrogenase-family enzyme oxidizes to 2-oxoglutarate. Organisms can encode either or both substrate-entry reactions. |
Metabolic Pathway | DRAFT | 2 | D-glucarate catabolic process D-galactarate catabolic process |
6 | 4 | 3 | 1 | 2 | 3 | 4/8 | 0 | ✗ | modules/glucarate_galactarate_catabolism.yaml | ||
Glucocorticoid receptor signaling pathway moduleMODULE:glucocorticoid_receptor_signaling Glucocorticoid receptor signaling couples steroid ligand binding, HSP90/co-chaperone regulation, nuclear translocation, and co-regulator exchange... [more...][less]Glucocorticoid receptor signaling couples steroid ligand binding, HSP90/co-chaperone regulation, nuclear translocation, and co-regulator exchange to anti-inflammatory and metabolic transcriptional programs. |
Signaling Pathway | DRAFT | metazoa |
3 | nuclear receptor-mediated glucocorticoid signaling pathway |
4 | 8 | 3 | 0 | 0 | 2 | 5/6 | 0 | ✓ | modules/glucocorticoid_receptor_signaling.yaml | |
Gluconeogenesis (human) with precursor-entry routesMODULE:gluconeogenesis_human_substrates Extension of the human gluconeogenesis module that makes the choice of non-carbohydrate precursor explicit. The three physiological precursors... [more...][less]Extension of the human gluconeogenesis module that makes the choice of non-carbohydrate precursor explicit. The three physiological precursors enter the pathway at different points: lactate (via lactate dehydrogenase) and the glucogenic amino acid alanine (via alanine aminotransferase) are converted to pyruvate and so require the pyruvate carboxylase / phosphoenolpyruvate carboxykinase backbone, whereas glycerol enters lower down — glycerol kinase and cytosolic glycerol-3-phosphate dehydrogenase feed dihydroxyacetone phosphate directly into the triose-phosphate pool, bypassing pyruvate carboxylase and PEPCK entirely. All routes converge on the shared fructose-1,6-bisphosphatase step and the terminal endoplasmic-reticulum glucose-6-phosphatase system (G6PC1 plus the SLC37A4 antiporter). Because glycerol bypasses the carboxylation arm, pyruvate carboxylase is no longer required by every route: the only steps common to all precursor routes are the terminal G6PC1·SLC37A4 system, which is therefore the single universal gate of free-glucose output. The module is built to be evaluated against tissue expression so that, per tissue, one can ask not just whether gluconeogenesis is possible but which precursors a tissue is equipped to use. |
Metabolic Pathway | DRAFT | 0 | gluconeogenesis |
23 | 13 | 10 | 6 | 12 | 0 | 11/13 | 0 | ✗ | modules/gluconeogenesis_human_substrates.yaml | ||
Gluconeogenesis (human, tissue- and compartment-resolved)MODULE:gluconeogenesis_human Human gluconeogenesis: the synthesis of free glucose from non-carbohydrate precursors (lactate, glucogenic amino acids such as alanine, and... [more...][less]Human gluconeogenesis: the synthesis of free glucose from non-carbohydrate precursors (lactate, glucogenic amino acids such as alanine, and glycerol). Unlike the taxon-neutral gluconeogenesis template, this module is grounded to specific human isozymes and is organised around the fact that in a metazoan the pathway is not uniformly active: every cell carries the genes, but free-glucose output is restricted to a few tissues. Three control points are encoded as variant sets over human isozymes that differ by tissue and subcellular compartment: the phosphoenolpyruvate-forming step (cytosolic PCK1 vs mitochondrial PCK2), the fructose-1,6-bisphosphatase step (gluconeogenic FBP1 vs muscle FBP2), and the terminal glucose-releasing step, which is a two-component endoplasmic-reticulum system requiring both a catalytic subunit and the glucose-6-phosphate antiporter SLC37A4. The terminal step is the physiological gate: only tissues expressing the gluconeogenic catalytic subunit G6PC1 together with SLC37A4 can release free glucose, which is why liver, kidney cortex, and intestine are gluconeogenic while skeletal muscle and brain are not. This module is designed to be evaluated against tissue expression data: each isozyme atom is an expressed/not-expressed predicate per context, so the realised route through the pathway can be resolved per tissue. |
Metabolic Pathway | DRAFT | 0 | gluconeogenesis |
12 | 7 | 7 | 2 | 4 | 4 | 5/7 | 1 | ✗ | modules/gluconeogenesis_human.yaml | ||
Glucose-6-phosphatase system (endogenous glucose production) — GSD Ia/Ib, G6PC3-SCN4MODULE:glucose_6_phosphatase_system The glucose-6-phosphatase system is the endoplasmic-reticulum machinery that carries out the terminal, committed step of endogenous glucose... [more...][less]The glucose-6-phosphatase system is the endoplasmic-reticulum machinery that carries out the terminal, committed step of endogenous glucose production, shared by gluconeogenesis and glycogenolysis: the hydrolysis of glucose-6-phosphate to free glucose for release into the blood. Because the catalytic site of the phosphatase faces the ER lumen while its substrate is generated in the cytosol, the system couples two integral ER-membrane proteins. The glucose-6-phosphate transporter SLC37A4 (G6PT) is a glucose-6-phosphate:phosphate antiporter that imports cytosolic glucose-6-phosphate into the ER lumen (exchanging for inorganic phosphate). There a glucose-6-phosphatase catalytic subunit hydrolyses it to glucose + Pi: the liver/kidney/intestine isoform G6PC1 supplies blood glucose during fasting, while the ubiquitously expressed paralog G6PC3 serves other tissues (and also handles the incidental substrate 1,5-anhydroglucitol-6-phosphate). The liberated glucose then exits the ER and the cell (via GLUT transporters). Inherited defects define a clinically instructive set: G6PC1 deficiency causes glycogen storage disease type Ia (von Gierke, fasting hypoglycemia/hepatomegaly/lactic acidosis); SLC37A4 deficiency causes GSD type Ib (the same metabolic phenotype PLUS neutropenia/neutrophil dysfunction, because the shared transporter also serves the neutrophil G6PC3 system); and G6PC3 deficiency causes severe congenital neutropenia type 4 (with cardiac/urogenital malformations), not a classic hepatic glycogenosis. |
Metabolic Pathway | DRAFT | 0 | gluconeogenesis |
3 | 2 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/glucose_6_phosphatase_system.yaml | ||
Glutamate / glutamine / ammonia metabolic hub (GLUL, GLS/GLS2, GLUD1/GLUD2)MODULE:glutamate_glutamine_ammonia_hub Glutamate, glutamine and ammonia sit at the crossroads of amino-acid, nitrogen and carbon metabolism, and three enzyme activities interconvert... [more...][less]Glutamate, glutamine and ammonia sit at the crossroads of amino-acid, nitrogen and carbon metabolism, and three enzyme activities interconvert them. Glutamine synthetase (GLUL) is the sole route of net ammonia fixation into organic form: it condenses L-glutamate + ammonia + ATP to L-glutamine, the body's principal non-toxic nitrogen carrier and a nitrogen donor for nucleotide, amino-sugar and amino-acid synthesis; it detoxifies ammonia in perivenous hepatocytes, astrocytes and muscle. Running the opposite direction, the phosphate-activated mitochondrial glutaminases GLS (kidney-type, KGA/GAC) and GLS2 (liver-type, LGA/GAB) hydrolyse L-glutamine back to L-glutamate + ammonia, initiating glutaminolysis and supplying glutamate for the astrocytic glutamate-glutamine cycle, renal ammoniagenesis and cancer glutamine addiction. Glutamate is then reversibly deaminated by mitochondrial glutamate dehydrogenase — the ubiquitous GLUD1 and the hominoid-specific, brain/testis GLUD2 — to 2-oxoglutarate (alpha-ketoglutarate) + ammonia with NAD(P)+, linking amino-acid nitrogen to the TCA cycle for energy and anaplerosis and, in pancreatic beta-cells, coupling amino-acid sensing to insulin secretion. Together GLUL and GLS establish the glutamate<->glutamine interconversion cycle, while GLUD channels glutamate carbon into the TCA cycle and releases its nitrogen as ammonia (destined for the urea cycle). Inherited defects highlight the hub's importance: GLUL deficiency (congenital glutamine deficiency / neonatal encephalopathy), GLS deficiency (epileptic encephalopathy) and gain-of-function (developmental delay), and GLUD1 activating mutations (the hyperinsulinism-hyperammonemia syndrome). |
Metabolic Pathway | DRAFT | 0 | L-glutamine biosynthetic process L-glutamine metabolic process |
4 | 3 | 3 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/glutamate_glutamine_ammonia_hub.yaml | ||
Glutathione biosynthesisMODULE:glutathione_biosynthesisABSTRACT A reusable two-reaction pathway that converts L-glutamate, L-cysteine, and glycine to glutathione through gamma-L-glutamyl-L-cysteine. The module... [more...][less]A reusable two-reaction pathway that converts L-glutamate, L-cysteine, and glycine to glutathione through gamma-L-glutamyl-L-cysteine. The module represents the conserved GshA/GCLC and GshB/GSS reaction roles independently of genomic arrangement or enzyme regulation. Glutathione reduction, conjugation, peroxide detoxification, degradation, and the wider gamma-glutamyl cycle are outside the boundary. |
Metabolic Pathway | COMPLETE | 4 | glutathione biosynthetic process |
3 | 3 | 2 | 0 | 0 | 1 | 11/11 | 0 | ✓ | modules/glutathione_biosynthesis.yaml | ||
Glutathione synthesis, recycling, and the gamma-glutamyl cycleMODULE:glutathione_synthesis_gamma_glutamyl_cycle Glutathione (GSH, gamma-L-glutamyl-L-cysteinylglycine) is the most abundant cellular thiol and the central small-molecule antioxidant and redox... [more...][less]Glutathione (GSH, gamma-L-glutamyl-L-cysteinylglycine) is the most abundant cellular thiol and the central small-molecule antioxidant and redox buffer, also serving in detoxification (as GSH conjugates), cysteine storage/transport and leukotriene metabolism. Its metabolism has three linked arms. Synthesis is a two-step, ATP-dependent cytosolic route: glutamate-cysteine ligase (GCL, a heterodimer of the catalytic subunit GCLC and the regulatory modifier subunit GCLM) joins L-glutamate and L-cysteine to gamma-glutamylcysteine (the rate-limiting, feedback-controlled step), and glutathione synthetase (GSS) adds glycine to make GSH. Recycling keeps the pool reduced: glutathione-disulfide reductase (GSR), an FAD/NADPH enzyme, reduces oxidized glutathione (GSSG) back to two GSH, sustaining the high GSH/GSSG ratio. Turnover proceeds through the gamma-glutamyl cycle: the cell-surface ectoenzyme gamma-glutamyltransferase GGT1 initiates extracellular GSH breakdown by transferring/hydrolysing its gamma-glutamyl group (yielding cysteinylglycine plus a gamma-glutamyl-amino acid), gamma-glutamylcyclotransferase (GGCT) converts the gamma-glutamyl-amino acid to 5-oxoproline plus the free amino acid, and 5-oxoprolinase (OPLAH) hydrolyses 5-oxoproline back to glutamate at the expense of ATP, closing the cycle. A parallel intracellular route, the ATF4/stress-induced glutathione-specific gamma-glutamylcyclotransferase CHAC1, degrades cytosolic GSH directly to 5-oxoproline plus cysteinylglycine (promoting apoptosis/ferroptosis on GSH depletion). Inherited defects cause hemolytic anemia (GCLC, GSR), glutathione synthetase deficiency / 5-oxoprolinuria (GSS), glutathionuria (GGT1) and 5-oxoprolinase deficiency (OPLAH). In fungi the cycle is organised differently: the gamma-glutamyl transpeptidase is a vacuolar-membrane enzyme that degrades glutathione stored in the vacuole, no GGCT-type gamma-glutamylcyclotransferase is present, and a cytosolic alternative (DUG) pathway cleaves glutathione with a Dug2-Dug3 glutamine-amidotransferase complex before an M20A-family Cys-Gly dipeptidase (Dug1; human CNDP2) releases cysteine and glycine. |
Metabolic Pathway | DRAFT | eukaryotes |
0 | glutathione biosynthetic process glutathione catabolic process |
12 | 12 | 9 | 1 | 2 | 12 | 27/28 | 0 | ✗ | modules/glutathione_synthesis_gamma_glutamyl_cycle.yaml | |
Glutathione-dependent formaldehyde detoxificationMODULE:glutathione_dependent_formaldehyde_detoxification A detoxification module found in bacteria and eukaryotes in which formaldehyde is captured by glutathione as S-(hydroxymethyl)glutathione, the... [more...][less]A detoxification module found in bacteria and eukaryotes in which formaldehyde is captured by glutathione as S-(hydroxymethyl)glutathione, the hemithioacetal is oxidized to S-formylglutathione by a class-III alcohol dehydrogenase, and the thioester is hydrolyzed to formate while regenerating glutathione. Chemical capture, oxidation, and hydrolysis are represented as separate steps; formate can then be oxidized to CO2 by an NAD-dependent formate dehydrogenase. |
Biological Process | DRAFT | bacteria eukaryotes |
2 | formaldehyde catabolic process |
5 | 3 | 4 | 0 | 0 | 3 | 5/9 | 1 | ✓ | modules/glutathione_dependent_formaldehyde_detoxification.yaml | |
Glutathione-dependent methylglyoxal detoxification (glyoxalase system)MODULE:methylglyoxal_detoxificationCONCRETE A two-reaction detoxification module, conserved from bacteria to eukaryotes, in which glyoxalase I converts the spontaneously formed... [more...][less]A two-reaction detoxification module, conserved from bacteria to eukaryotes, in which glyoxalase I converts the spontaneously formed methylglyoxal-glutathione hemithioacetal to (R)-S-lactoylglutathione and glyoxalase II hydrolyzes that intermediate to D-lactate while regenerating glutathione. Glyoxalase II is carried out by non-orthologous metallo-beta-lactamase-fold enzymes in bacteria (GloB) and eukaryotes (HAGH/GLO2), and some fungi have separate cytosolic and mitochondrial glyoxalase II isozymes. Glutathione biosynthesis, methylglyoxal generation, glutathione-independent routes (glyoxalase III, methylglyoxal reductases) and downstream D-lactate oxidation are separate modules. |
Metabolic Pathway | DRAFT | 0 | methylglyoxal catabolic process |
6 | 4 | 2 | 1 | 3 | 1 | 9/13 | 0 | ✗ | modules/methylglyoxal_detoxification.yaml | ||
Glycerol synthesis and utilisation via glycerol 3-phosphate and dihydroxyacetoneMODULE:glycerol_metabolismCONCRETE Glycerol metabolism in eukaryotic microbes connects the triose-phosphate pool of glycolysis with free glycerol through two opposing arms. In the... [more...][less]Glycerol metabolism in eukaryotic microbes connects the triose-phosphate pool of glycolysis with free glycerol through two opposing arms. In the synthetic arm, a cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase reduces dihydroxyacetone phosphate (DHAP) to sn-glycerol 3-phosphate, and a specific glycerol-3-phosphate phosphatase releases glycerol. The arm reoxidizes cytosolic NADH, which makes it a redox sink under anaerobic or respiration-deficient conditions, and it produces glycerol as the main compatible solute during hyperosmotic stress. In the utilisation arm, glycerol is returned to DHAP by one of two routes. In the phosphorylating route, glycerol kinase forms sn-glycerol 3-phosphate in the cytosol, and a FAD-dependent glycerol-3-phosphate:quinone oxidoreductase on the outer face of the mitochondrial inner membrane oxidizes it to DHAP, passing electrons to ubiquinone. In the oxidative (dihydroxyacetone) route, a glycerol dehydrogenase oxidizes glycerol to dihydroxyacetone, which a dihydroxyacetone kinase phosphorylates to DHAP. Organisms use one or both routes. Both arms share DHAP with glycolysis and gluconeogenesis, and the dehydrogenase pair at the centre of the module is the same pair that forms the glycerol-3-phosphate shuttle. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | glycerol metabolic process |
11 | 7 | 8 | 1 | 2 | 4 | 17/18 | 0 | ✗ | modules/glycerol_metabolism.yaml | |
Glycerol-3-phosphate shuttle (GPD1 + GPD2)MODULE:glycerol_phosphate_shuttle The glycerol-3-phosphate (glycerophosphate) shuttle is the second mechanism, alongside the malate-aspartate shuttle, for delivering cytosolic... [more...][less]The glycerol-3-phosphate (glycerophosphate) shuttle is the second mechanism, alongside the malate-aspartate shuttle, for delivering cytosolic reducing equivalents to the mitochondrial respiratory chain — and the dominant one in tissues such as brown adipose tissue, skeletal muscle and pancreatic beta-cells. Unlike the malate-aspartate shuttle it is unidirectional and feeds electrons directly into the ubiquinone pool rather than to Complex I, so it yields fewer ATP per cytosolic NADH but operates rapidly. In the cytosol, the NAD-linked glycerol-3-phosphate dehydrogenase GPD1 reduces dihydroxyacetone phosphate (DHAP) to sn-glycerol-3-phosphate, oxidising a cytosolic NADH to NAD+. The glycerol-3-phosphate then diffuses to the outer face of the inner mitochondrial membrane, where the FAD-dependent glycerol-3-phosphate dehydrogenase GPD2 (mGPDH) re-oxidises it back to DHAP and passes the two electrons through its FAD cofactor to ubiquinone, reducing it to ubiquinol; the DHAP returns to the cytosol to complete the cycle. Because GPD2 faces the intermembrane space, no metabolite crosses the inner membrane. GPD1 also supplies glycerol-3-phosphate for glycerolipid/triacylglycerol synthesis; loss-of-function of GPD1 causes transient infantile hypertriglyceridemia, and the shuttle is important in beta-cell glucose-stimulated insulin secretion. |
Metabolic Pathway | DRAFT | 0 | glycerol-3-phosphate shuttle |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/glycerol_phosphate_shuttle.yaml | ||
Glycerolipid / triacylglycerol biosynthesis (glycerol-3-phosphate and DHAP routes)MODULE:triacylglycerol_biosynthesisCONCRETE Triacylglycerol (TAG) is the principal energy-storage lipid of eukaryotic cells. It is assembled from a three-carbon glycerol backbone and fatty... [more...][less]Triacylglycerol (TAG) is the principal energy-storage lipid of eukaryotic cells. It is assembled from a three-carbon glycerol backbone and fatty acyl-CoAs, and the pathway's intermediates phosphatidic acid (PA) and diacylglycerol (DAG) are also the branch points to the membrane glycerophospholipids. Lysophosphatidic acid (LPA) is formed either by sn-1 acylation of glycerol-3-phosphate (glycerol-3-phosphate acyltransferase, GPAT) or by acylation of dihydroxyacetone phosphate followed by NADPH-dependent reduction of 1-acyl-DHAP; in fungi the same GPAT enzymes accept both acceptors, whereas the DHAP acyltransferase of animals belongs to peroxisomal ether-lipid synthesis. LPA is acylated at sn-2 to PA by 1-acylglycerol-3-phosphate O-acyltransferases (LPAATs) of the AGPAT family and, in fungi, also by MBOAT-family and lipid-droplet acyltransferases. A Mg2+-dependent lipin-family phosphatidate phosphatase, a soluble enzyme that acts on membranes, dephosphorylates PA to DAG. DAG is finally esterified at sn-3 either with an acyl-CoA by the diacylglycerol O-acyltransferases (the MBOAT-family DGAT1 and the DGAT2-family enzymes) or, independently of acyl-CoA, by a phospholipid:diacylglycerol acyltransferase (PDAT) that transfers an acyl chain from a glycerophospholipid. Synthesis takes place on the endoplasmic reticulum and on lipid droplets, into which TAG is packaged; in animals the first acylation is also performed at the mitochondrial outer membrane. Inherited defects in the mammalian enzymes cause metabolic disease (AGPAT2 congenital generalized lipodystrophy, LPIN1 recurrent rhabdomyolysis, DGAT1 congenital diarrhoea). |
Metabolic Pathway | DRAFT | Eukaryota |
0 | triglyceride biosynthetic process phosphatidic acid biosynthetic process diacylglycerol biosynthetic process |
12 | 11 | 7 | 2 | 4 | 4 | 22/22 | 0 | ✗ | modules/triacylglycerol_biosynthesis.yaml | |
Glycine biosynthesis in Drosophila melanogasterMODULE:dmel_glycine_biosynthesisCONCRETE Glycine can be made by two routes. From threonine, mitochondrial L-threonine 3-dehydrogenase (Tdh) oxidizes threonine to 2-amino-3-ketobutyrate,... [more...][less]Glycine can be made by two routes. From threonine, mitochondrial L-threonine 3-dehydrogenase (Tdh) oxidizes threonine to 2-amino-3-ketobutyrate, which 2-amino-3-ketobutyrate CoA ligase (Gcat) cleaves with coenzyme A into glycine and acetyl-CoA. From serine, serine hydroxymethyltransferase (Shmt) converts serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate, linking glycine supply to one-carbon metabolism. Both reactions are reversible or bidirectional in context, so the enzymes also contribute to glycine and serine interconversion. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | glycine biosynthetic process |
4 | 3 | 3 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/dmel_glycine_biosynthesis.yaml | |
Glycine cleavage systemMODULE:glycine_cleavage_systemCONCRETE A four-component lipoyl-relay system that oxidatively decarboxylates glycine, transfers its one-carbon unit to tetrahydrofolate, and regenerates... [more...][less]A four-component lipoyl-relay system that oxidatively decarboxylates glycine, transfers its one-carbon unit to tetrahydrofolate, and regenerates the oxidized H-protein carrier. The P protein loads the aminomethyl intermediate onto the H protein, the H protein carries it to the T protein, the T protein forms 5,10-methylenetetrahydrofolate and ammonium, and the shared L protein reoxidizes the reduced lipoyl arm with NAD+. H-protein lipoylation, glycine-generating pathways, and downstream one-carbon metabolism are separate modules. |
Metabolic Pathway | COMPLETE | 3 | glycine decarboxylation via glycine cleavage system glycine cleavage complex |
5 | 4 | 4 | 0 | 0 | 4 | 20/20 | 0 | ✗ | modules/glycine_cleavage_system.yaml | ||
Glycine formation and glycine-serine interconversionMODULE:glycine_serine_interconversion Routes that supply the cellular glycine pool and interconvert glycine with L-serine, as found in fungi, bacteria and animals. Glycine is formed by... [more...][less]Routes that supply the cellular glycine pool and interconvert glycine with L-serine, as found in fungi, bacteria and animals. Glycine is formed by up to three enzymatically unrelated, pyridoxal 5'-phosphate-dependent reactions: aldol cleavage of L-threonine to glycine and acetaldehyde by threonine aldolase; transamination of glyoxylate with L-alanine by alanine:glyoxylate aminotransferase; and the reversible tetrahydrofolate-dependent serine hydroxymethyltransferase (SHMT) reaction, which converts L-serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate. Run in reverse, SHMT turns glycine made by the first two reactions into L-serine, giving a serine supply that does not depend on the phosphorylated pathway. Eukaryotes commonly have compartment-specific SHMT isozymes in the cytosol and in the mitochondrial matrix, and the direction of net flux through each depends on nutrient supply. In budding yeast, threonine aldolase is the main glycine source during growth on glucose, while the glucose-repressed glyoxylate transamination route supplies glycine and, through SHMT, serine on non-fermentable carbon sources. The relative weight of the routes differs between lineages; in mammals SHMT is the main source of glycine. The phosphorylated serine pathway, the glycine cleavage system, and downstream folate one-carbon reactions are separate modules. |
Metabolic Pathway | DRAFT | 0 | glycine biosynthetic process |
7 | 4 | 2 | 2 | 4 | 1 | 7/9 | 0 | ✗ | modules/glycine_serine_interconversion.yaml | ||
Glycogen biosynthesis (UDP-glucose → glycogen) — GSD 0/IV/XV, UGP2-DEEMODULE:glycogen_biosynthesis Glycogen biosynthesis is the cytosolic pathway that builds the branched glucose polymer glycogen from the activated sugar donor UDP-glucose,... [more...][less]Glycogen biosynthesis is the cytosolic pathway that builds the branched glucose polymer glycogen from the activated sugar donor UDP-glucose, storing glucose for later mobilisation. Four steps: UDP-glucose pyrophosphorylase (UGP2) activates glucose-1-phosphate with UTP to form UDP-glucose + pyrophosphate; glycogenin (GYG1) primes synthesis by autoglucosylating a specific tyrosine, using UDP-glucose to build a short covalently-attached alpha-1,4-glucan (~8-12 residues) that nucleates the granule; glycogen synthase (muscle GYS1, liver GYS2) then elongates the chain by processively adding UDP-glucose-derived glucose units in alpha-1,4 linkage; and the glycogen branching enzyme (GBE1) transfers ~6-7-residue segments to internal positions via alpha-1,6 linkages, creating the branches that make glycogen soluble and multiply the non-reducing ends for both synthesis and later degradation. Glycogen synthase is the rate-controlling, tightly regulated step (inhibited by phosphorylation, allosterically activated by glucose-6-phosphate). Inherited defects define disorders across the pathway: UGP2 deficiency causes a developmental and epileptic encephalopathy; GYG1 deficiency causes glycogen storage disease type XV (polyglucosan-body myopathy/cardiomyopathy); GYS2 deficiency causes hepatic glycogen storage disease type 0a (fasting ketotic hypoglycemia) and GYS1 deficiency muscle GSD 0b (cardiomyopathy, sudden death); and GBE1 deficiency causes GSD type IV (Andersen disease) and adult polyglucosan body disease — accumulation of poorly branched, amylopectin-like polyglucosan. |
Metabolic Pathway | DRAFT | 0 | glycogen biosynthetic process |
5 | 4 | 4 | 0 | 0 | 5 | 5/5 | 0 | ✗ | modules/glycogen_biosynthesis.yaml | ||
Glycogenolysis (glycogen breakdown to glucose-1/6-phosphate) — GSD III/V/VI, PGM1-CDGMODULE:glycogenolysis Glycogenolysis is the cytosolic breakdown of stored glycogen to release glucose units for glycolysis (muscle) or blood-glucose maintenance (liver).... [more...][less]Glycogenolysis is the cytosolic breakdown of stored glycogen to release glucose units for glycolysis (muscle) or blood-glucose maintenance (liver). Glycogen phosphorylase (the rate-limiting, PLP-dependent enzyme; muscle PYGM, liver PYGL, brain PYGB isoforms) sequentially phosphorolyses the alpha-1,4-glycosidic bonds at the non-reducing ends of glycogen, releasing glucose-1-phosphate, until it stalls about four glucose residues from an alpha-1,6 branch point (leaving a "limit dextrin"). The bifunctional glycogen debranching enzyme (AGL) then remodels the branch: its 4-alpha-glucanotransferase activity transfers a maltotriosyl unit to a nearby chain, exposing the single alpha-1,6-linked glucose, which its amylo-alpha-1,6-glucosidase activity hydrolyses to free glucose — restoring a linear chain that phosphorylase can continue to degrade. Finally phosphoglucomutase (PGM1) reversibly isomerises the glucose-1-phosphate to glucose-6-phosphate (via a glucose-1,6-bisphosphate intermediate, Mg2+-dependent), which enters glycolysis or, in liver/kidney, is dephosphorylated by the glucose-6-phosphatase system for export as free glucose. Inherited defects define glycogen storage diseases: PYGM deficiency causes GSD V (McArdle disease, exercise intolerance/myoglobinuria); PYGL deficiency GSD VI (Hers disease, hepatomegaly/hypoglycemia); AGL deficiency GSD III (Cori/Forbes disease, with abnormal limit-dextrin-like glycogen); and PGM1 deficiency PGM1-CDG (a mixed glycogenosis and congenital disorder of glycosylation). |
Metabolic Pathway | DRAFT | 0 | glycogen catabolic process |
4 | 3 | 3 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/glycogenolysis.yaml | ||
Glycolysis I — investment phase (glucose → glyceraldehyde-3-phosphate); GSD VII/XII, TPI/GPI deficiencyMODULE:glycolysis_investment_phase The investment (preparatory) phase of glycolysis is the first half of the cytosolic pathway that converts one molecule of glucose into two... [more...][less]The investment (preparatory) phase of glycolysis is the first half of the cytosolic pathway that converts one molecule of glucose into two molecules of glyceraldehyde-3-phosphate, at the net cost of two ATP, priming the sugar for the energy-yielding payoff phase. Five steps: a hexokinase (HK1-3 or the glucose-sensor glucokinase GCK) phosphorylates glucose to glucose-6-phosphate; glucose-6-phosphate isomerase (GPI) isomerises it to fructose-6-phosphate; 6-phosphofructokinase-1 (the committed, rate-limiting, allosterically controlled step; muscle PFKM) phosphorylates fructose-6-phosphate to fructose-1,6-bisphosphate; class-I fructose-bisphosphate aldolase (muscle ALDOA) cleaves it to dihydroxyacetone phosphate (DHAP) + glyceraldehyde-3-phosphate; and triosephosphate isomerase (TPI1) interconverts DHAP and glyceraldehyde-3-phosphate so that both trioses continue into the payoff phase. Inherited defects across this phase mostly present as hereditary nonspherocytic hemolytic anemia and/or myopathy, with distinctive extras: HK1 deficiency (hemolytic anemia; other HK1 variants cause neuropathy/retinopathy); GCK mutations cause MODY2/neonatal diabetes or hyperinsulinism (glucose-sensing, not hemolysis); GPI deficiency (hemolytic anemia); PFKM deficiency = glycogen storage disease type VII (Tarui, exercise intolerance); ALDOA deficiency = GSD type XII; and TPI1 deficiency is a severe hemolytic anemia with progressive neurodegeneration. |
Metabolic Pathway | DRAFT | 0 | glycolytic process |
6 | 5 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/glycolysis_investment_phase.yaml | ||
Glycolysis II — payoff phase (glyceraldehyde-3-phosphate → pyruvate); PGK/PGAM/enolase/PK deficienciesMODULE:glycolysis_payoff_phase The payoff (energy-yielding) phase of glycolysis is the second half of the cytosolic pathway, converting each glyceraldehyde-3-phosphate produced... [more...][less]The payoff (energy-yielding) phase of glycolysis is the second half of the cytosolic pathway, converting each glyceraldehyde-3-phosphate produced in the investment phase into pyruvate while generating ATP and NADH. Five steps: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) oxidises and phosphorylates glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, reducing NAD+ to NADH; phosphoglycerate kinase (PGK1) transfers a phosphate from 1,3-bisphosphoglycerate to ADP, forming 3-phosphoglycerate and the first ATP (substrate-level phosphorylation); phosphoglycerate mutase (muscle PGAM2) isomerises 3-phosphoglycerate to 2-phosphoglycerate; enolase (muscle ENO3) dehydrates 2-phosphoglycerate to phosphoenolpyruvate; and pyruvate kinase (liver/RBC PKLR, or muscle/other PKM) transfers the phosphate of phosphoenolpyruvate to ADP, forming pyruvate and the second ATP. Per glucose (two trioses) the payoff phase yields 4 ATP and 2 NADH, for a net glycolytic gain of 2 ATP + 2 NADH + 2 pyruvate. Because mature erythrocytes rely entirely on glycolytic ATP, defects here characteristically cause hereditary nonspherocytic hemolytic anemia, often combined with tissue-specific features: PGK1 deficiency (X-linked hemolytic anemia + myopathy + CNS disease); PGAM2 deficiency = glycogen storage disease type X (muscle); ENO3 deficiency = GSD type XIII (muscle); and PKLR deficiency = pyruvate kinase deficiency, the commonest glycolytic cause of hemolytic anemia. |
Metabolic Pathway | DRAFT | 0 | glycolytic process |
6 | 5 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/glycolysis_payoff_phase.yaml | ||
Glycosphingolipid / sphingolipid lysosomal degradation to ceramide and sphingosine (the sphingolipidoses); ARSA/GALC/GBA/SMPD1/ASAH1 + GM2A/PSAPMODULE:glycosphingolipid_lysosomal_degradation Complex sphingolipids are catabolised in the lysosome by a branched cascade of soluble acid hydrolases that strip the head group one residue at a... [more...][less]Complex sphingolipids are catabolised in the lysosome by a branched cascade of soluble acid hydrolases that strip the head group one residue at a time and converge on ceramide, which is finally hydrolysed to sphingosine. Sphingomyelin is cleaved by acid sphingomyelinase (SMPD1) directly to ceramide; glucosylceramide is cleaved by acid beta-glucocerebrosidase (GBA); galactosylceramide by galactocerebrosidase (GALC); and sulfatide is first desulfated by arylsulfatase A (ARSA) to galactosylceramide, which GALC then degrades. Gangliosides feed in from above (GM1 via acid beta-galactosidase GLB1, modelled here as the ganglioside entry step; GM2 via beta-hexosaminidase A + the GM2-activator and globosides via GLA/HEXA-HEXB, not yet modelled here), ultimately yielding glucosylceramide; GLB1 also hydrolyses lactosylceramide to glucosylceramide. The convergent final step is acid ceramidase (ASAH1), which hydrolyses ceramide to sphingosine and a free fatty acid. Because the substrates are membrane-embedded lipids, most of these hydrolases require small non-enzymatic lipid-presenting cofactors: the four saposins (A, B, C, D) generated from prosaposin (PSAP) activate GALC, ARSA/GLB1, GBA and ASAH1 respectively, and the GM2-activator (GM2A) presents GM2 ganglioside to beta-hexosaminidase A. Each hydrolase and cofactor defines a sphingolipidosis: metachromatic leukodystrophy (ARSA), Krabbe disease (GALC), Gaucher disease (GBA), Niemann-Pick A/B (SMPD1), Farber disease / SMA-PME (ASAH1), the AB-variant GM2 gangliosidosis (GM2A) and combined saposin deficiency (PSAP). |
Metabolic Pathway | DRAFT | 0 | glycosphingolipid catabolic process sphingolipid catabolic process |
8 | 8 | 7 | 0 | 0 | 6 | 8/8 | 0 | ✗ | modules/glycosphingolipid_lysosomal_degradation.yaml | ||
Glycosphingolipid biosynthesis (ceramide -> GlcCer/GalCer -> LacCer -> ganglio/globo/lacto series)MODULE:glycosphingolipid_biosynthesis Glycosphingolipids are ceramide-anchored glycans that cover the outer leaflet of the plasma membrane, clustering in lipid rafts and serving as... [more...][less]Glycosphingolipids are ceramide-anchored glycans that cover the outer leaflet of the plasma membrane, clustering in lipid rafts and serving as blood-group antigens, cell-adhesion and signalling receptors, and receptors hijacked by toxins and pathogens. Their synthesis is a Golgi-based branching tree built on ceramide. Two committed glycosylations start the two major limbs: glucosylceramide synthase UGCG adds glucose to ceramide (glucosylceramide, GlcCer, the trunk of the ganglio/globo/lacto glycosphingolipids), while UGT8 in the ER adds galactose to make galactosylceramide (GalCer, precursor of the myelin galactolipids and sulfatide). GlcCer is galactosylated by the beta-1,4-galactosyltransferases B4GALT5 (major) and B4GALT6 to lactosylceramide (LacCer), the central branch point. From LacCer three series diverge: the GANGLIO series begins when the sialyltransferase ST3GAL5 (GM3 synthase) adds sialic acid to make GM3, which ST8SIA1 (GD3 synthase) can further sialylate to GD3, and which B4GALNT1 (GM2/GD2 synthase) elongates with GalNAc toward the complex a-/b-series gangliosides; the GLOBO series begins when A4GALT (Gb3/CD77 synthase) adds an alpha-galactose to make globotriaosylceramide (Gb3, the Shiga-toxin receptor and Pk antigen), which B3GALNT1 (globoside synthase) extends to globoside (Gb4, the P antigen); and the (neo)LACTO series begins when B3GNT5 adds GlcNAc to make lactotriaosylceramide (Lc3), the scaffold for Lewis/blood-group glycans. Inherited defects at almost every node cause disease: UGCG is the drug target for glycosphingolipidoses, ST3GAL5 deficiency causes GM3-synthase-deficiency epileptic encephalopathy, B4GALNT1 deficiency causes hereditary spastic paraplegia (SPG26), and A4GALT/B3GALNT1 variants define the P blood-group system. |
Metabolic Pathway | DRAFT | 0 | glycosphingolipid biosynthetic process ganglioside biosynthetic process |
10 | 9 | 9 | 0 | 0 | 8 | 10/10 | 0 | ✗ | modules/glycosphingolipid_biosynthesis.yaml | ||
Glyoxylate cycleMODULE:glyoxylate_cycle The glyoxylate cycle (glyoxylate shunt) lets bacteria, fungi, plants and nematodes grow on two-carbon compounds such as acetate, ethanol or fatty... [more...][less]The glyoxylate cycle (glyoxylate shunt) lets bacteria, fungi, plants and nematodes grow on two-carbon compounds such as acetate, ethanol or fatty acids by converting acetyl-CoA into four-carbon dicarboxylic acids without losing carbon as CO2. It shares the citrate synthase, aconitase and malate dehydrogenase reactions with the tricarboxylic acid cycle but replaces the two oxidative decarboxylations with two signature reactions: isocitrate lyase cleaves isocitrate into succinate and glyoxylate, and malate synthase condenses glyoxylate with a second acetyl-CoA to form malate. Malate is oxidized back to oxaloacetate to close the cycle, so each turn takes in two acetyl-CoA and releases one succinate, which is used for gluconeogenesis and biosynthesis. In bacteria all reactions are cytoplasmic and the TCA-cycle enzymes are shared. In eukaryotes the cycle is split between compartments and uses dedicated isozymes: in plant seedlings the enzymes are concentrated in glyoxysomes, a specialized form of peroxisome, whereas in budding yeast citrate synthase is peroxisomal while aconitase, isocitrate lyase and the main malate dehydrogenase are cytosolic and malate synthase is cytosolic on ethanol but peroxisomal on fatty acids, so intermediates cross the peroxisomal membrane. Nematodes and Euglena carry isocitrate lyase and malate synthase as two domains of one bifunctional protein. Mammals lack the signature enzymes. |
Metabolic Pathway | DRAFT | Bacteria Fungi Nematoda Viridiplantae |
0 | glyoxylate cycle |
8 | 6 | 5 | 1 | 2 | 5 | 6/14 | 0 | ✗ | modules/glyoxylate_cycle.yaml | |
Glyoxylate metabolism and oxalate detoxification (the primary hyperoxalurias); AGXT/GRHPR/HOGA1/HAO1/AGXT2MODULE:glyoxylate_oxalate_metabolism Glyoxylate is a reactive two-carbon metabolite that, if not detoxified, is oxidised to oxalate — an end product that cannot be further metabolised... [more...][less]Glyoxylate is a reactive two-carbon metabolite that, if not detoxified, is oxidised to oxalate — an end product that cannot be further metabolised and precipitates as insoluble calcium oxalate, damaging the kidney. Hepatic glyoxylate handling therefore determines systemic oxalate load, and its enzymes define the primary hyperoxalurias. Glyoxylate arises from two main sources: peroxisomal glycolate oxidase (HAO1), an FMN enzyme that oxidises glycolate to glyoxylate (generating H2O2), and mitochondrial 4-hydroxy-2-oxoglutarate aldolase (HOGA1), the terminal enzyme of hydroxyproline catabolism, which cleaves 4-hydroxy-2-oxoglutarate to glyoxylate and pyruvate. Glyoxylate is then detoxified by two routes: the peroxisomal, pyridoxal-phosphate-dependent alanine-glyoxylate aminotransferase (AGXT/AGT) transaminates it back to glycine (using L-alanine), and the cytosolic NADPH- dependent glyoxylate/hydroxypyruvate reductase (GRHPR) reduces it to glycolate; a mitochondrial aminotransferase (AGXT2) provides an additional transamination route (and also degrades the NO-synthase inhibitors ADMA/SDMA). When detoxification fails, glyoxylate is oxidised to oxalate. Inherited defects each cause a primary hyperoxaluria: PH1 (AGXT), PH2 (GRHPR) and PH3 (HOGA1); HAO1, which makes glyoxylate, is a validated drug target (the siRNA lumasiran silences HAO1 to lower oxalate). |
Metabolic Pathway | DRAFT | 0 | glyoxylate metabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/glyoxylate_oxalate_metabolism.yaml | ||
Golgi apparatus lifecycleMODULE:golgi_apparatus_lifecycleCONCRETE The Golgi apparatus is built and maintained by membrane traffic: COPII vesicles bring proteins and lipids from the ER, cisternae mature as COPI... [more...][less]The Golgi apparatus is built and maintained by membrane traffic: COPII vesicles bring proteins and lipids from the ER, cisternae mature as COPI vesicles return ER residents and recycle Golgi enzymes, the cisternae glycosylate and sort their cargo, and carriers leave the trans-Golgi network for the plasma membrane and endosomes. In animal cells the Golgi also disassembles at mitosis and reassembles in the daughter cells. This umbrella module composes the modules for those stages by reference. COPI coat assembly is required in every eukaryote; ER export by COPII is optional because the only COPII module is written for Drosophila. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | Golgi organization Golgi apparatus |
3 | 0 | 2 | 0 | 0 | 1 | 0/0 | 0 | ✗ | modules/golgi_apparatus_lifecycle.yaml | |
Gram-negative bacterial post-translational Sec protein exportMODULE:bacterial_sec_posttranslational_protein_exportCONCRETE A reusable bacterial protein-export module in which SecB carries an unfolded precursor to the SecA ATPase, SecA drives the precursor into the... [more...][less]A reusable bacterial protein-export module in which SecB carries an unfolded precursor to the SecA ATPase, SecA drives the precursor into the SecYEG protein-conducting channel, optional SecDF associated with YajC uses proton motive force to improve late-stage translocation, and signal peptidase I removes the N-terminal signal peptide. The module models the canonical post-translational route used by Gram-negative bacteria. Cotranslational SRP targeting, YidC-dependent membrane insertion, Tat export of folded proteins, lipoprotein maturation, and outer-membrane secretion are neighboring modules. |
Biological Process | DRAFT | bacteria |
3 | protein transport by the Sec complex |
6 | 9 | 5 | 0 | 0 | 4 | 18/18 | 0 | ✗ | modules/bacterial_sec_posttranslational_protein_export.yaml | |
Gram-negative lipoprotein-peptidoglycan tether remodelingMODULE:gram_negative_lipoprotein_peptidoglycan_tether_remodeling A reusable Gram-negative bacterial module for reversible covalent attachment of an outer-membrane lipoprotein to peptidoglycan. An ErfK-family... [more...][less]A reusable Gram-negative bacterial module for reversible covalent attachment of an outer-membrane lipoprotein to peptidoglycan. An ErfK-family L,D-transpeptidase transfers a tetrapeptide-stem donor onto the C terminus of a Braun-lipoprotein-like substrate, and a YafK/LdtF-family cysteine hydrolase can release the lipoprotein by cleaving the resulting amide bond. These reactions remodel the connection between the outer membrane and sacculus; they do not represent peptidoglycan glycan polymerization or canonical 4-3 peptide crosslinking by penicillin-binding proteins. |
Biological Process | DRAFT | 0 | peptidoglycan-protein cross-linking |
3 | 2 | 2 | 0 | 0 | 1 | 2/7 | 0 | ✓ | modules/gram_negative_lipoprotein_peptidoglycan_tether_remodeling.yaml | ||
Gram-negative outer-membrane protein chaperone deliveryMODULE:gram_negative_omp_biogenesisCONCRETE A periplasmic carrier-holdase module for Gram-negative beta-barrel outer-membrane protein biogenesis. SurA is the primary route for bulk OMP... [more...][less]A periplasmic carrier-holdase module for Gram-negative beta-barrel outer-membrane protein biogenesis. SurA is the primary route for bulk OMP transit to the BAM/YaeT assembly complex, while the trimeric Skp chaperone provides a parallel ATP-independent holdase route that maintains OMP clients in soluble unfolded states and cooperates with lipopolysaccharide; DegP contributes an optional quality-control branch that can clear or, under some conditions, protect unfolded OMPs in protease-chaperone cages. Sec export across the inner membrane, BAM-mediated membrane insertion itself, and LPS synthesis are outside this focused module. |
Biological Process | DRAFT | bacteria |
0 | Gram-negative-bacterium-type cell outer membrane assembly unfolded protein holdase activity |
4 | 5 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/gram_negative_omp_biogenesis.yaml | |
HGF-MET signaling pathway moduleMODULE:hgf_met_signaling Hepatocyte growth factor activates the MET receptor tyrosine kinase, recruiting multisite docking adaptors that coordinate motility, invasive... [more...][less]Hepatocyte growth factor activates the MET receptor tyrosine kinase, recruiting multisite docking adaptors that coordinate motility, invasive growth, survival, and epithelial morphogenesis. |
Signaling Pathway | DRAFT | metazoa |
3 | hepatocyte growth factor receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 2/5 | 0 | ✓ | modules/hgf_met_signaling.yaml | |
HIF oxygen sensing — prolyl hydroxylation of HIF-alpha by PHD1-3, CRL2(VHL) ubiquitination and degradation, FIH asparaginyl hydroxylation, and HIF-alpha/ARNT dimerisation with p300/CBP; EGLN1/EGLN2/EGLN3/OS9/VHL/ELOB/ELOC/CUL2/RBX1/SAT2/HIF1AN/HIF1A/EPAS1/HIF3A/ARNT/ARNT2/EP300/CREBBP/RACK1/SAT1MODULE:hif_oxygen_sensingCONCRETE Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the metazoan response to low oxygen. It is a heterodimer of an... [more...][less]Hypoxia-inducible factor (HIF) is the master transcriptional regulator of the metazoan response to low oxygen. It is a heterodimer of an oxygen-labile alpha subunit (HIF-1alpha, HIF-2alpha/EPAS1, or HIF-3alpha) and a constitutive bHLH-PAS beta subunit (ARNT, also called HIF-1beta, or its paralog ARNT2). The oxygen signal is read by two families of Fe(II)- and 2-oxoglutarate-dependent dioxygenases that use molecular O2 as a cosubstrate, so their activity falls as oxygen falls. The prolyl hydroxylases PHD1, PHD2 and PHD3 (EGLN2, EGLN1 and EGLN3) hydroxylate two prolines in the oxygen-dependent degradation domain of the alpha subunit. trans-4-Hydroxyproline creates the recognition mark for the von Hippel-Lindau protein (VHL), the substrate receptor of a cullin-2 RING ubiquitin ligase (CRL2) in which the Elongin B/C module (ELOB, ELOC) bridges VHL's VHL-box to the CUL2 scaffold and the RING subunit RBX1 transfers ubiquitin. Polyubiquitinated HIF-alpha is destroyed by the proteasome, giving the protein a half-life of minutes in oxygenated cells. In parallel, the asparaginyl hydroxylase FIH (HIF1AN) hydroxylates a conserved asparagine in the C-terminal transactivation domain, which blocks binding of the coactivators p300 (EP300) and CBP (CREBBP) and so silences the fraction of alpha subunit that escapes degradation. When oxygen is scarce both hydroxylations fail: the alpha subunit accumulates, enters the nucleus, dimerises with ARNT through its bHLH and PAS domains, binds hypoxia response elements and recruits p300/CBP to activate transcription of genes for angiogenesis, erythropoiesis, glycolysis and iron handling. Several proteins tune the switch without sensing oxygen themselves: OS-9 scaffolds HIF-1alpha with the prolyl hydroxylases, SSAT2 (SAT2) stabilises the VHL-Elongin C interaction, and RACK1 with SSAT1 (SAT1) recruits the Elongin B/C ligase to HIF-1alpha independently of hydroxylation and of VHL. Loss of VHL abolishes degradation and gives constitutive HIF activity, the basis of von Hippel-Lindau disease and of clear-cell renal carcinoma; EPAS1 and EGLN1 mutations cause erythrocytosis and paraganglioma. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | hypoxia-inducible factor-1alpha signaling pathway |
17 | 20 | 8 | 3 | 8 | 7 | 9/20 | 0 | ✗ | modules/hif_oxygen_sensing.yaml | |
HOPS and CORVET tethering complexes in Drosophila melanogasterMODULE:dmel_hops_corvet_tetheringCONCRETE HOPS and CORVET are related hexameric tethering complexes of the endolysosomal system that share a class C Vps core of Vps11, Vps16, Vps18 and the... [more...][less]HOPS and CORVET are related hexameric tethering complexes of the endolysosomal system that share a class C Vps core of Vps11, Vps16, Vps18 and the Sec1/Munc18-family protein Vps33. HOPS adds Vps39 and Vps41, binds active Rab7 and promotes SNARE-dependent fusion of late endosomes, autophagosomes and lysosome-related organelles with lysosomes. CORVET uses Vps8 (with Vps3 in yeast and mammals) and acts at the Rab5-positive early endosome stage. In Drosophila the core subunits are encoded by Vps11, Vps16A, deep orange (dor, Vps18) and carnation (car, Vps33A), and the HOPS-specific subunits by Vps39 and light (lt, Vps41); several of these were identified as eye-colour mutants with pigment granule defects. Drosophila also has paralogs Vps16B and Vps33B, which form a separate complex related to the mammalian VPS33B-VIPAS39 (CHEVI) complex. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | HOPS complex CORVET complex |
5 | 4 | 4 | 0 | 0 | 0 | 0/9 | 0 | ✗ | modules/dmel_hops_corvet_tethering.yaml | |
HSF-driven cytosolic heat shock responseMODULE:heat_shock_responseCONCRETE The heat shock response couples proteotoxic stress to transcriptional induction of the cytosolic chaperone network. Its driver is heat shock factor... [more...][less]The heat shock response couples proteotoxic stress to transcriptional induction of the cytosolic chaperone network. Its driver is heat shock factor (HSF), a winged helix-turn-helix transcription factor found across eukaryotes. HSF binds heat shock elements (HSEs), inverted nGAAn pentamer repeats, as a homotrimer and activates RNA polymerase II transcription of chaperone genes. How HSF is held in check differs between lineages. In metazoans, exemplified by human HSF1, HSF is kept as an inert monomer in complexes with HSP90 and HSP70. Proteotoxic stress titrates these chaperones away, and HSF1 then trimerizes, binds HSEs and concentrates in nuclear stress granules. The induced chaperones feed back to switch HSF1 off. In budding yeast, Hsf1 is constitutively trimeric and nuclear. Its essential job is to maintain basal expression of the Hsp70 and Hsp90 genes, and stress raises its activity further. The chaperone output falls into three activities. Hsp70 family foldases refold non-native clients by ATP-driven cycles. J-domain co-chaperones deliver clients and stimulate the Hsp70 ATPase, and HSP110- and BAG-family nucleotide-exchange factors reset the cycle. HSP90 is an ATP-dependent chaperone for metastable signaling and structural clients and is also the main repressor of metazoan HSF1. Small heat shock proteins are ATP-independent holdases that keep heat-denatured proteins soluble and refolding-competent for the ATP-dependent chaperones. Nematodes add an HSF-1/DAF-16-co-regulated branch of atypical 12-kDa small HSPs that contributes to longevity rather than to the acute response. In C. elegans the capacity of the response also falls sharply at the onset of reproduction, when repressive chromatin at stress loci blocks HSF-1 binding. |
Biological Process | DRAFT | Eukaryota Fungi Metazoa Nematoda |
6 | cellular response to heat |
8 | 10 | 5 | 1 | 2 | 6 | 20/20 | 0 | ✗ | modules/heat_shock_response.yaml | |
HSFA1-driven heat stress response in ArabidopsisMODULE:plant_hsfa1_heat_stress_responseCONCRETE In Arabidopsis thaliana, the transcriptional response to high temperature is a cascade headed by the four class A1 heat stress transcription... [more...][less]In Arabidopsis thaliana, the transcriptional response to high temperature is a cascade headed by the four class A1 heat stress transcription factors (HSFA1a, HSFA1b, HSFA1d and HSFA1e). These are constitutively expressed master regulators. In unstressed cells they are held inactive by the cytosolic chaperones HSP90 and HSC70/HSP70. Heat titrates the chaperones away, and the HSFA1s then accumulate in the nucleus, bind heat shock elements (HSEs) and switch on most heat-responsive genes. Their targets include genes for secondary transcription factors that amplify and prolong the response. DREB2A, an AP2/ERF factor also used in drought signalling, has an HSE in its promoter and is induced by HSFA1. DREB2A in turn induces HSFA3, the only HSF known to be controlled by DREB2A. HSFA2 is the most strongly heat-induced HSF and sustains chaperone expression during recovery and heat acclimation memory. The cascade's output is the cytosolic chaperone network. The AAA+ disaggregase HSP101 (ClpB1) is essential for acquired thermotolerance. With HSP70 it pulls proteins out of heat-induced aggregates, including those held by the ATP-independent small HSP (sHSP) holdases. HSP90 and HSP70 refold and stabilise clients and also feed back to repress HSFA1. Loss of HSFA1a/b/d globally abolishes heat-induced gene expression and greatly reduces heat tolerance. Loss of HSP101 abolishes acquired thermotolerance. |
Biological Process | DRAFT | Arabidopsis thaliana |
0 | cellular response to heat heat acclimation |
6 | 13 | 5 | 0 | 0 | 7 | 12/12 | 0 | ✗ | modules/plant_hsfa1_heat_stress_response.yaml | |
Hair-cell mechanotransduction — CDH23/PCDH15 tip link, TMC1/TMC2 MET channel with LHFPL5/TMIE/CIB2, USH1 upper tip-link density tensioning, MYO1C adaptation and inner hair cell VGLUT3/otoferlin ribbon-synapse output; CDH23/PCDH15/TMC1/TMC2/LHFPL5/TMIE/CIB2/USH1C/USH1G/MYO7A/MYO1C/SLC17A8/OTOFMODULE:hair_cell_mechanotransductionCONCRETE Hair cells of the cochlea and of the vestibular organs convert deflection of their apical hair bundle into an electrical signal. The hair bundle is... [more...][less]Hair cells of the cochlea and of the vestibular organs convert deflection of their apical hair bundle into an electrical signal. The hair bundle is a staircase of actin-filled stereocilia. The tip of each shorter stereocilium is joined to the side of its taller neighbour by a tip link, a fine extracellular filament made of two cadherins: a parallel homodimer of cadherin 23 (CDH23) forms the upper part and a homodimer of protocadherin 15 (PCDH15) the lower part, and the two meet tip to tip. At the lower end of the tip link, PCDH15 is bound to the mechanoelectrical transduction (MET) channel complex in the stereocilium membrane. The pore of that channel is formed by the transmembrane channel-like protein TMC1, or by its paralog TMC2, which is expressed in vestibular hair cells and only transiently in neonatal cochlear hair cells. The tetraspan LHFPL5 (TMHS) and the two-pass TMIE couple PCDH15 to the pore, and the EF-hand protein CIB2 (with CIB3 in vestibular hair cells) binds the cytoplasmic side of TMC1/TMC2 and is needed for transduction. At the upper end of the tip link, CDH23 is anchored in the upper tip-link density, where the PDZ scaffold harmonin (USH1C), the scaffold SANS (USH1G) and the motor myosin VIIa (MYO7A) form a complex thought to hold the tip link under resting tension. Deflection of the bundle towards its tallest row raises tip-link tension and increases the open probability of the channels, and the resulting cation influx depolarises the cell. Sustained deflection is followed by adaptation; the slow component in vestibular hair cells is mediated by myosin-1c (MYO1C) slipping and climbing along the stereocilium actin core to reset tension. In inner hair cells of the cochlea, the receptor potential drives glutamate release at ribbon synapses onto type I spiral ganglion neurons. Synaptic vesicles are loaded with glutamate by the vesicular glutamate transporter VGLUT3 (SLC17A8), and Ca2+-triggered fusion requires otoferlin (OTOF), a multi-C2-domain protein that binds Ca2+ and the SNARE proteins and is the main Ca2+ sensor for exocytosis at this synapse. Outer hair cells use the same transduction apparatus to drive electromotile amplification. Loss-of-function variants in CDH23, PCDH15, USH1C, USH1G, MYO7A and CIB2 cause Usher syndrome type 1 or nonsyndromic deafness; variants in TMC1, LHFPL5 and TMIE cause nonsyndromic deafness; OTOF variants cause auditory neuropathy (DFNB9); and SLC17A8 variants cause DFNA25. |
Biological Process | DRAFT | Homo sapiens |
0 | detection of mechanical stimulus involved in sensory perception of sound detection of mechanical stimulus involved in equilibrioception |
9 | 10 | 6 | 1 | 2 | 5 | 6/13 | 0 | ✗ | modules/hair_cell_mechanotransduction.yaml | |
Hedgehog signaling pathway in Drosophila melanogasterMODULE:dmel_hedgehog_signalingCONCRETE Hedgehog (Hh) is a secreted morphogen that is autoprocessed and modified with cholesterol and, by the acyltransferase Rasp, with palmitate. The... [more...][less]Hedgehog (Hh) is a secreted morphogen that is autoprocessed and modified with cholesterol and, by the acyltransferase Rasp, with palmitate. The transmembrane protein Dispatched releases lipid-modified Hh from producing cells. In receiving cells Hh binds its receptor Patched together with the co-receptors Ihog and Boi. In the absence of Hh, Patched keeps the seven-pass transmembrane protein Smoothened inactive, and the Hedgehog signaling complex of the kinesin-like protein Costal-2 (Cos), the kinase Fused and the zinc-finger transcription factor Cubitus interruptus (Ci) promotes processing of Ci into a repressor form. Hh binding relieves Patched inhibition, Smoothened accumulates at the plasma membrane and recruits the Cos-Fused complex, Ci processing is blocked and full-length Ci activates Hh target genes. The pathway patterns embryonic segments and the anterior-posterior axis of imaginal discs. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | smoothened signaling pathway |
6 | 8 | 5 | 0 | 0 | 4 | 10/10 | 0 | ✗ | modules/dmel_hedgehog_signaling.yaml | |
Heme degradation (heme -> biliverdin -> bilirubin)MODULE:heme_degradation Heme (iron-protoporphyrin IX), released chiefly from senescent-erythrocyte hemoglobin, is both an essential cofactor and, when free, a pro-oxidant;... [more...][less]Heme (iron-protoporphyrin IX), released chiefly from senescent-erythrocyte hemoglobin, is both an essential cofactor and, when free, a pro-oxidant; its controlled catabolism recovers iron, produces the signalling gas carbon monoxide, and generates the antioxidant bile pigments. Degradation proceeds in two enzymatic steps. First, heme oxygenase — the highly inducible, cytoprotective HMOX1 (HO-1/HSP32) and the constitutive HMOX2 (HO-2, an oxygen sensor in brain and vasculature) — uses molecular O2 and electrons from NADPH--cytochrome P450 reductase to oxidatively cleave the alpha-methene bridge of heme, releasing biliverdin IX-alpha, carbon monoxide (CO) and free ferrous iron (Fe2+); this is the rate-limiting step, and the iron is recaptured by ferritin while CO acts as a vasodilatory/anti-inflammatory messenger. Second, biliverdin reductase reduces the green biliverdin to the yellow, lipophilic, potently antioxidant bilirubin: the cytosolic NAD(P)H-dependent BLVRA acts on the major IX-alpha isomer (and additionally moonlights as a signalling kinase/scaffold), while the broad-specificity NADPH flavin reductase BLVRB reduces the IX-beta isomer (prominent in fetal heme catabolism) as well as flavins and other substrates. Bilirubin is subsequently glucuronidated (UGT1A1) for biliary excretion. Inherited defects cause severe systemic inflammation with hemolysis (HMOX1 deficiency) and green jaundice / hyperbiliverdinemia (BLVRA deficiency). |
Metabolic Pathway | DRAFT | 0 | heme catabolic process heme oxidation |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/heme_degradation.yaml | ||
Heme-induced iron-recycling macrophage differentiationMODULE:heme_induced_iron_recycling_macrophage_differentiationABSTRACT Macrophages that engulf aged or damaged red blood cells digest them in the phagolysosome and release heme. The heme transporter HRG1 carries heme... [more...][less]Macrophages that engulf aged or damaged red blood cells digest them in the phagolysosome and release heme. The heme transporter HRG1 carries heme out of the phagolysosome into the cytosol. Heme then switches on a differentiation programme. The transcriptional repressor BACH1 normally keeps the gene for the transcription factor SPI-C silent. Heme binds BACH1 through its cysteine-proline motifs and triggers its proteasomal degradation, which de-represses Spic. SPI-C drives monocytes to become iron-recycling macrophages: splenic red pulp macrophages and VCAM1-positive bone marrow macrophages. The same heme signal also de-represses the iron-recycling enzymes and transporters these cells use, heme oxygenase 1 and ferroportin. |
Developmental Process | DRAFT | Mammalia |
2 | macrophage differentiation |
5 | 5 | 4 | 0 | 0 | 6 | 5/11 | 0 | ✗ | modules/heme_induced_iron_recycling_macrophage_differentiation.yaml | |
Heparan sulfate and chondroitin sulfate proteoglycan biosynthesis in Drosophila melanogasterMODULE:dmel_glycosaminoglycan_biosynthesisCONCRETE Heparan sulfate and chondroitin sulfate chains are built in the endoplasmic reticulum and Golgi on serine residues of core proteins such as the... [more...][less]Heparan sulfate and chondroitin sulfate chains are built in the endoplasmic reticulum and Golgi on serine residues of core proteins such as the glypicans Dally and Dally-like, Syndecan and Perlecan. Both start on a shared tetrasaccharide linker (xylose-galactose-galactose-glucuronic acid) made by Oxt, beta4GalT7, beta3GalTII and GlcAT-I. Addition of N-acetylglucosamine by Brother of tout-velu (Botv) commits the chain to heparan sulfate; the Tout-velu (Ttv) and Sister of tout-velu (Sotv) exostosin complex then polymerizes alternating glucuronic acid and N-acetylglucosamine. The chain is modified by the N-deacetylase/N-sulfotransferase Sulfateless (Sfl), the C5-epimerase Hsepi and the 2-O-, 6-O- and 3-O-sulfotransferases (Hs2st, Hs6st, Hs3st-A, Hs3st-B). Addition of N-acetylgalactosamine by Csgalnact instead starts chondroitin chains, which are polymerized by Chsy and Chpf and sulfated by C4st. Heparan sulfate made by this pathway is required for Wingless, Hedgehog, Dpp and FGF signaling in Drosophila. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | glycosaminoglycan biosynthetic process heparan sulfate proteoglycan biosynthetic process chondroitin sulfate proteoglycan biosynthetic process |
18 | 16 | 17 | 0 | 0 | 13 | 1/17 | 0 | ✗ | modules/dmel_glycosaminoglycan_biosynthesis.yaml | |
Heparan sulfate lysosomal degradation (the mucopolysaccharidoses); IDS/IDUA/SGSH/HGSNAT/NAGLU/GNS/GUSBMODULE:heparan_sulfate_lysosomal_degradation Heparan sulfate is degraded in the lysosome by an ordered, strictly sequential exolytic cascade that removes one monosaccharide or sulfate group at... [more...][less]Heparan sulfate is degraded in the lysosome by an ordered, strictly sequential exolytic cascade that removes one monosaccharide or sulfate group at a time from the non-reducing end of the chain; each enzyme can act only after the preceding one has exposed its substrate, so a deficiency of any single step blocks the whole pathway and causes a mucopolysaccharidosis (MPS) with lysosomal heparan-sulfate storage. Iduronate-2-sulfatase (IDS) first removes the 2-O-sulfate from a terminal iduronate-2-sulfate; alpha-L-iduronidase (IDUA) then hydrolyses the exposed iduronate; sulfamidase (SGSH) removes the N-sulfate from the terminal N-sulfoglucosamine; the lysosomal-membrane transacetylase HGSNAT then N-acetylates the freed glucosamine (using cytosolic acetyl-CoA) so that alpha-N-acetylglucosaminidase (NAGLU) can hydrolyse it; N-acetylglucosamine-6-sulfatase (GNS) removes a 6-O-sulfate; and beta-glucuronidase (GUSB) hydrolyses the terminal glucuronate — regenerating a substrate for IDS/IDUA as the cycle repeats. The three sulfatases (IDS, SGSH, GNS) additionally require the formylglycine catalytic residue generated by SUMF1. Each enzyme defines a distinct disease: MPS II (IDS, Hunter), MPS I (IDUA, Hurler-Scheie), MPS IIIA (SGSH, Sanfilippo A), MPS IIIC (HGSNAT, Sanfilippo C), MPS IIIB (NAGLU, Sanfilippo B), MPS IIID (GNS, Sanfilippo D) and MPS VII (GUSB, Sly). |
Metabolic Pathway | DRAFT | 0 | heparan sulfate proteoglycan catabolic process glycosaminoglycan catabolic process |
8 | 7 | 7 | 0 | 0 | 6 | 7/7 | 0 | ✗ | modules/heparan_sulfate_lysosomal_degradation.yaml | ||
Hepatic trimethylamine N-oxygenation and metaorganismal TMAO synthesisMODULE:hepatic_trimethylamine_n_oxygenationCONCRETE Conserved mammalian hepatic monooxygenase module in which endoplasmic reticulum membrane-anchored flavin-containing monooxygenase 3 (FMO3)... [more...][less]Conserved mammalian hepatic monooxygenase module in which endoplasmic reticulum membrane-anchored flavin-containing monooxygenase 3 (FMO3) catalyzes the NADPH- and O2-dependent N-oxygenation of gut microbiota-derived trimethylamine (TMA) to odorless trimethylamine N-oxide (TMAO), as well as the N- and S-oxygenation of diverse nucleophilic xenobiotics and drugs. In both humans and mice, dietary quaternary amines (phosphatidylcholine, choline, carnitine) are cleaved by gut microbial lyases (CutC/CutD, CntA/CntB) to release volatile TMA, which enters the portal circulation and is oxidized in hepatocytes by FMO3 via a stable C4a-hydroperoxyflavin intermediate. Loss of human FMO3 causes autosomal recessive trimethylaminuria (fish-odor syndrome), and loss of mouse Fmo3 abolishes hepatic TMA-to-TMAO conversion. |
Metabolic Pathway | DRAFT | Homo sapiens Mammalia Mus musculus |
0 | trimethylamine monooxygenase activity N,N-dimethylaniline monooxygenase activity amine catabolic process xenobiotic metabolic process |
1 | 1 | 0 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/hepatic_trimethylamine_n_oxygenation.yaml | |
Hepatocyte ASGR1/ASGR2 GalNAc-conjugate uptake and endosomal routing — clathrin/AP-2/DNM2 internalization, V-ATPase acidification, EHD1 receptor recycling vs. ESCRT/RAB7A late-endosomal maturation, CTSD lysosomal degradation, and cytosolic oligonucleotide escapeMODULE:asgr_galnac_hepatocyte_delivery Hepatocyte-targeted N-acetylgalactosamine (GalNAc)-conjugated siRNA and antisense oligonucleotide therapeutics, as well as desialylated plasma... [more...][less]Hepatocyte-targeted N-acetylgalactosamine (GalNAc)-conjugated siRNA and antisense oligonucleotide therapeutics, as well as desialylated plasma glycoproteins, are selectively captured at the sinusoidal hepatocyte surface by the hetero-oligomeric asialoglycoprotein receptor complex (ASGR1/HL-1 and ASGR2/HL-2). Receptor-ligand complexes are concentrated into clathrin-coated pits by the AP-2 adaptor complex (AP2M1) and clathrin heavy chain (CLTC) and severed from the plasma membrane by the mechanochemical GTPase dynamin-2 (DNM2). Following vesicle uncoating, V-ATPase (ATP6V1A) acidifies the early sorting endosome lumen (pH ~6.0-5.5), triggering Ca2+ loss from the C-type lectin carbohydrate-recognition domains of ASGR1/ASGR2 and releasing the GalNAc-conjugate payload. From the acidified sorting endosome, flux partitions across three competing branches: (1) rapid tubular endocytic recycling of uncoupled ASGR1/ASGR2 back to the sinusoidal plasma membrane mediated by EHD1; (2) ESCRT-I (TSG101) multivesicular body sorting and RAB7A-driven early-to-late endosomal maturation, which delivers the vast majority of internalized GalNAc oligonucleotide and glycoprotein cargo to late endosomes and lysosomes for sequestration or hydrolytic/proteolytic turnover (represented by CTSD; PMID:12171918, PMID:29069408); and (3) a slow, rate-limiting endosomal membrane translocation step that releases a small productive fraction of oligonucleotide payload into the hepatocyte cytosol to engage RISC or RNase H1 (a minuscule fraction in vivo for GalNAc conjugates [PMID:29069408], modeled qualitatively as ~10% at baseline under uniform uncalibrated ABM transition rates with RAB7A-dependent late-endosomal competition extrapolated from hepatic LNP delivery [PMID:41814093]). |
Transport Step | DRAFT | 0 | carbohydrate binding receptor-mediated endocytosis endosomal lumen acidification endocytic recycling endosome to lysosome transport |
8 | 10 | 7 | 0 | 0 | 7 | 12/12 | 1 | ✗ | Agent Based | modules/asgr_galnac_hepatocyte_delivery.yaml | |
Hippo signaling pathway in Drosophila melanogasterMODULE:dmel_hippo_signalingCONCRETE The Hippo pathway restricts tissue growth by limiting the activity of the transcriptional coactivator Yorkie. At the apical cortex of epithelial... [more...][less]The Hippo pathway restricts tissue growth by limiting the activity of the transcriptional coactivator Yorkie. At the apical cortex of epithelial cells, the Kibra-Expanded-Merlin complex promotes activation of the Ste20-like kinase Hippo, which with its scaffold Salvador phosphorylates and activates the NDR family kinase Warts and its coactivator Mats. Warts phosphorylates Yorkie, which leads to its retention in the cytoplasm. When the pathway is off, Yorkie enters the nucleus and, with the TEAD transcription factor Scalloped, activates genes that promote cell proliferation and inhibit apoptosis, such as cycE, diap1 and bantam. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | hippo signaling |
6 | 6 | 5 | 0 | 0 | 3 | 0/10 | 0 | ✗ | modules/dmel_hippo_signaling.yaml | |
Hippo-YAP/TAZ signaling pathway moduleMODULE:hippo_signaling A compact Hippo pathway module. Upstream polarity, junctional, mechanical, and stress inputs activate the MST1/2 kinase tier, which activates... [more...][less]A compact Hippo pathway module. Upstream polarity, junctional, mechanical, and stress inputs activate the MST1/2 kinase tier, which activates LATS1/2 kinases through scaffolded phosphorylation. Active LATS1/2 phosphorylate YAP/TAZ, causing cytoplasmic retention or degradation and suppressing TEAD-dependent growth programs. When the kinase cassette is inactive, YAP/TAZ enter the nucleus and coactivate TEAD transcription factors. The module is grounded in GO:0035329, with PAINT anchors for STK4/MST1 and LATS1 where local seed rows support the kinase-pathway roles. |
Signaling Pathway | DRAFT | metazoa |
4 | hippo signaling |
4 | 5 | 3 | 0 | 0 | 2 | 3/5 | 0 | ✗ | modules/hippo_signaling.yaml | |
Histamine synthesis and recycling in Drosophila melanogasterMODULE:dmel_histamine_metabolismCONCRETE Histamine is the neurotransmitter of Drosophila photoreceptors and some central neurons. Histidine decarboxylase (Hdc) makes histamine from... [more...][less]Histamine is the neurotransmitter of Drosophila photoreceptors and some central neurons. Histidine decarboxylase (Hdc) makes histamine from histidine, and LOVIT, a putative vesicular histamine transporter, maintains histamine in photoreceptor synaptic terminals. After release, histamine is taken up by surrounding epithelial glia, in part by the histamine-specific transporter HisT. In glia, Ebony conjugates histamine with beta-alanine to form carcinine (beta-alanyl-histamine), which returns to photoreceptors through the carcinine transporter CarT. Tan then hydrolyses carcinine, releasing histamine for reuse. This glia-photoreceptor recycling loop sustains visual transmission when de novo synthesis is limiting. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | histamine metabolic process |
7 | 6 | 6 | 0 | 0 | 6 | 0/6 | 0 | ✗ | modules/dmel_histamine_metabolism.yaml | |
Histidine catabolism to glutamateMODULE:histidine_catabolismCONCRETE A reusable pathway for degradation of L-histidine to L-glutamate. Three conserved reactions convert histidine through trans-urocanate and... [more...][less]A reusable pathway for degradation of L-histidine to L-glutamate. Three conserved reactions convert histidine through trans-urocanate and 4-imidazolone-5-propanoate to N-formimidoyl-L-glutamate. Terminal processing then differs among organisms. A two-step route uses HutF and HutG to release ammonium and formate; a one-step route uses a formimidoylglutamase to release formamide directly. The folate-coupled route instead transfers the formimino group to tetrahydrofolate and feeds it into one-carbon metabolism. |
Metabolic Pathway | DRAFT | 1 | L-histidine catabolic process |
12 | 8 | 8 | 1 | 3 | 5 | 10/11 | 0 | ✓ | modules/histidine_catabolism.yaml | ||
Homocysteine metabolism (remethylation and transsulfuration)MODULE:homocysteine_metabolism The two competing cytosolic fates of L-homocysteine, the branch-point metabolite of the methionine cycle. Homocysteine is generated from... [more...][less]The two competing cytosolic fates of L-homocysteine, the branch-point metabolite of the methionine cycle. Homocysteine is generated from S-adenosylhomocysteine after SAM-dependent methylation reactions, and its two disposal routes determine methionine/one-carbon homeostasis and sulfur-amino-acid supply. (1) Remethylation regenerates L-methionine: methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyl-THF, the methyl donor that cobalamin-dependent methionine synthase (MTR) uses to transfer a methyl group to homocysteine (via an enzyme-bound methylcobalamin cofactor), producing methionine and regenerating tetrahydrofolate. Because MTR's cobalamin is periodically oxidised to inactive cob(II)alamin, methionine synthase reductase (MTRR), an NADPH-dependent diflavin oxidoreductase, reductively reactivates it; and the upstream cobalamin-processing enzyme MMACHC (cblC) decyanates/dealkylates incoming cobalamin to the cob(II)alamin precursor that supplies both methylcobalamin (to MTR) and adenosylcobalamin (to methylmalonyl-CoA mutase). (2) Transsulfuration commits homocysteine's sulfur to cysteine: the PLP-dependent cystathionine beta-synthase (CBS) condenses homocysteine with L-serine to cystathionine, which cystathionine gamma-lyase (CTH/CSE) then cleaves to L-cysteine (plus 2-oxobutanoate and ammonia); CBS and CTH are also the principal enzymatic sources of the gasotransmitter hydrogen sulfide. Inherited defects all cause homocystinuria / hyperhomocysteinemia with distinct biochemistry: CBS → classic homocystinuria (with hypermethioninemia); MTHFR → homocystinuria with low methionine; MTR → cblG and MTRR → cblE homocystinuria; MMACHC → cblC (combined methylmalonic aciduria and homocystinuria); CTH → (largely benign) cystathioninuria. |
Metabolic Pathway | DRAFT | 0 | homocysteine metabolic process |
6 | 6 | 5 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/homocysteine_metabolism.yaml | ||
Homogentisate catabolismMODULE:homogentisate_catabolismABSTRACT A conserved three-reaction lower pathway that opens the aromatic ring of homogentisate to form maleylacetoacetate, isomerizes maleylacetoacetate to... [more...][less]A conserved three-reaction lower pathway that opens the aromatic ring of homogentisate to form maleylacetoacetate, isomerizes maleylacetoacetate to fumarylacetoacetate, and hydrolyzes fumarylacetoacetate to fumarate and acetoacetate. The same three enzyme families (homogentisate 1,2-dioxygenase, zeta-class glutathione transferase-type maleylacetoacetate isomerase, and fumarylacetoacetase) carry out these steps in bacteria, fungi, plants, and animals. In animals the pathway is the terminal segment of phenylalanine and tyrosine catabolism, and loss of homogentisate 1,2-dioxygenase or fumarylacetoacetase causes alkaptonuria or hereditary tyrosinemia type I respectively. In bacteria such as Pseudomonas putida the lower pathway also receives homogentisate from 3-hydroxyphenylacetate and other aromatic routes. The products, fumarate and acetoacetate, enter central carbon metabolism. |
Metabolic Pathway | COMPLETE | cellular organisms |
2 | homogentisate catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 9/9 | 0 | ✓ | modules/homogentisate_catabolism.yaml | |
Homologous recombination repair of DNA double-strand breaks — MRN-CtIP and EXO1/BLM-DNA2 end resection, RPA coating, BRCA1-PALB2-BRCA2 and RAD51-paralog loading of RAD51, strand invasion with RAD54, D-loop extension, and BTR dissolution versus SLX4-MUS81/GEN1 resolution; MRE11/RAD50/NBN/RBBP8/EXO1/BLM/DNA2/RPA/BRCA1/PALB2/BRCA2/RAD51B/RAD51C/RAD51D/XRCC2/XRCC3/RAD51/RAD54L/RAD54BMODULE:homologous_recombination_dsb_repairCONCRETE Homologous recombination (HR) repairs a DNA double-strand break (DSB) by copying the missing information from an intact homologous duplex, normally... [more...][less]Homologous recombination (HR) repairs a DNA double-strand break (DSB) by copying the missing information from an intact homologous duplex, normally the sister chromatid, and is therefore restricted to the S and G2 phases of the cell cycle. Once the upstream ATM signalling cascade has marked the break and BRCA1 has displaced 53BP1-RIF1, the DNA ends are resected to expose 3' single-stranded tails. Resection begins with short-range processing by the MRE11-RAD50-NBN (MRN) complex, whose MRE11 endonuclease, stimulated by phosphorylated CtIP (RBBP8), nicks the 5'-terminated strand at a distance from the end and MRE11 3'-5' exonuclease then degrades back toward the break. Long-range resection extends the tail over kilobases through either of two machineries: the 5'-3' exonuclease EXO1, or the RecQ helicase BLM (or WRN) unwinding the duplex while the DNA2 nuclease degrades the 5' strand. The heterotrimeric single-stranded DNA binding protein RPA coats the exposed tails, removing secondary structure and protecting them. BRCA1 binds PALB2, which in turn binds BRCA2; BRCA2 delivers RAD51 to the RPA-coated DNA and stabilises nascent RAD51 filaments, and the RAD51 paralog complexes BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3) assist RAD51 nucleation and filament stability. The RAD51-ssDNA presynaptic filament searches for homology and invades the donor duplex, forming a displacement loop (D-loop); the Swi2/Snf2-family translocases RAD54 (RAD54L) and RAD54B promote homologous pairing and remodel the D-loop. The invading 3' end is extended by DNA polymerase delta, with polymerase eta able to initiate synthesis on D-loops. The D-loop can then be resolved by synthesis-dependent strand annealing, by break-induced replication, or by second-end capture to form a double Holliday junction. Double Holliday junctions are either dissolved into non-crossover products by the BLM-TOP3A-RMI1-RMI2 (BTR) dissolvasome, or cleaved by the structure-specific endonucleases SLX1-SLX4, MUS81-EME1 and GEN1, which can give crossovers. |
Biological Process | DRAFT | Homo sapiens |
0 | double-strand break repair via homologous recombination |
15 | 22 | 8 | 3 | 6 | 7 | 13/32 | 0 | ✗ | modules/homologous_recombination_dsb_repair.yaml | |
Human DNA mismatch repair — MutSalpha/MutSbeta mismatch recognition, RFC-PCNA-directed MutLalpha incision, EXO1 excision with RPA protection, and POLD resynthesis with LIG1 ligation; MSH2/MSH6/MSH3/MLH1/PMS2/RFC1-5/PCNA/EXO1/HMGB1/RPA1-3/POLD1-4/LIG1MODULE:eukaryotic_mismatch_repairCONCRETE Post-replicative DNA mismatch repair (MMR) removes base-base mismatches and small insertion/deletion loops that escape the proofreading of... [more...][less]Post-replicative DNA mismatch repair (MMR) removes base-base mismatches and small insertion/deletion loops that escape the proofreading of replicative DNA polymerases. In human cells a mismatch is recognised by one of two MutS homologue heterodimers that share MSH2: MutSalpha (MSH2-MSH6) binds base-base mismatches and one- or two-nucleotide insertion/deletion loops, and MutSbeta (MSH2-MSH3) binds larger insertion/deletion loops and has only a limited role in base-base mismatch repair. MutSalpha is pre-enriched on chromatin through binding of the MSH6 PWWP domain to H3K36me3. In an ATP-dependent step the mismatch-bound MutS complex recruits MutLalpha (MLH1-PMS2). MutLalpha is a latent endonuclease whose active site lies in PMS2; it is activated by the mismatch, MutSalpha, ATP and the PCNA sliding clamp that replication factor C (RFC1-5) loads at the strand break or primer terminus. Because RFC loads PCNA in a fixed orientation, the activated MutLalpha nicks the discontinuous (newly synthesised) strand, which is how the daughter strand is identified. Exonuclease 1 (EXO1), activated by MutSalpha, removes the error-containing tract 5' to 3' from a nick, and excision stops after the mispair is removed through the combined action of MutLalpha and RPA, the heterotrimeric single-stranded DNA-binding protein (RPA1-RPA3) that coats and protects the gap. The chromatin protein HMGB1 stimulates MutSalpha-activated excision. The gap is filled by DNA polymerase delta (POLD1-POLD4) working with PCNA and RFC, and DNA ligase 1 (LIG1) seals the remaining nick. Loss of MSH2, MSH6, MLH1 or PMS2 causes microsatellite instability and Lynch syndrome. Mismatch avoidance by polymerase proofreading, MMR-dependent signalling of DNA damage, meiotic crossover resolution and the specialised mutagenic MMR of antibody genes are outside this module. |
Biological Process | DRAFT | Homo sapiens |
0 | mismatch repair |
10 | 10 | 7 | 1 | 2 | 8 | 3/21 | 0 | ✗ | modules/eukaryotic_mismatch_repair.yaml | |
Human GABAergic transmission through ionotropic GABA-A receptorsMODULE:gabaergic_transmissionCONCRETE Fast GABAergic inhibition in the vertebrate nervous system. GAD1/GAD2 decarboxylate glutamate to GABA in the cytosol of the GABAergic terminal,... [more...][less]Fast GABAergic inhibition in the vertebrate nervous system. GAD1/GAD2 decarboxylate glutamate to GABA in the cytosol of the GABAergic terminal, VGAT (SLC32A1) loads GABA into synaptic vesicles, and calcium-triggered exocytosis releases it. Released GABA opens pentameric GABA-A receptors, which are GABA-gated chloride channels. Two receptor classes are modelled as alternatives. Synaptic gamma2-containing receptors, with (alpha1)2(beta2)2gamma2 as the most abundant example, mediate phasic inhibitory postsynaptic currents. Extrasynaptic delta-containing alpha4/alpha6 receptors respond to ambient GABA and mediate tonic inhibition. The retinal rho1 homopentamer (formerly "GABA-C") is an optional comparator. The plasma-membrane GABA transporter GAT-1 (SLC6A1) terminates the signal by sodium- and chloride-coupled reuptake. Metabotropic GABA-B signalling, GABA catabolism and gephyrin-dependent receptor clustering are outside this module. |
Biological Process | DRAFT | Homo sapiens |
2 | synaptic transmission, GABAergic |
11 | 5 | 5 | 2 | 5 | 0 | 3/8 | 0 | ✗ | modules/gabaergic_transmission.yaml | |
Human NMDA receptor family channel gating by GluN1 and its partner subunitsMODULE:nmda_receptor_gatingCONCRETE How the heterotetrameric receptors built on the GluN1 subunit are opened. Every receptor of this family contains two GluN1 subunits, which bind the... [more...][less]How the heterotetrameric receptors built on the GluN1 subunit are opened. Every receptor of this family contains two GluN1 subunits, which bind the co-agonist glycine or D-serine, and two partner subunits. With GluN2 partners (GluN2A to GluN2D) the partner binds glutamate, and the channel opens only when both ligands are bound; the open pore conducts sodium, potassium and calcium and is blocked by magnesium at resting potential, so current also requires depolarisation. With GluN3 partners (GluN3A or GluN3B) both subunit types bind glycine and glutamate is not needed: glycine at GluN3 opens the channel, whereas glycine at GluN1 limits the current. These channels have low calcium permeability and no magnesium block. The module covers ligand sensing by each subunit and conduction by the assembled tetramer. Receptor assembly and trafficking, synaptic anchoring by PSD-95 family scaffolds, allosteric modulation, and signalling downstream of calcium entry are outside it. |
Molecular Function | DRAFT | Homo sapiens |
0 | NMDA glutamate receptor activity glycine-gated cation channel activity |
12 | 9 | 3 | 2 | 8 | 3 | 1/7 | 0 | ✓ | modules/nmda_receptor_gating.yaml | |
Human acetylcholine transmission and comparative receptor mechanismsMODULE:acetylcholine_signalingCONCRETE Human cholinergic transmission combines choline uptake by SLC5A7, cytosolic acetylcholine synthesis by CHAT, vesicular loading by SLC18A3,... [more...][less]Human cholinergic transmission combines choline uptake by SLC5A7, cytosolic acetylcholine synthesis by CHAT, vesicular loading by SLC18A3, calcium-triggered exocytosis, receptor activation and extracellular acetylcholinesterase-mediated clearance. Nicotinic receptors are specific pentameric cation-channel assemblies: adult and fetal muscle receptors, neuronal heteromers, alpha7 homopentamers and alpha9/alpha10 heteromers. Their subunit requirements and ligand-binding interfaces differ. Muscarinic receptors activate heterotrimeric G proteins: M1/M3/M5 preferentially couple to Gq/11 and M2/M4 predominantly couple to Gi/o, with ligand, tissue and assay-dependent variation. GRKs and RGS proteins regulate signal duration. Channel calcium entry need not cause net excitation: alpha9/alpha10 activation in hair cells recruits calcium-sensitive potassium conductance. Optional rat and chicken receptor segments expose experimentally measured differences in calcium permeability and downstream calcium handling; they do not establish a complete conserved vertebrate circuit. Generic exocytosis and downstream PLC/cAMP pathways are explicit interfaces. Neuromuscular receptor clustering and synapse assembly are separate processes. |
Signaling Pathway | COMPLETE | Gallus gallus Homo sapiens Mus musculus Rattus norvegicus |
0 | acetylcholine receptor signaling pathway synaptic transmission, cholinergic |
56 | 38 | 21 | 9 | 34 | 15 | 43/43 | 0 | ✗ | modules/acetylcholine_signaling.yaml | |
Human canonical microRNA pathway — Microprocessor (DROSHA-DGCR8) pri-miRNA cleavage, XPO5-RAN-GTP pre-miRNA export, DICER1-TARBP2/PRKRA dicing, AGO1-4 RISC loading, and TNRC6-directed CCR4-NOT/PAN2-PAN3 deadenylation, DCP2 decapping and XRN1 decayMODULE:mirna_biogenesis_and_silencingCONCRETE MicroRNAs (miRNAs) are ~22-nucleotide RNAs that guide Argonaute proteins to partially complementary sites, mostly in the 3' untranslated regions of... [more...][less]MicroRNAs (miRNAs) are ~22-nucleotide RNAs that guide Argonaute proteins to partially complementary sites, mostly in the 3' untranslated regions of messenger RNAs, and so repress translation and promote decay of hundreds of transcripts. Most human miRNAs are transcribed by RNA polymerase II as long primary transcripts (pri-miRNAs) that fold into stem-loop hairpins. In the nucleus the Microprocessor, made of the RNase III enzyme DROSHA and its double-stranded RNA-binding partner DGCR8, cuts the hairpin out of the pri-miRNA to release a ~60-70-nucleotide precursor (pre-miRNA) with a two-nucleotide 3' overhang. Exportin-5 (XPO5) binds the pre-miRNA together with GTP-bound RAN and carries it through the nuclear pore; GTP hydrolysis in the cytoplasm releases the cargo. The cytoplasmic RNase III enzyme DICER1, partnered by the dsRNA-binding protein TARBP2 (TRBP) or PRKRA (PACT), removes the terminal loop and leaves a ~22-base-pair miRNA duplex. The duplex is loaded into one of the four human Argonautes (AGO1-AGO4); one strand, the guide, is kept and the other is discarded, forming the miRNA-induced silencing complex (miRISC). AGO2 is the only efficient slicer and can cut fully complementary targets, but most animal miRNA targets pair only through the seed (guide nucleotides 2-7) and are silenced without cleavage. For those, AGO binds a GW182-family protein (TNRC6A, TNRC6B or TNRC6C), whose tryptophan-containing motifs recruit the CCR4-NOT deadenylase complex (through CNOT1 and CNOT9) and the PAN2-PAN3 deadenylase (through PAN3, which also binds the poly(A)-binding protein PABPC1). Deadenylation is followed by removal of the 5' cap by the DCP2-DCP1 decapping complex with its activators DDX6, PATL1, EDC3 and EDC4, and by 5'-to-3' degradation by XRN1. The same CCR4-NOT-DDX6 axis represses translation of the target. A few miRNAs bypass parts of this route: mirtrons are excised by the spliceosome instead of DROSHA, and miR-451 is matured by AGO2 slicing instead of DICER1. |
Biological Process | DRAFT | Homo sapiens |
0 | miRNA processing miRNA-mediated post-transcriptional gene silencing |
17 | 19 | 10 | 2 | 6 | 7 | 7/34 | 0 | ✗ | modules/mirna_biogenesis_and_silencing.yaml | |
Human glycinergic transmission through strychnine-sensitive glycine receptorsMODULE:glycinergic_transmissionCONCRETE Fast glycinergic inhibition, mainly in the spinal cord and brainstem. Glycine is loaded into synaptic vesicles by VGAT (SLC32A1), the same... [more...][less]Fast glycinergic inhibition, mainly in the spinal cord and brainstem. Glycine is loaded into synaptic vesicles by VGAT (SLC32A1), the same vesicular carrier used for GABA, and released by calcium-triggered exocytosis. Released glycine opens pentameric glycine receptors (GlyRs), which are glycine-gated chloride channels. Adult synaptic receptors contain alpha1 and beta subunits; the beta subunit binds gephyrin and anchors the receptor at the postsynaptic density. Homomeric alpha2 receptors predominate before the postnatal switch to alpha1beta. Two sodium- and chloride-coupled transporters clear glycine. Presynaptic GlyT2 (SLC6A5) recaptures glycine into the terminal and is needed to refill vesicles. Glial GlyT1 (SLC6A9) sets glycine concentrations at the synapse. Glycine's separate role as an NMDA-receptor co-agonist is outside this module, as are gephyrin scaffold assembly and glycine biosynthesis. |
Biological Process | DRAFT | Homo sapiens |
1 | synaptic transmission, glycinergic |
7 | 4 | 4 | 1 | 2 | 0 | 0/5 | 0 | ✗ | modules/glycinergic_transmission.yaml | |
Human mRNA nuclear export — TREX loading on spliced mRNA, NXF1-NXT1 handover, nuclear pore translocation and DDX19-GLE1 remodelling, with the CRM1 route for specific mRNAs; THOC1/THOC2/THOC3/THOC5/THOC6/THOC7/DDX39B/ALYREF/CHTOP/SARNP/NXF1/NXT1/MCM3AP/ENY2/PCID2/DDX19B/GLE1/NUP214/XPO1/RANMODULE:mrna_nuclear_exportCONCRETE A mature mRNA, capped, spliced and polyadenylated in the nucleus, must cross the nuclear pore complex (NPC) before it can be translated. In human... [more...][less]A mature mRNA, capped, spliced and polyadenylated in the nucleus, must cross the nuclear pore complex (NPC) before it can be translated. In human cells bulk export is coupled to splicing and to the cap. The transcription-export complex TREX, built from the multi-subunit THO complex (THOC1, THOC2, THOC3, THOC5, THOC6, THOC7) with the DEAD-box ATPase UAP56 (DDX39B) and the export adaptors ALYREF, CHTOP and CIP29 (SARNP), is deposited near the 5' end of the spliced mRNA through an interaction between ALYREF and the cap-binding protein CBP80. UAP56 uses its ATPase cycle to load ALYREF and CHTOP onto the mRNA. The adaptors then recruit the export receptor, the NXF1-NXT1 (TAP-p15) heterodimer: ALYREF and THOC5 contact NXF1 and switch it from an autoinhibited state into one that exposes its arginine-rich RNA-binding domain, and the mRNA is handed over from ALYREF to NXF1. TREX-2 (GANP/MCM3AP with ENY2 and PCID2), anchored on the nuclear basket, helps deliver NXF1-bound mRNPs to the pore. NXF1-NXT1 carries the mRNP through the central channel by transient contacts between its NTF2-like and UBA domains and the phenylalanine-glycine (FG) repeats of the nucleoporins, on a scaffold whose outer rings are built from the Nup107-160 (Y) complex. At the cytoplasmic filaments the DEAD-box ATPase DDX19 (DDX19B), anchored on NUP214, is activated by GLE1 and its small-molecule cofactor inositol hexakisphosphate (IP6). DDX19 remodels the emerging mRNP, stripping export factors so that they recycle to the nucleus and making the passage directional. A minority of mRNAs leave by a second, Ran-dependent route through the karyopherin CRM1 (XPO1), which is recruited by mRNA-specific adaptors: LRPPRC with eIF4E for mRNAs that carry the eIF4E-sensitivity element, HuR (ELAVL1) with pp32 and APRIL (ANP32A, ANP32B) for AU-rich-element mRNAs, NXF3, and FMRP for N6-methyladenosine-marked mRNAs. RanGTP loads the cargo onto CRM1 in the nucleus, and GTP hydrolysis by Ran, stimulated by RanGAP1 with RanBP1 and RanBP2 at the cytoplasmic face, releases it. |
Biological Process | DRAFT | Homo sapiens |
0 | mRNA export from nucleus |
11 | 20 | 6 | 1 | 4 | 5 | 3/45 | 0 | ✗ | modules/mrna_nuclear_export.yaml | |
Human mitochondrial translation — mt-tRNA modification, aminoacylation and Glu-tRNAGln transamidation, mitoribosome, and initiation/elongation factorsMODULE:mitochondrial_translation Thirteen polypeptides of the oxidative phosphorylation (OXPHOS) system — seven Complex I subunits, cytochrome b of Complex III, three Complex IV... [more...][less]Thirteen polypeptides of the oxidative phosphorylation (OXPHOS) system — seven Complex I subunits, cytochrome b of Complex III, three Complex IV subunits and two Complex V subunits — are encoded by mitochondrial DNA and are made inside the mitochondrial matrix by a dedicated translation system whose protein components are all nuclear-encoded and imported. The system has four kinds of part. (1) The 22 mtDNA-encoded tRNAs must be post-transcriptionally modified to read the mitochondrial genetic code: the GTPBP3-MTO1 complex installs 5-taurinomethyluridine (taum5U) at the wobble position U34 of mt-tRNAs for Leu(UUR), Trp, Gln, Glu and Lys; NSUN3 methylates C34 of the single mt-tRNAMet to m5C34, which the dioxygenase ALKBH1 oxidises to 5-formylcytidine (f5C34) so that one tRNAMet can decode both AUG and AUA; and TRIT1 isopentenylates A37 (i6A37) of a subset of mt-tRNAs. (2) Nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (the *ARS2 family, e.g. DARS2) charge the tRNAs; because mitochondria lack a glutaminyl-tRNA synthetase, EARS2 first mischarges tRNAGln with glutamate and (3) the heterotrimeric glutamyl-tRNA(Gln) amidotransferase GatCAB (QRSL1/GatA, GATB, GATC) transamidates Glu-tRNAGln to Gln-tRNAGln. (4) The 55S mitoribosome — whose 28S small subunit contains, among others, uS7m (MRPS7), mS22 (MRPS22) and the pentatricopeptide-repeat protein mS39 (PTCD3) at the mRNA entry channel — translates the leaderless mt-mRNAs with the initiation factors MTIF2 and MTIF3 and the elongation factors TUFM (EF-Tu), TSFM (EF-Ts, its nucleotide exchange factor) and GFM1 (EF-G1). Because every one of the 13 products depends on the same apparatus, a lesion anywhere in it produces a combined (multi-complex) OXPHOS deficiency rather than a single-complex defect. The dismech knowledge base curates these as the combined oxidative phosphorylation deficiency series: GTPBP3 -> COXPD23 (MONDO:0014525); MTO1 -> MTO1 deficiency / COXPD10 (MONDO:0013865); NSUN3 -> COXPD48 (MONDO:0033566); TRIT1 -> COXPD35 (MONDO:0054742); GATC -> COXPD42 (MONDO:0030008); MRPS7 -> COXPD34 (MONDO:0054741), also a Perrault syndrome gene (MONDO:0017312); PTCD3 -> COXPD51 (MONDO:0033631); and TUFM -> COXPD4 (MONDO:0012534). Biallelic MRPS22 variants cause combined oxidative phosphorylation deficiency 5 (COXPD5, MIM:611719; not yet a dismech entry), with reduced 12S mt-rRNA and multiple respiratory chain deficiency; other MRPS22 missense alleles cause isolated ovarian dysgenesis 7 (MONDO:0020857), which dismech curates as a subtype of 46,XX gonadal dysgenesis (MONDO:0009299). ALKBH1 is curated in the dismech COXPD48 entry as the pathway partner of NSUN3, not as a disease gene. |
Biological Process | DRAFT | 0 | mitochondrial translation |
7 | 15 | 6 | 0 | 0 | 8 | 18/18 | 0 | ✗ | modules/mitochondrial_translation.yaml | ||
Human serotonergic signalling through ionotropic 5-HT3 receptorsMODULE:serotonergic_5ht3_signalingCONCRETE The ionotropic arm of serotonergic transmission. Serotonin is synthesised from tryptophan by TPH2 and DDC, loaded into vesicles by VMAT2 (SLC18A2)... [more...][less]The ionotropic arm of serotonergic transmission. Serotonin is synthesised from tryptophan by TPH2 and DDC, loaded into vesicles by VMAT2 (SLC18A2) and released by calcium-triggered exocytosis. Released serotonin opens 5-HT3 receptors, the only pentameric ligand-gated channels among the serotonin receptors; the other 5-HT receptor classes are G-protein-coupled and are outside this module. Two receptor forms are modelled as alternatives: the 5-HT3A homopentamer, which is calcium-permeable but has a conductance too small to resolve directly, and the 5-HT3A/5-HT3B heteromer, which has a large single-channel conductance and low calcium permeability. The signal is terminated by SERT (SLC6A4), which recaptures serotonin into the presynaptic terminal. Melatonin synthesis, monoamine oxidase degradation and the metabotropic 5-HT receptors are outside this module. |
Biological Process | DRAFT | Homo sapiens |
2 | synaptic transmission, serotonergic serotonin-gated cation-selective signaling pathway |
8 | 3 | 5 | 1 | 2 | 0 | 0/3 | 0 | ✗ | modules/serotonergic_5ht3_signaling.yaml | |
Hydroxycinnamate and vanillate catabolism to protocatechuateMODULE:hydroxycinnamate_vanillate_catabolismCONCRETE A four-step bacterial peripheral aromatic-catabolism route that funnels the hydroxycinnamate ferulate to protocatechuate by the non-beta-oxidative... [more...][less]A four-step bacterial peripheral aromatic-catabolism route that funnels the hydroxycinnamate ferulate to protocatechuate by the non-beta-oxidative CoA-dependent pathway. A feruloyl-CoA synthetase (Fcs) activates ferulate to feruloyl-CoA; a crotonase-fold hydroxycinnamoyl-CoA hydratase-lyase (Ech/HCHL) hydrates the thioester and cleaves it to vanillin and acetyl-CoA; an NAD-dependent vanillin dehydrogenase (Vdh) oxidizes vanillin to vanillate; and the two-component Rieske oxygenase VanAB O-demethylates vanillate to protocatechuate and formaldehyde. Aromatic-acid uptake, formaldehyde detoxification, gallate catabolism and the downstream protocatechuate beta-ketoadipate pathway are separate modules. |
Metabolic Pathway | COMPLETE | Pseudomonadales with the CoA-dependent ferulate route |
0 | ferulate catabolic process aerobic phenol-containing compound catabolic process |
5 | 5 | 4 | 0 | 0 | 4 | 9/9 | 0 | ✗ | modules/hydroxycinnamate_vanillate_catabolism.yaml | |
Hypothalamic leptin-melanocortin signaling moduleMODULE:leptin_melanocortin_signaling The central adipostat: adipocyte-derived leptin acts on the long leptin receptor isoform of hypothalamic arcuate neurons, whose JAK2-STAT3 output... [more...][less]The central adipostat: adipocyte-derived leptin acts on the long leptin receptor isoform of hypothalamic arcuate neurons, whose JAK2-STAT3 output raises POMC and lowers AGRP expression; prohormone convertases cleave POMC in dense-core granules to release alpha-MSH, which activates MC4R on second-order neurons to suppress appetite, while AGRP from a reciprocal neuronal population antagonises the same receptor. |
Signaling Pathway | DRAFT | mammals |
2 | negative regulation of appetite by leptin-mediated signaling pathway energy homeostasis |
6 | 7 | 5 | 0 | 0 | 5 | 6/7 | 0 | ✗ | modules/leptin_melanocortin_signaling.yaml | |
Hypoxia-inducible factor (Sima-Tgo) in Drosophila melanogasterMODULE:dmel_hif_complexCONCRETE Hypoxia-inducible factor is a bHLH-PAS heterodimer that activates transcription when oxygen is low. The oxygen-regulated alpha subunit Sima... [more...][less]Hypoxia-inducible factor is a bHLH-PAS heterodimer that activates transcription when oxygen is low. The oxygen-regulated alpha subunit Sima (similar) is hydroxylated by the prolyl hydroxylase Fatiga in normoxia and degraded; in hypoxia it accumulates, enters the nucleus and dimerizes with the constitutive beta subunit Tango (tgo), the Drosophila ARNT homolog, to bind hypoxia response elements. Sima-Tgo drives hypoxia-induced gene expression, including tracheal branching responses, and Sima also has roles in growth control under normoxia. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | RNA polymerase II transcription regulator complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_hif_complex.yaml | |
Hypusine biosynthesis in Drosophila melanogasterMODULE:dmel_hypusine_biosynthesisCONCRETE Hypusine is a modified lysine found only in translation factor eIF5A, where it is needed for eIF5A to support translation elongation through... [more...][less]Hypusine is a modified lysine found only in translation factor eIF5A, where it is needed for eIF5A to support translation elongation through difficult sequences such as polyproline stretches. It is made in two steps. Deoxyhypusine synthase (Dhps) transfers the aminobutyl group of spermidine to a specific lysine of eIF5A, forming deoxyhypusine. Deoxyhypusine hydroxylase, encoded in Drosophila by nero, then hydroxylates this residue to hypusine. In flies, nero mutations affect cell and organ growth and autophagy. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | peptidyl-hypusine biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/dmel_hypusine_biosynthesis.yaml | |
IL-1 signaling pathway moduleMODULE:il1_signaling IL-1 cytokines activate IL1R1/IL1RAP receptor complexes and MyD88-IRAK-TRAF6 signaling assemblies to induce NF-kappaB and inflammatory... [more...][less]IL-1 cytokines activate IL1R1/IL1RAP receptor complexes and MyD88-IRAK-TRAF6 signaling assemblies to induce NF-kappaB and inflammatory transcriptional responses. |
Signaling Pathway | DRAFT | metazoa |
10 | interleukin-1-mediated signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 3/6 | 0 | ✓ | modules/il1_signaling.yaml | |
IL-6 signaling pathway moduleMODULE:il6_signaling IL-6 engages IL6R and gp130/IL6ST receptor complexes, activating JAK kinases and STAT3-centered transcriptional programs that control inflammation,... [more...][less]IL-6 engages IL6R and gp130/IL6ST receptor complexes, activating JAK kinases and STAT3-centered transcriptional programs that control inflammation, acute-phase responses, and differentiation. |
Signaling Pathway | DRAFT | metazoa |
10 | interleukin-6-mediated signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 4/6 | 0 | ✓ | modules/il6_signaling.yaml | |
INO80 chromatin remodeling complex in Drosophila melanogasterMODULE:dmel_ino80_complexCONCRETE The INO80 complex is an ATP-dependent chromatin remodeler of the INO80 subfamily that slides nucleosomes and positions the +1 nucleosome at... [more...][less]The INO80 complex is an ATP-dependent chromatin remodeler of the INO80 subfamily that slides nucleosomes and positions the +1 nucleosome at promoters, and contributes to transcription regulation and DNA repair. In Drosophila it contains the Ino80 ATPase, the AAA+ ATPases Pontin and Reptin, actin and the actin-related proteins Arp5 and Arp8. FlyBase also places the Polycomb group DNA-binding protein Pho (the YY1 homolog) in the complex, consistent with a role of INO80 in recruiting Polycomb proteins. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Ino80 complex |
5 | 4 | 4 | 0 | 0 | 0 | 0/7 | 0 | ✗ | modules/dmel_ino80_complex.yaml | |
IRM adhesion complexes in Drosophila melanogasterMODULE:dmel_irm_myoblast_adhesionCONCRETE The IRM (Irre cell recognition module) proteins are four immunoglobulin- superfamily adhesion receptors that bind each other in trans between... [more...][less]The IRM (Irre cell recognition module) proteins are four immunoglobulin- superfamily adhesion receptors that bind each other in trans between neighbouring cells. Kin of irre (Kirre, also called Dumbfounded) and Roughest (Rst) form one pair of paralogs, and Sticks and stones (Sns) and Hibris (Hbs) the other; each Kirre/Rst protein can bind each Sns/Hbs protein. In the embryonic mesoderm, Kirre and Rst on founder cells bind Sns and Hbs on fusion-competent myoblasts to attract them and initiate myoblast fusion. The same heterophilic pairs pattern the interommatidial cells of the eye and, in nephrocytes, Sns and Kirre form the slit diaphragm. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | myoblast fusion cell-cell adhesion |
5 | 4 | 0 | 1 | 4 | 0 | 4/4 | 0 | ✗ | modules/dmel_irm_myoblast_adhesion.yaml | |
ISWI chromatin remodeling complexes in Drosophila melanogasterMODULE:dmel_iswi_complexesCONCRETE ISWI is an ATP-dependent chromatin remodeler that slides nucleosomes. In Drosophila the single ISWI ATPase is the catalytic subunit of several... [more...][less]ISWI is an ATP-dependent chromatin remodeler that slides nucleosomes. In Drosophila the single ISWI ATPase is the catalytic subunit of several complexes defined by their accessory subunits. ACF (with Acf) and CHRAC (Acf plus the histone-fold pair Chrac-14 and Chrac-16) assemble and space regularly arrayed nucleosomes. NURF (with the large subunit E(bx)/NURF301, Caf1-55 and the pyrophosphatase Nurf-38) helps activate transcription of target genes, for example in ecdysone and JAK/STAT signaling. RSF, NORC and TORC (with Toutatis and CtBP) are further ISWI complexes; TORC is linked to transcriptional repression. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ISWI-type complex |
7 | 6 | 0 | 1 | 6 | 0 | 1/10 | 0 | ✗ | modules/dmel_iswi_complexes.yaml | |
Imd signaling pathway in Drosophila melanogasterMODULE:dmel_imd_signalingCONCRETE The immune deficiency (Imd) pathway is the main Drosophila defense against Gram-negative bacteria and some Gram-positive bacilli. It is triggered... [more...][less]The immune deficiency (Imd) pathway is the main Drosophila defense against Gram-negative bacteria and some Gram-positive bacilli. It is triggered when DAP-type peptidoglycan binds the transmembrane receptor PGRP-LC or the intracellular receptor PGRP-LE. The receptors recruit the death-domain protein Imd, which assembles a complex with the adaptor Fadd and the caspase Dredd. Dredd cleaves Imd, and the E3 ligase Diap2, with the E2 enzymes Bendless and Effete and the E2 variant Uev1A, attaches K63-linked ubiquitin chains. These chains recruit the Tak1-Tab2 kinase complex, which activates the IKK complex (IKKbeta and Kenny). IKK phosphorylates the NF-kappa-B factor Relish, Dredd cleaves it, and the Rel homology domain enters the nucleus to induce antimicrobial peptide genes. Tak1 also activates the JNK branch (Hemipterous, Basket) that acts through AP-1 (Jra, Kayak). |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | peptidoglycan recognition protein signaling pathway |
11 | 16 | 10 | 0 | 0 | 7 | 3/19 | 0 | ✗ | modules/dmel_imd_signaling.yaml | |
Insulin receptor signaling pathway moduleMODULE:insulin_receptor_signaling A compact insulin receptor signaling module. Insulin binding activates the receptor tyrosine kinase INSR, which autophosphorylates and... [more...][less]A compact insulin receptor signaling module. Insulin binding activates the receptor tyrosine kinase INSR, which autophosphorylates and phosphorylates IRS adaptors. IRS phosphotyrosines recruit PI3K and route the signal into PIP3-AKT signaling, controlling FOXO-dependent transcription, glucose uptake, glycogen metabolism, growth, and survival. The module is grounded in GO:0008286 and uses PAINT PTN anchors for the insulin receptor and AKT-family signaling roles where local IBD seed rows support them. |
Signaling Pathway | DRAFT | metazoa |
4 | insulin receptor signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 3/5 | 0 | ✗ | modules/insulin_receptor_signaling.yaml | |
Insulin-like receptor signaling pathway in Drosophila melanogasterMODULE:dmel_insulin_like_receptor_signalingCONCRETE Drosophila insulin-like peptides (Ilps), several of them secreted by the insulin-producing cells of the brain, bind the single insulin-like... [more...][less]Drosophila insulin-like peptides (Ilps), several of them secreted by the insulin-producing cells of the brain, bind the single insulin-like receptor InR, a receptor tyrosine kinase. Activated InR phosphorylates the adaptor Chico (IRS) and acts with the adaptor Lnk (SH2B), recruiting the class IA phosphatidylinositol 3-kinase made of the catalytic subunit Pi3K92E (Dp110) and the regulatory subunit Pi3K21B (p60). The resulting PIP3 recruits Pdk1 and Akt; Akt phosphorylates and excludes the transcription factor FOXO from the nucleus and promotes TORC1 activity through Rheb, leading to S6 kinase activation and inhibition of the translational repressor Thor (4E-BP). The pathway controls cell and organismal growth, carbohydrate and lipid metabolism, reproduction and lifespan. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | insulin receptor signaling pathway |
10 | 28 | 9 | 0 | 0 | 7 | 10/29 | 0 | ✗ | modules/dmel_insulin_like_receptor_signaling.yaml | |
Insulin-stimulated GLUT4 glucose uptake — AKT2 inhibition of the TBC1D4/TBC1D1 Rab GAPs, RAB10 or RAB8A/RAB13 activation, motor-driven GLUT4 storage vesicle movement, cortical actin remodelling, STX4-SNAP23-VAMP2 fusion and SLC2A4 glucose transport; AKT2/TBC1D4/TBC1D1/RAB10/DENND4C/RAB8A/RAB13/KIF5B/MYO5A/MYO1C/RAC1/PAK1/STX4/SNAP23/VAMP2/STXBP3/STXBP4/SLC2A4MODULE:glut4_insulin_stimulated_glucose_uptakeCONCRETE In fat cells and in skeletal and cardiac muscle, insulin raises glucose uptake by moving the facilitative glucose transporter GLUT4 (SLC2A4) from... [more...][less]In fat cells and in skeletal and cardiac muscle, insulin raises glucose uptake by moving the facilitative glucose transporter GLUT4 (SLC2A4) from intracellular stores to the cell surface. In the unstimulated cell most GLUT4 sits in small GLUT4 storage vesicles (GSVs, the insulin-responsive compartment) that are retained inside the cell. Insulin receptor signalling through IRS proteins and class I PI3K activates the kinase AKT2. AKT2 phosphorylates the Rab GTPase-activating proteins TBC1D4 (AS160) and its paralogue TBC1D1, which suppresses their GAP activity toward GSV Rabs. The GTP-bound Rab that results is RAB10 in adipocytes, loaded by the exchange factor DENND4C, and RAB8A and RAB13 in muscle cells. Active Rabs, together with kinesin-1 (KIF5B) on microtubules and the myosins MYO5A (itself an AKT2 substrate) and MYO1C on cortical actin, carry GSVs to the cell periphery. In muscle, insulin also activates RAC1, which through PAK1 and the ARP2/3 complex remodels the cortical actin meshwork beneath the plasma membrane, a cycle of actin branching and cofilin-mediated severing that is needed for GLUT4 to reach the surface. GSVs then fuse with the plasma membrane through a SNARE complex of the vesicle SNARE VAMP2 with the plasma membrane SNAREs syntaxin-4 (STX4) and SNAP23, regulated by the syntaxin-4-binding proteins Munc18c (STXBP3) and Synip (STXBP4); AKT2 phosphorylation of Synip releases it from syntaxin-4. GLUT4 inserted into the plasma membrane then transports D-glucose down its gradient into the cell. Defects at several of these steps (AKT2 mutations, truncating TBC1D4 variants, reduced syntaxin-4) cause insulin resistance. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | glucose import in response to insulin stimulus |
9 | 19 | 6 | 1 | 2 | 6 | 6/21 | 0 | ✗ | modules/glut4_insulin_stimulated_glucose_uptake.yaml | |
Integrator complex in Drosophila melanogasterMODULE:dmel_integrator_complexCONCRETE Integrator is a multisubunit complex that binds promoter-proximal RNA polymerase II and cleaves nascent transcripts. Its endonuclease module, in... [more...][less]Integrator is a multisubunit complex that binds promoter-proximal RNA polymerase II and cleaves nascent transcripts. Its endonuclease module, in which IntS11 is the catalytic subunit related to the cleavage and polyadenylation endonuclease Cpsf73, processes the 3' ends of snRNAs and terminates transcription of paused or non-productive polymerases at protein-coding genes, enhancers and long noncoding RNA loci. Integrator also recruits protein phosphatase 2A through IntS6 and IntS8, forming the Integrator-PP2A (INTAC) complex that dephosphorylates the polymerase C-terminal domain and Spt5 and opposes P-TEFb. In Drosophila, Integrator attenuates transcription at many genes and is required for snRNA processing. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | integrator complex INTAC complex |
5 | 4 | 4 | 0 | 0 | 0 | 2/17 | 0 | ✗ | modules/dmel_integrator_complex.yaml | |
Integrin-FAK-SRC signaling pathway moduleMODULE:integrin_fak_src_signaling A compact integrin signaling module. Extracellular-matrix engagement clusters integrins, talin/kindlin link cytoplasmic integrin tails to actin,... [more...][less]A compact integrin signaling module. Extracellular-matrix engagement clusters integrins, talin/kindlin link cytoplasmic integrin tails to actin, FAK/PTK2 and SRC-family kinases are recruited and activated at focal adhesions, and adaptor scaffolds such as paxillin route the signal to Rho GTPase, MAPK, PI3K, migration, survival, and mechanotransduction outputs. The module is grounded in GO:0007229 and includes PAINT PTN anchors for the FAK/SRC tyrosine kinase tier where local IBD rows support the role. |
Signaling Pathway | DRAFT | metazoa |
3 | integrin-mediated signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 4/5 | 0 | ✗ | modules/integrin_fak_src_signaling.yaml | |
Interleukin-21 signaling pathway moduleMODULE:il21_signaling Secreted Interleukin-21 (IL21) binds the private alpha receptor subunit IL21R and recruits the shared common gamma chain (IL2RG) to assemble a... [more...][less]Secreted Interleukin-21 (IL21) binds the private alpha receptor subunit IL21R and recruits the shared common gamma chain (IL2RG) to assemble a heterodimeric class I cytokine receptor complex on B cells, T cells, and natural killer (NK) cells. Receptor assembly juxtaposes and activates receptor-associated Janus kinases JAK1 (on IL21R) and JAK3 (on IL2RG), which phosphorylate IL21R cytoplasmic tyrosines (notably Y519) to recruit and phosphorylate STAT3 (and contextually STAT1 and STAT5), driving germinal center B cell differentiation, immunoglobulin class-switch recombination, T follicular helper (Tfh) cell differentiation, and NK/CD8+ T cell effector maturation. |
Signaling Pathway | DRAFT | bony vertebrates |
7 | interleukin-21-mediated signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 5/7 | 0 | ✗ | modules/il21_signaling.yaml | |
Interleukin-22 signaling pathway moduleMODULE:il22_signaling Secreted Interleukin-22 (IL22), produced by Th17/Th22 cells, gamma-delta T cells, and group 3 innate lymphoid cells (ILC3), binds with high... [more...][less]Secreted Interleukin-22 (IL22), produced by Th17/Th22 cells, gamma-delta T cells, and group 3 innate lymphoid cells (ILC3), binds with high affinity to the private epithelial receptor subunit IL22RA1 (IL-22R1) and recruits the shared class II cytokine receptor subunit IL10RB (IL-10R2) into a ternary signaling complex on barrier epithelial cells, keratinocytes, and hepatocytes. Receptor assembly activates IL22RA1-associated JAK1 and IL10RB-associated TYK2, which phosphorylate IL22RA1 cytoplasmic tyrosines (Y251, Y301) to recruit and phosphorylate STAT3, driving antimicrobial peptide expression, acute-phase protein synthesis, and epithelial barrier proliferation and repair. Extracellular IL22 bioactivity is antagonized by the secreted soluble decoy receptor IL22RA2 (IL-22BP). |
Signaling Pathway | DRAFT | bony vertebrates |
4 | interleukin-22-mediated signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 4/6 | 0 | ✗ | modules/il22_signaling.yaml | |
Interleukin-34 / CSF1R signaling pathway moduleMODULE:il34_signaling Secreted homodimeric Interleukin-34 (IL34) binds the N-terminal immunoglobulin-like domains of the class III receptor tyrosine kinase CSF1R... [more...][less]Secreted homodimeric Interleukin-34 (IL34) binds the N-terminal immunoglobulin-like domains of the class III receptor tyrosine kinase CSF1R (macrophage colony-stimulating factor 1 receptor), which it shares with the structurally homologous but sequence-unrelated cytokine CSF1. Ligand binding dimerizes the receptor and activates its intracellular tyrosine kinase, initiating signaling that supports monocyte viability, macrophage differentiation, and the tissue-specific maintenance of Langerhans cells and microglia. |
Signaling Pathway | DRAFT | bony vertebrates |
3 | interleukin-34-mediated signaling pathway |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/il34_signaling.yaml | |
Intracellular endosomal trafficking and cargo routing — clathrin/AP-2 uptake, V-ATPase acidification, EHD1 recycling vs. ESCRT/RAB7A late-endosomal maturation, CTSD lysosomal proteolysis, and cytosolic escapeMODULE:endosomal_trafficking_routing Receptor-bound macromolecular cargo and therapeutic nanoparticles (including diferric transferrin bound to TfR1/TFRC and apolipoprotein-coated... [more...][less]Receptor-bound macromolecular cargo and therapeutic nanoparticles (including diferric transferrin bound to TfR1/TFRC and apolipoprotein-coated lipid nanoparticles) enter cells via clathrin- and AP-2-mediated endocytosis into nascent endocytic vesicles that mature into early sorting endosomes. V-ATPase (catalytic subunit ATP6V1A) acidifies the early endosomal lumen (pH ~6.0-5.5), triggering ligand uncoupling (such as iron release from transferrin) and protonation of ionizable lipids. From the acidified sorting endosome, cargo partitions across three competing fates: (1) tubular endocytic recycling back to the plasma membrane driven by the membrane-remodeling ATPase EHD1; (2) multivesicular body (MVB) sorting by ESCRT-I (TSG101) and early-to-late endosomal maturation governed by the small GTPase RAB7A, which delivers cargo to lysosomes for luminal proteolysis by aspartic cathepsins (CTSD); and (3) endosomal membrane destabilization and productive escape into the cytosol. Because active RAB7A-driven late endosomal maturation sequesters cargo into the degradative lysosomal pathway, loss of RAB7A diverts endosomal flux away from lysosomal degradation and markedly increases cytosolic escape of lipid nanoparticle cargo (Jozić et al. 2026, PMID:41814093). |
Transport Step | DRAFT | 0 | receptor-mediated endocytosis endosomal lumen acidification endocytic recycling endosome to lysosome transport |
8 | 8 | 7 | 0 | 0 | 7 | 9/9 | 1 | ✗ | Agent Based | modules/endosomal_trafficking_routing.yaml | |
Intracellular triacylglycerol lipolysis (ABHD5-ATGL, HSL, MGLL)MODULE:triacylglycerol_lipolysis Neutral (cytoplasmic) lipolysis is the stepwise hydrolysis of triacylglycerol stored in cytoplasmic lipid droplets to glycerol and three fatty... [more...][less]Neutral (cytoplasmic) lipolysis is the stepwise hydrolysis of triacylglycerol stored in cytoplasmic lipid droplets to glycerol and three fatty acids. Adipose triglyceride lipase (ATGL/PNPLA2) catalyzes the first, rate-limiting step, hydrolyzing triacylglycerol to diacylglycerol on the lipid droplet surface; its activity is strongly stimulated by the non-catalytic co-activator ABHD5 (CGI-58). Hormone-sensitive lipase (HSL/LIPE) then hydrolyzes diacylglycerol to monoacylglycerol, and monoglyceride lipase (MGLL) completes the pathway by hydrolyzing monoacylglycerol to glycerol and a fatty acid. The pathway operates in adipocytes, where it supplies fatty acids to other tissues during fasting, and in most other cells including skeletal and cardiac muscle. Biallelic loss of ABHD5 causes neutral lipid storage disease with ichthyosis (Chanarin-Dorfman syndrome) and biallelic loss of PNPLA2 causes neutral lipid storage disease with myopathy; both show triacylglycerol accumulation in cytoplasmic droplets of many tissues. |
Metabolic Pathway | DRAFT | 0 | triglyceride catabolic process |
5 | 4 | 4 | 0 | 0 | 3 | 3/4 | 0 | ✗ | modules/triacylglycerol_lipolysis.yaml | ||
Intraflagellar transportMODULE:intraflagellar_transportCONCRETE Intraflagellar transport (IFT) is the bidirectional, motor-driven movement of large protein trains along the ciliary axoneme that builds and... [more...][less]Intraflagellar transport (IFT) is the bidirectional, motor-driven movement of large protein trains along the ciliary axoneme that builds and maintains cilia. It is ancestral in ciliated eukaryotes and has been lost along with cilia in lineages such as most fungi, flowering plants and Dictyostelium. IFT trains are polymers of two multisubunit complexes. IFT-B (including IFT88, IFT52, IFT57, IFT80, IFT70, IFT38, IFT46, IFT54, IFT56, IFT172, IFT20 and the IFT74/IFT81 tubulin-binding module) is needed to extend the axoneme and carries tubulin and other axonemal precursors. IFT-A (IFT140, IFT122, IFT144, IFT139, IFT121 and IFT43) is needed for retrograde transport and for ciliary import of membrane proteins. Heterotrimeric kinesin-II (two kinesin-2 motor subunits and a non-motor KAP subunit) carries trains from the ciliary base through the transition zone toward the tip. Some lineages add a homodimeric kinesin-2 accessory motor. In Caenorhabditis elegans sensory cilia, OSM-3 takes trains over from kinesin-II in a handover zone and alone builds the distal singlet segment, and the IFT-B subunit DYF-1 is required for OSM-3 to dock onto trains. At the tip trains turn around and are returned to the base by IFT-dynein (cytoplasmic dynein-2), whose heavy chain is DYNC2H1 (worm CHE-3). Ciliary kinases of the MAK/CILK1 family (worm DYF-5, human CILK1) regulate motor behaviour, train turnaround and cilium length; DYF-5 phosphorylates the tubulin-binding module of IFT-74 to promote tubulin unloading, and CILK1 phosphorylates the kinesin-II subunit KIF3A. The BBSome couples IFT-A and IFT-B and regulates IFT assembly at the base and turnaround at the tip. Loss of IFT-B, IFT-A, kinesin-II or dynein-2 function causes absent, truncated or malformed cilia; in worms this prevents dye uptake by sensory neurons, and in humans IFT gene mutations cause skeletal and renal ciliopathies. |
Biological Process | DRAFT | Eukaryota |
0 | intraciliary transport cilium assembly |
9 | 7 | 7 | 1 | 1 | 7 | 31/31 | 0 | ✗ | modules/intraflagellar_transport.yaml | |
Intraflagellar transport complexes A and B in Drosophila melanogasterMODULE:dmel_intraflagellar_transportCONCRETE Intraflagellar transport (IFT) moves protein cargo along the axoneme between the ciliary base and tip. IFT trains are built from two multi-subunit... [more...][less]Intraflagellar transport (IFT) moves protein cargo along the axoneme between the ciliary base and tip. IFT trains are built from two multi-subunit complexes: IFT-B, which is carried toward the tip by kinesin-2 and is required for anterograde transport and axoneme assembly, and IFT-A, which is needed mainly for retrograde transport by cytoplasmic dynein 2 and for import of membrane proteins. In Drosophila, cilia occur only on type I sensory neurons and on sperm. IFT is required to build the sensory cilia of chordotonal and external sensory neurons, and mutants such as nompB (IFT88) lack mechanosensory potentials, whereas most of the sperm axoneme is assembled without IFT. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | intraciliary transport particle |
3 | 2 | 2 | 0 | 0 | 1 | 0/16 | 0 | ✗ | modules/dmel_intraflagellar_transport.yaml | |
Intrinsic apoptotic signaling pathway moduleMODULE:intrinsic_apoptotic_signaling Cell-intrinsic stress signals regulate BCL2-family mitochondrial permeabilization, cytochrome c release, apoptosome assembly, and initiator... [more...][less]Cell-intrinsic stress signals regulate BCL2-family mitochondrial permeabilization, cytochrome c release, apoptosome assembly, and initiator caspase-9 activation. |
Signaling Pathway | DRAFT | metazoa |
3 | intrinsic apoptotic signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✓ | modules/intrinsic_apoptotic_signaling.yaml | |
Isoprenoid (prenyl) diphosphate biosynthesis (IPP/DMAPP -> GPP -> FPP -> GGPP)MODULE:isoprenoid_diphosphate_biosynthesisCONCRETE The isoprenoid-diphosphate trunk converts the universal five-carbon isoprene units produced by the mevalonate pathway (or, in bacteria and... [more...][less]The isoprenoid-diphosphate trunk converts the universal five-carbon isoprene units produced by the mevalonate pathway (or, in bacteria and plastids, the MEP pathway; both curated separately) into the linear trans-prenyl diphosphates that seed the major downstream isoprenoid classes. Isopentenyl- diphosphate delta-isomerase (type 1 IDI) reversibly interconverts isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP), supplying the allylic primer. Farnesyl diphosphate synthase then carries out two sequential head-to-tail (trans, 1'-4) condensations: DMAPP + IPP -> geranyl diphosphate (GPP, C10), and GPP + IPP -> farnesyl diphosphate (FPP, C15). FPP is the central branch point: it feeds sterol synthesis (cholesterol in animals, ergosterol in fungi, via squalene), heme A, ubiquinone side chains, dolichol (cis-prenyltransferases) and protein farnesylation. A geranylgeranyl diphosphate synthase adds one more IPP to FPP giving geranylgeranyl diphosphate (GGPP, C20), the donor for protein geranylgeranylation. The GGPP step has two architectures: a dedicated homomeric GGPP synthase (human GGPS1, budding-yeast BTS1), or, in fission yeast, which lacks a GGPS1/BTS1 homolog, a heteromer of the FPP synthase Fps1 with an inactive FPP-synthase-like subunit Spo9. All enzymes are soluble Mg2+-dependent isomerases/prenyltransferases (animal IDI1/IDI2 also peroxisomal). The pathway is the pharmacological target of nitrogen bisphosphonates (FDPS); human GGPS1 loss-of-function causes a muscular dystrophy / sensorineural hearing loss / ovarian insufficiency syndrome. |
Metabolic Pathway | DRAFT | 0 | isoprenoid biosynthetic process trans, trans-farnesyl diphosphate biosynthetic process geranylgeranyl diphosphate biosynthetic process |
6 | 4 | 3 | 1 | 2 | 2 | 10/10 | 0 | ✗ | modules/isoprenoid_diphosphate_biosynthesis.yaml | ||
JAK-STAT signaling pathway in Drosophila melanogasterMODULE:dmel_jak_stat_signalingCONCRETE The Drosophila JAK-STAT pathway has a minimal set of core components. The secreted Unpaired cytokines (Upd1, Upd2, Upd3) bind the receptor... [more...][less]The Drosophila JAK-STAT pathway has a minimal set of core components. The secreted Unpaired cytokines (Upd1, Upd2, Upd3) bind the receptor Domeless, which is related to vertebrate gp130-type cytokine receptors. Receptor activation stimulates the associated Janus kinase Hopscotch, which phosphorylates Domeless and the single STAT, Stat92E. Phosphorylated Stat92E dimerizes, enters the nucleus and activates target genes. The pathway acts in embryonic segmentation, stem cell maintenance, hematopoiesis, intestinal regeneration, cellular immunity and stress responses. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | cell surface receptor signaling pathway via JAK-STAT |
6 | 7 | 5 | 0 | 0 | 3 | 0/7 | 0 | ✗ | modules/dmel_jak_stat_signaling.yaml | |
JAK-independent STAT signaling in Caenorhabditis elegansMODULE:c_elegans_jak_independent_stat_signalingCONCRETE Caenorhabditis elegans has no Janus kinase, no interferon system and no cytokine receptors that dock JAKs, yet both of its STAT-family... [more...][less]Caenorhabditis elegans has no Janus kinase, no interferon system and no cytokine receptors that dock JAKs, yet both of its STAT-family transcription factors act in immune gene regulation. Each paralog is wired into a different upstream input and controls transcription in the opposite direction. STA-1 binds promoters in intestinal cells and acts mainly as a constitutive repressor of genes induced by Orsay virus. Its repressive function genetically requires the ACK-family non-receptor tyrosine kinase SID-3, and repression is relieved during infection. STA-2 acts in the epidermis. It is held at apical hemidesmosomes by the matrix receptor MUP-4, physically associates with the SLC6 transporter SNF-12, and is the point of convergence for a fungal-infection and wounding p38 MAPK cascade and for hemidesmosome or cuticle-collagen damage. STA-2 is required to induce antimicrobial peptide genes of the nlp-29 cluster. STA-2 lacks the conserved C-terminal phosphotyrosine motif that JAKs target in canonical STATs. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | innate immune response |
8 | 7 | 5 | 1 | 2 | 4 | 7/7 | 0 | ✓ | modules/c_elegans_jak_independent_stat_signaling.yaml | |
JAK-independent STAT signaling in Dictyostelium discoideumMODULE:dicty_jak_independent_stat_signalingCONCRETE The social amoeba Dictyostelium discoideum has four STAT-family transcription factors (STATa to STATd) but no Janus kinase and no kinases of the... [more...][less]The social amoeba Dictyostelium discoideum has four STAT-family transcription factors (STATa to STATd) but no Janus kinase and no kinases of the tyrosine-kinase group. Its STATs are instead tyrosine phosphorylated by tyrosine kinase-like (TKL) kinases, and they dimerize, accumulate in the nucleus and regulate transcription during multicellular development and stress. The two best-studied paralogs are wired to different inputs. STATc is activated by the prestalk morphogen DIF-1 and by hyperosmotic and other stresses. Its activating Tyr922 is phosphorylated by the TKL kinases Pyk2 and Pyk3, which bind the STATc SH2 domain through autophosphorylated tyrosines. The kinase activity is largely constitutive, so the signal is set mainly by the tyrosine phosphatase PTP3: DIF-1 and stress induce serine phosphorylation of PTP3 (in part by the TKL kinase Phg2), which inhibits it and shifts STATc toward the phosphorylated state. Nuclear STATc activates stress-response genes and restricts graded expression of the prestalk gene ecmA. STATa is tyrosine phosphorylated on Tyr702 within seconds of extracellular cAMP binding the serpentine receptor cAR1, apparently without the G-beta subunit. The receptor-like TKL kinase DrkA phosphorylates STATa in vitro and is a candidate STATa kinase. STATa stays nuclear in the prestalk cells of the slug tip, where it represses the stalk gene ecmB and directly activates cudA, a transcription factor needed for culmination. |
Signaling Pathway | DRAFT | Dictyostelium discoideum |
0 | cell surface receptor signaling pathway via STAT |
10 | 10 | 7 | 1 | 2 | 7 | 10/10 | 0 | ✓ | modules/dicty_jak_independent_stat_signaling.yaml | |
JNK (c-Jun N-terminal kinase) stress-activated MAPK cascade moduleMODULE:jnk_cascade A taxon-neutral decomposition of the JNK (c-Jun N-terminal kinase) cascade, the stress- and cytokine-activated concrete realization of the generic... [more...][less]A taxon-neutral decomposition of the JNK (c-Jun N-terminal kinase) cascade, the stress- and cytokine-activated concrete realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Environmental stress and inflammatory cytokines signal through upstream MAP3Ks (MEKK1/MAP3K1, ASK1, MLK family) to the dual-specificity MAP2Ks MKK4 (MAP2K4) and MKK7 (MAP2K7), which dually phosphorylate the JNK MAPKs (JNK1/2/3) on their TPY activation-loop motif. Active JNK phosphorylates the transcription factor c-Jun (and JunD, ATF2), assembling the AP-1 transcriptional program that controls stress responses, apoptosis, and proliferation. The kinase relay - MAP3K -> MKK4/7 -> JNK - is declared as an inner bundle that `conforms_to` mapk_relay, while the stress/cytokine input and the JNK/AP-1 output and DUSP-mediated feedback are this cascade's free extensions around the conforming core. Grounded in GO:0007254 (JNK cascade) / GO:0051403 (stress-activated MAPK cascade). |
Signaling Pathway | DRAFT | 3 | JNK cascade stress-activated MAPK cascade |
8 | 6 | 7 | 0 | 0 | 5 | 4/4 | 3 | ✗ | modules/jnk_cascade.yaml | ||
Jasmonate perception and JAZ derepression (JAR1-COI1-JAZ-NINJA/TPL-MYC module)MODULE:jasmonate_coi1_jaz_signalingABSTRACT Jasmonate signaling in vascular plants works by hormone-triggered derepression. Jasmonic acid is activated by the GH3-family jasmonoyl-amino acid... [more...][less]Jasmonate signaling in vascular plants works by hormone-triggered derepression. Jasmonic acid is activated by the GH3-family jasmonoyl-amino acid conjugate synthetase JAR1, which adenylates JA and conjugates it to L-isoleucine to form jasmonoyl-L-isoleucine (JA-Ile), the bioactive hormone. JA-Ile is perceived by a co-receptor formed by the F-box/LRR protein COI1 and a JAZ (JASMONATE ZIM-domain) repressor: the hormone sits in an open pocket of the COI1 leucine-rich-repeat domain, is trapped by the Jas-motif degron of JAZ, and the complex is potentiated by inositol phosphate. COI1 is the substrate adaptor of an SCF E3 ubiquitin ligase (COI1-ASK1/ASK2-CUL1-RBX1), so hormone-dependent JAZ binding leads to JAZ polyubiquitination and 26S proteasome-dependent degradation. In the resting state, JAZ proteins bind the N-terminal JAZ-interaction domain of the bHLH transcription factors MYC2, MYC3 and MYC4 through their Jas motif, competitively blocking MYC recruitment of the Mediator subunit MED25; through their TIFY/ZIM domain they bind the adaptor NINJA, whose EAR motif recruits the Groucho/Tup1-type corepressor TOPLESS (TPL) and TPL-related proteins. JA-Ile-triggered JAZ degradation therefore removes both the MYC-blocking and the corepressor-recruiting activities, releasing MYC factors to activate jasmonate-responsive genes that control defense against insects and necrotrophic pathogens, wound responses, secondary metabolism and growth inhibition. Many JAZ genes are themselves MYC targets, providing negative feedback. Jasmonate biosynthesis upstream of JA (13-LOX, AOS, AOC, OPR3 and beta-oxidation), JA-Ile catabolism and JAZ-independent COI1 functions are outside this module. |
Signaling Pathway | DRAFT | vascular plants |
0 | jasmonic acid mediated signaling pathway |
6 | 7 | 5 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/jasmonate_coi1_jaz_signaling.yaml | |
KEOPS threonylcarbamoyl transferase complex in Drosophila melanogasterMODULE:dmel_threonylcarbamoyl_transferase_complexCONCRETE The KEOPS (EKC) complex transfers a threonylcarbamoyl group onto adenosine 37 of tRNAs that decode ANN codons, forming t6A, a modification needed... [more...][less]The KEOPS (EKC) complex transfers a threonylcarbamoyl group onto adenosine 37 of tRNAs that decode ANN codons, forming t6A, a modification needed for accurate decoding. Threonylcarbamoyl-AMP is supplied by a separate enzyme (Sua5/YRDC). The catalytic subunit is the Kae1/OSGEP ortholog (Tcs3 in flies); Bud32/TP53RK (Tcs5) is an atypical kinase-like ATPase subunit and Pcc1/LAGE3 (Tcs6) is a small dimerization subunit. In Drosophila, KEOPS subunits are required for growth. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | EKC/KEOPS complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_threonylcarbamoyl_transferase_complex.yaml | |
KMN network of the outer kinetochore in Drosophila melanogasterMODULE:dmel_kmn_networkCONCRETE The KMN network (Knl1, Mis12 complex and Ndc80 complex) is the core microtubule-binding module of the outer kinetochore. The Mis12 complex links... [more...][less]The KMN network (Knl1, Mis12 complex and Ndc80 complex) is the core microtubule-binding module of the outer kinetochore. The Mis12 complex links the network to the centromere-proximal inner kinetochore; in Drosophila it binds the CENP-C homolog Cenp-C, because flies lack the CENP-T pathway. The Ndc80 complex binds spindle microtubules directly and forms load-bearing attachments. Knl1 (Spc105R in Drosophila) provides a scaffold for spindle assembly checkpoint proteins and for protein phosphatase 1. Drosophila has two Nnf1 paralogs, Nnf1a and Nnf1b, which form alternative Mis12 complexes. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | outer kinetochore |
6 | 4 | 3 | 1 | 2 | 2 | 0/8 | 0 | ✗ | modules/dmel_kmn_network.yaml | |
Kallikrein-kinin cascade — contact activation, kinin release from kininogen, B1/B2 receptor signaling, kininase inactivation and serpin controlMODULE:kallikrein_kinin_cascadeCONCRETE The kallikrein-kinin system is an extracellular protease cascade that releases the vasoactive kinin peptides bradykinin and kallidin... [more...][less]The kallikrein-kinin system is an extracellular protease cascade that releases the vasoactive kinin peptides bradykinin and kallidin (Lys-bradykinin) from a single precursor, kininogen, and terminates them by peptidase cleavage. Two routes feed the cascade. In the plasma (contact) route, coagulation factor XII (F12, Hageman factor) binds negatively charged surfaces or misfolded protein aggregates and is autoactivated or activated by traces of protease; surface-bound F12a then activates plasma prekallikrein (KLKB1), which circulates in complex with high-molecular-weight kininogen, and the formed kallikrein activates further F12 in a reciprocal positive-feedback loop. Prolylcarboxypeptidase (PRCP) on the endothelial membrane provides a factor XII-independent prekallikrein activator. Active plasma kallikrein cleaves high-molecular-weight kininogen and liberates the nonapeptide bradykinin. In the tissue route, tissue kallikrein (KLK1), secreted by kidney, pancreas and salivary gland, cleaves low-molecular-weight kininogen at two sites and releases the decapeptide kallidin. The kinins act as short-lived local hormones on two G protein-coupled receptors: the constitutively expressed B2 receptor (BDKRB2), whose agonists are bradykinin and kallidin, and the inducible B1 receptor (BDKRB1), whose agonists are the des-Arg metabolites generated at the kinin C terminus by the carboxypeptidases CPN1 (plasma, kininase I) and CPM (membrane-bound). Receptor occupancy raises intracellular calcium and drives vasodilation, increased vascular permeability, release of inflammatory mediators and stimulation of sensory neurons. Several peptidases act as kininases and destroy kinin activity: angiotensin-converting enzyme (ACE, kininase II), neprilysin (MME) and membrane-bound aminopeptidase P (XPNPEP2). The proteases of the cascade are restrained by serpins and by alpha-2-macroglobulin: C1 inhibitor (SERPING1) and A2M are the principal plasma inhibitors of kallikrein and F12a, and kallistatin (SERPINA4) inhibits tissue kallikrein. |
Biological Process | DRAFT | 0 | kinin cascade |
10 | 17 | 7 | 1 | 2 | 9 | 3/15 | 0 | ✗ | modules/kallikrein_kinin_cascade.yaml | ||
Karyopherin-mediated nuclear protein importMODULE:karyopherin_nuclear_protein_importABSTRACT Signal-dependent import of a protein cargo from the cytosol into the nucleus through the nuclear pore complex, driven by the Ran GTPase gradient. A... [more...][less]Signal-dependent import of a protein cargo from the cytosol into the nucleus through the nuclear pore complex, driven by the Ran GTPase gradient. A karyopherin carrier recognizes the cargo in the cytosol, either through an importin-alpha adaptor that binds a classical nuclear localization signal and bridges it to importin-beta1, or directly through an importin-beta-family carrier (importin-beta1, importin-7, importin-8). The carrier-cargo complex moves through the pore by transient contacts with FG-repeat nucleoporins. In the nucleus, RanGTP (kept high by the chromatin-bound exchange factor RCC1) binds the carrier and releases the cargo into the nucleoplasm. Carriers return to the cytosol, importin-alpha by the RanGTP-dependent exporter CSE1L, and cytosolic RanGAP1 with RanBP1 hydrolyses the exported RanGTP; NTF2 returns RanGDP to the nucleus. The module is cargo-neutral so that signalling modules can include it wherever a transcription factor activated in the cytosol must reach its nuclear targets (STATs, SMADs). |
Biological Process | DRAFT | Eukaryota |
0 | protein import into nucleus |
8 | 10 | 5 | 1 | 2 | 5 | 0/13 | 0 | ✗ | modules/karyopherin_nuclear_protein_import.yaml | |
Kdo2-lipid A biosynthesis (Raetz pathway)MODULE:lipid_a_raetz_biosynthesisCONCRETE The constitutive nine-enzyme Raetz pathway that builds Kdo2-lipid A, the minimal essential lipopolysaccharide anchor, at the cytoplasmic face of... [more...][less]The constitutive nine-enzyme Raetz pathway that builds Kdo2-lipid A, the minimal essential lipopolysaccharide anchor, at the cytoplasmic face of the Gram-negative inner membrane. LpxA reversibly transfers an (R)-3-hydroxyacyl chain from acyl carrier protein (ACP) to UDP-GlcNAc; the zinc deacetylase LpxC then irreversibly removes the N-acetyl group, the committed step that sets pathway flux. LpxD adds the second (R)-3-hydroxyacyl chain, LpxH cleaves part of the UDP-diacylglucosamine pool to lipid X, LpxB condenses lipid X with UDP-diacylglucosamine to the beta-1',6-linked disaccharide, and LpxK phosphorylates the 4' position to give lipid IVA. The bifunctional Kdo transferase WaaA adds two Kdo residues from CMP-Kdo, and the late acyltransferases LpxL and LpxM add laurate and myristate to the Kdo2-lipid IVA acceptor to give hexa-acylated Kdo2-lipid A. Flux is set at LpxC by FtsH-mediated proteolysis tuned by the adaptor LapB and the anti-adaptor YejM (PbgA), represented here as an optional regulatory part rather than as pathway chemistry. |
Metabolic Pathway | DRAFT | Escherichia coli K-12 |
0 | lipid A biosynthetic process Kdo2-lipid A biosynthetic process |
11 | 12 | 10 | 0 | 0 | 12 | 0/12 | 0 | ✗ | modules/lipid_a_raetz_biosynthesis.yaml | |
Kennedy pathway (CDP-choline / CDP-ethanolamine synthesis of PC and PE)MODULE:kennedy_pathway_phospholipid_synthesisCONCRETE The Kennedy pathway is the principal de-novo route to the two most abundant membrane glycerophospholipids, phosphatidylcholine (PC) and... [more...][less]The Kennedy pathway is the principal de-novo route to the two most abundant membrane glycerophospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE). It runs as two parallel three-step branches that converge on a common diacylglycerol (DAG) acceptor. In the CDP-choline branch, choline kinase (CHKA/CHKB) phosphorylates choline to phosphocholine; the rate-limiting, membrane-regulated CTP:phosphocholine cytidylyltransferase (PCYT1A/PCYT1B) converts phosphocholine + CTP to CDP-choline; and a CDP-alcohol phosphotransferase (CHPT1, or the dual-specificity CEPT1) transfers phosphocholine from CDP-choline onto DAG to make PC + CMP. In the parallel CDP-ethanolamine branch, ethanolamine kinase (ETNK1/ETNK2) makes phosphoethanolamine, the rate-controlling CTP:phosphoethanolamine cytidylyltransferase (PCYT2) makes CDP-ethanolamine, and the ethanolaminephosphotransferases (the selenoprotein SELENOI/EPT1, or CEPT1) transfer phosphoethanolamine onto DAG to make PE + CMP. The two branches are linked by phosphatidylethanolamine N-methyltransferase (PEMT), an ER enzyme (liver-enriched) that performs three sequential SAM-dependent methylations of PE to PC — the only way to make PC without preformed choline, and a major consumer of methyl groups. The amphitropic cytidylyltransferase PCYT1A senses membrane PC content, making it the key regulatory node. Inherited defects span a striking phenotypic range: PCYT1A congenital lipodystrophy / spondylometaphyseal dysplasia with cone-rod dystrophy, CHKB megaconial congenital muscular dystrophy, and PCYT2 and SELENOI hereditary spastic paraplegia. The same three-step branches operate in fungi, where the kinases are cytosolic, the cytidylyltransferases associate with the nuclear/ER membrane, and the two CDP-alcohol phosphotransferases overlap in specificity (the yeast ethanolaminephosphotransferase also uses CDP-choline, and fission yeast has a single dual-specificity enzyme). In fungi the Kennedy pathway runs in parallel with the CDP-diacylglycerol pathway, which makes PE by phosphatidylserine decarboxylation and PC by PE methylation when ethanolamine and choline are not supplied. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | phosphatidylcholine biosynthetic process phosphatidylethanolamine biosynthetic process |
8 | 7 | 7 | 0 | 0 | 5 | 21/21 | 0 | ✗ | modules/kennedy_pathway_phospholipid_synthesis.yaml | |
Keratan and chondroitin sulfate lysosomal degradation (Morquio / GM2); GALNS/GLB1/HEXA/HEXBMODULE:keratan_chondroitin_sulfate_lysosomal_degradation Keratan sulfate and the galactose/N-acetylhexosamine termini of chondroitin, dermatan and keratan sulfate are degraded in the lysosome by an... [more...][less]Keratan sulfate and the galactose/N-acetylhexosamine termini of chondroitin, dermatan and keratan sulfate are degraded in the lysosome by an ordered exolytic cascade that complements the heparan-sulfate pathway. Keratan sulfate is a repeating -Gal-GlcNAc- polymer with 6-O- sulfates on both sugars: N-acetylgalactosamine-6-sulfatase / galactose-6-sulfatase (GALNS) removes the 6-O-sulfate from a terminal galactose-6-sulfate (and, in chondroitin-6-sulfate, from GalNAc-6-sulfate), and GlcNAc-6-sulfatase (GNS, in the heparan-sulfate module) removes it from GlcNAc-6-sulfate; lysosomal acid beta-galactosidase (GLB1) then hydrolyses the exposed terminal beta-galactose; and lysosomal beta-hexosaminidase — the alpha-beta heterodimer hexosaminidase A (HEXA+HEXB) and the beta-beta homodimer hexosaminidase B (HEXB) — removes the terminal beta-N-acetylhexosamine, regenerating a substrate for the next round. These enzymes are broadly specific: GLB1 also degrades the GM1 ganglioside, and hexosaminidase A (with the GM2-activator) degrades the GM2 ganglioside, so the same genes underlie both mucopolysaccharide and glycosphingolipid storage diseases. Disorders: MPS IVA (GALNS, Morquio A), GM1 gangliosidosis / MPS IVB (GLB1, Morquio B), Tay-Sachs (HEXA) and Sandhoff (HEXB) GM2 gangliosidoses. |
Metabolic Pathway | DRAFT | 0 | keratan sulfate proteoglycan catabolic process glycosaminoglycan metabolic process |
4 | 4 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/keratan_chondroitin_sulfate_lysosomal_degradation.yaml | ||
Ketogenesis (hepatic ketone body synthesis)MODULE:ketogenesis Ketogenesis is the mitochondrial pathway, operating chiefly in liver during fasting, starvation, prolonged exercise and low-carbohydrate states,... [more...][less]Ketogenesis is the mitochondrial pathway, operating chiefly in liver during fasting, starvation, prolonged exercise and low-carbohydrate states, that converts acetyl-CoA (mostly from fatty-acid beta-oxidation) into the circulating ketone bodies acetoacetate and (R)-3-hydroxybutyrate, which supply oxidizable fuel to brain, heart and muscle when glucose is scarce. Four mitochondrial-matrix steps: mitochondrial acetyl-CoA acetyltransferase (thiolase, ACAT1) condenses two acetyl-CoA to acetoacetyl-CoA; the rate-limiting, fasting-induced mitochondrial HMG-CoA synthase (HMGCS2) adds a third acetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA lyase (HMGCL) cleaves HMG-CoA to acetoacetate + acetyl-CoA; and the inner-membrane NAD+-dependent D-3-hydroxybutyrate dehydrogenase (BDH1) reversibly reduces acetoacetate to (R)-3-hydroxybutyrate, the predominant blood ketone. The pathway shares the HMGCL step with leucine catabolism and shares BDH1 (run in reverse) with ketolysis; liver exports the ketone bodies because it lacks the ketolytic enzyme OXCT1/SCOT. Inherited defects: HMGCS2 deficiency and HMGCL deficiency cause fasting hypoketotic hypoglycemia; ACAT1 (beta-ketothiolase) deficiency affects both ketone-body and isoleucine metabolism. (Ketone-body UTILIZATION/ketolysis in peripheral tissues — BDH1 -> OXCT1 -> ACAT1 -> 2 acetyl-CoA — is modelled separately in MODULE:ketone_body_oxidation.) |
Metabolic Pathway | DRAFT | 0 | ketone body biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/ketogenesis.yaml | ||
Ketone-body uptake and oxidationMODULE:ketone_body_oxidationCONCRETE A reusable pathway for use of D-3-hydroxybutyrate as a carbon and energy source. D-3-hydroxybutyrate is oxidized to acetoacetate, acetoacetate is... [more...][less]A reusable pathway for use of D-3-hydroxybutyrate as a carbon and energy source. D-3-hydroxybutyrate is oxidized to acetoacetate, acetoacetate is activated to acetoacetyl-CoA, and a thiolase can cleave acetoacetyl-CoA to acetyl-CoA. Organisms differ in the activation reaction: animal ketolysis generally uses a succinyl-CoA-dependent CoA transferase, whereas some bacteria use an ATP-dependent acetoacetate-CoA ligase. Substrate import is an optional upstream role for organisms that consume extracellular ketone bodies. Intracellular D-3-hydroxybutyrate released from storage-polymer metabolism can enter at the oxidation step. Pseudomonas putida KT2440 provides candidate exemplars for import, oxidation, and ATP-dependent activation; their pathway dominance and the terminal thiolase remain to be resolved experimentally. |
Metabolic Pathway | DRAFT | 0 | ketone body catabolic process |
7 | 5 | 4 | 1 | 2 | 3 | 6/7 | 0 | ✗ | modules/ketone_body_oxidation.yaml | ||
Kip1 ubiquitination-promoting complex in Drosophila melanogasterMODULE:dmel_kpc_ubiquitin_ligaseCONCRETE The Kip1 ubiquitination-promoting complex (KPC) is a heterodimeric E3 ubiquitin ligase first described in mammals, where the RING-finger protein... [more...][less]The Kip1 ubiquitination-promoting complex (KPC) is a heterodimeric E3 ubiquitin ligase first described in mammals, where the RING-finger protein KPC1 (RNF123) ubiquitylates substrates and KPC2 (UBAC1), a ubiquitin-like and UBA domain protein, links ubiquitylated substrates to the proteasome. Mammalian KPC promotes cytoplasmic degradation of the CDK inhibitor p27Kip1 in G1. Drosophila Kpc1 and Kpc2 are the orthologs of these two subunits. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ubiquitin ligase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_kpc_ubiquitin_ligase.yaml | |
Kit signaling pathway moduleMODULE:kit_signaling Stem cell factor (KIT ligand) binds and dimerizes the class III receptor tyrosine kinase KIT, whose autophosphorylated intracellular tyrosines... [more...][less]Stem cell factor (KIT ligand) binds and dimerizes the class III receptor tyrosine kinase KIT, whose autophosphorylated intracellular tyrosines recruit SH2-domain effectors (GRB2, PI3K p85, SHP2, Src-family kinases) that drive Ras-MAPK, PI3K-AKT, and STAT5 outputs controlling survival, proliferation, and migration of hematopoietic progenitors, mast cells, melanocytes, germ cells, and interstitial cells of Cajal. |
Signaling Pathway | DRAFT | bony vertebrates |
15 | Kit signaling pathway |
4 | 9 | 3 | 0 | 0 | 2 | 10/10 | 0 | ✓ | modules/kit_signaling.yaml | |
Kynurenine pathway / de novo NAD+ biosynthesis from tryptophan (TDO2/IDO1/AFMID/KMO/KYNU/HAAO/ACMSD/QPRT)MODULE:kynurenine_nad_de_novo The kynurenine pathway is the major route of L-tryptophan catabolism and the sole de novo source of NAD+ in humans, converting tryptophan through a... [more...][less]The kynurenine pathway is the major route of L-tryptophan catabolism and the sole de novo source of NAD+ in humans, converting tryptophan through a series of ring-opening and modification steps to quinolinate and then to nicotinate mononucleotide (NaMN), which enters the common NAD+ pathway. It also generates neuroactive branch metabolites (kynurenic acid, quinolinic acid) and is central to immune regulation. The committed first step — oxidative ring cleavage of L-tryptophan to N-formyl-L-kynurenine — is catalysed by two heme dioxygenases with distinct physiology: the hepatic, rate-limiting TDO2 (tryptophan 2,3-dioxygenase) and the broadly IFN-gamma-inducible, immunoregulatory IDO1 (indoleamine 2,3-dioxygenase). The formamidase AFMID then hydrolyses N-formyl-kynurenine to L-kynurenine. Flux toward NAD+ requires the FAD-dependent, outer-mitochondrial-membrane kynurenine 3-monooxygenase KMO to hydroxylate kynurenine to 3-hydroxykynurenine (diverting away from the kynurenic-acid branch made by the aminotransferases AADAT/GOT2), followed by the PLP-dependent kynureninase KYNU, which cleaves 3-hydroxykynurenine to 3-hydroxyanthranilate. The Fe(II)-dependent dioxygenase HAAO opens the aromatic ring of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate semialdehyde (ACMS), which spontaneously cyclises to quinolinate — unless the zinc enzyme ACMSD decarboxylates ACMS instead, diverting flux away from NAD+ toward full oxidation (picolinate/ acetyl-CoA). Finally quinolinate phosphoribosyltransferase QPRT condenses quinolinate with PRPP to NaMN, completing de novo NAD+ synthesis and detoxifying excitotoxic quinolinate. Inherited HAAO and KYNU deficiencies cause a congenital NAD-deficiency malformation syndrome (niacin-preventable in models); the pathway's enzymes (IDO1, TDO2, KMO, ACMSD) are drug targets in cancer immunotherapy, neurodegeneration and metabolic disease. |
Metabolic Pathway | DRAFT | 0 | 'de novo' NAD+ biosynthetic process from L-tryptophan L-tryptophan catabolic process |
4 | 8 | 3 | 0 | 0 | 2 | 8/8 | 0 | ✗ | modules/kynurenine_nad_de_novo.yaml | ||
L-arginine biosynthesis via acetylated ornithineMODULE:arginine_biosynthesisABSTRACT De novo L-arginine synthesis through acetylated glutamate and ornithine intermediates in characterized bacterial, archaeal, fungal and plant... [more...][less]De novo L-arginine synthesis through acetylated glutamate and ornithine intermediates in characterized bacterial, archaeal, fungal and plant systems. The reaction template distinguishes acetyl-CoA-dependent initiation from acetylornithine-dependent recycling: ArgJ family membership does not establish both activities. Linear ArgA/ArgE and cyclic acetyl-transfer implementations converge on ornithine, followed by carbamoylation, argininosuccinate synthesis and cleavage. Selected fungal implementations separate mitochondrial ornithine formation from downstream reactions; budding and fission yeast differ in ornithine carbamoyltransferase location. Plant plastid enzymes and an experimentally monofunctional archaeal ArgJ provide comparative anchors without implying that every lineage implements every step or shares one compartment. Dedicated fungal carbamoyl-phosphate supply is an optional side branch; shared substrate supply, transport, catabolism, and LysW-, succinylated-intermediate or acetylcitrulline routes lie outside this reaction-chain boundary. |
Metabolic Pathway | COMPLETE | Archaea Bacteria Fungi Viridiplantae |
1 | L-arginine biosynthetic process |
20 | 16 | 9 | 4 | 10 | 9 | 44/44 | 0 | ✓ | modules/arginine_biosynthesis.yaml | |
L-arginine metabolism in Drosophila melanogasterMODULE:dmel_arginine_metabolismCONCRETE Three conserved urea-cycle enzymes interconvert citrulline, arginine and ornithine in Drosophila. Argininosuccinate synthase (Ass) condenses... [more...][less]Three conserved urea-cycle enzymes interconvert citrulline, arginine and ornithine in Drosophila. Argininosuccinate synthase (Ass) condenses citrulline with aspartate to form argininosuccinate, argininosuccinate lyase (Argl) cleaves it to arginine and fumarate, and arginase (Arg) hydrolyses arginine to ornithine and urea. Together the first two steps regenerate arginine from citrulline, and arginase links arginine to ornithine, the precursor of proline and polyamines. Insects are not known to run a complete urea cycle, so the three enzymes act as a branch of amino acid metabolism rather than as the main route of nitrogen excretion. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | arginine metabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/dmel_arginine_metabolism.yaml | |
L-aspartate and L-asparagine metabolism in Drosophila melanogasterMODULE:dmel_aspartate_asparagine_metabolismCONCRETE Aspartate aminotransferases interconvert oxaloacetate and L-aspartate by transferring an amino group from L-glutamate, producing 2-oxoglutarate.... [more...][less]Aspartate aminotransferases interconvert oxaloacetate and L-aspartate by transferring an amino group from L-glutamate, producing 2-oxoglutarate. Drosophila has a cytosolic isozyme (Got1) and a mitochondrial isozyme (Got2), which also act in the malate-aspartate shuttle. Asparagine synthetase (Asns) then converts aspartate to L-asparagine in an ATP-dependent reaction that uses glutamine as the nitrogen donor. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | aspartate metabolic process L-asparagine biosynthetic process |
3 | 3 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/dmel_aspartate_asparagine_metabolism.yaml | |
L-aspartate de novo and selected salvage routes to NAD+MODULE:nad_biosynthesis_salvage A reusable, scope-limited route set for organisms that use the L-aspartate de novo pathway and/or selected nicotinate, nicotinamide, and NMN... [more...][less]A reusable, scope-limited route set for organisms that use the L-aspartate de novo pathway and/or selected nicotinate, nicotinamide, and NMN salvage alternatives. Every realization is end-to-end: NaMN made by L-aspartate de novo synthesis, PncB, or PncC must pass through deamido-NAD to NAD+, whereas NMN made by NAMPT must be adenylylated directly to NAD+. Alternative adenylyltransferase families and NAD synthetase nitrogen donors are modeled as variants. This is not a universal NAD+ biosynthesis hub: de novo synthesis through L-tryptophan and the kynurenine pathway is owned by the existing MODULE:kynurenine_nad_de_novo module and is not duplicated here. Nicotinate degradation, pyridine-nucleotide transhydrogenases, NAD kinase and NADP formation, NAD-consuming reactions, and unrelated aldehyde metabolism are outside the boundary. |
Metabolic Pathway | DRAFT | 3 | NAD+ biosynthetic process |
22 | 13 | 11 | 4 | 10 | 9 | 10/19 | 0 | ✓ | modules/nad_biosynthesis_salvage.yaml | ||
L-aspartate, L-asparagine and L-alanine formation and turnoverMODULE:aspartate_asparagine_metabolismCONCRETE Reversible aspartate and alanine transamination connects oxaloacetate and pyruvate to amino-acid metabolism in the sampled fungi, animals and... [more...][less]Reversible aspartate and alanine transamination connects oxaloacetate and pyruvate to amino-acid metabolism in the sampled fungi, animals and plants. Glutamine-dependent asparagine synthetase amidates aspartate using ATP and glutamine amide nitrogen, releasing glutamate, AMP and diphosphate. Asparaginases instead hydrolyse asparagine to aspartate and ammonium without a glutamate cosubstrate. Cytosolic, mitochondrial and plant plastid aminotransferases provide different implementations; their net flux depends on substrates, compartment and physiological conditions. Plant plastids include both conventional AspAT and a distinct bifunctional aspartate/prephenate aminotransferase. Asparagine hydrolysis is optional at this formation/turnover boundary and uses structurally distinct asparaginase families in the demonstrated yeast and plant examples. Secreted yeast Asp3 is strain dependent. Alanine transamination is a parallel reaction, not an asserted chemical link in the aspartate/asparagine chain. The taxonomic envelope does not imply universal retention, identical compartments or simultaneous flux through every branch. |
Metabolic Pathway | DRAFT | Eukaryota Viridiplantae |
0 | L-aspartate biosynthetic process L-asparagine biosynthetic process L-asparagine catabolic process |
12 | 9 | 4 | 2 | 7 | 2 | 25/25 | 0 | ✗ | modules/aspartate_asparagine_metabolism.yaml | |
L-carnitine biosynthesis in Drosophila melanogasterMODULE:dmel_carnitine_biosynthesisCONCRETE L-carnitine carries long-chain fatty acids into mitochondria for beta-oxidation. In animals it is made from N6,N6,N6-trimethyllysine, released by... [more...][less]L-carnitine carries long-chain fatty acids into mitochondria for beta-oxidation. In animals it is made from N6,N6,N6-trimethyllysine, released by degradation of proteins carrying methylated lysines, in four steps. Trimethyllysine dioxygenase (Tmlh) hydroxylates trimethyllysine to 3-hydroxy-trimethyllysine; an aldolase cleaves this to 4-trimethylaminobutyraldehyde and glycine; an aldehyde dehydrogenase oxidizes the aldehyde to gamma-butyrobetaine; and gamma-butyrobetaine dioxygenase hydroxylates gamma-butyrobetaine to carnitine. In Drosophila, CG10814 is the homolog of gamma-butyrobetaine dioxygenase, and the aldolase step is attributed to the threonine-aldolase-like protein CG10184 and to serine hydroxymethyltransferase (Shmt), which in mammals has hydroxytrimethyllysine aldolase activity. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | carnitine biosynthetic process |
4 | 4 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/dmel_carnitine_biosynthesis.yaml | |
L-fucose degradation (mammalian non-phosphorylative pathway)MODULE:mammalian_l_fucose_degradationCONCRETE Catabolism of free cytosolic L-fucose to pyruvate and L-lactate by a five-reaction, non-phosphorylative (oxidative) route described biochemically... [more...][less]Catabolism of free cytosolic L-fucose to pyruvate and L-lactate by a five-reaction, non-phosphorylative (oxidative) route described biochemically in pig and rabbit liver and kidney and in human. beta-L-Fucose is oxidized by NAD+-dependent L-fucose dehydrogenase (HSD17B14) to L-fucono-1,5-lactone, which rearranges non-enzymatically to L-fucono-1,4-lactone; a lactonase that has not been molecularly identified in mammals hydrolyses the lactone to L-fuconate; L-fuconate dehydratase (ENOSF1, the rTS-gamma isoform) forms 2-keto-3-deoxy-L-fuconate; an NAD+-dependent 2-keto-3-deoxy-L-fuconate 4-dehydrogenase (BDH2 is the leading candidate) forms 2,4-diketo-3-deoxy-L-fuconate; and an unidentified hydrolase cleaves this to pyruvate and L-lactate. Two of the five steps therefore have no assigned gene and a third has a candidate whose physiological role is unsettled. The route is chemically analogous to the bacterial non-phosphorylative pathway (Xanthomonas, Burkholderia, Herbaspirillum) and is distinct from the phosphorylative FucI/FucK/FucA route of Escherichia coli, from the salvage of L-fucose to GDP-L-fucose, and from lysosomal release of L-fucose from glycoconjugates. The pathway is not universal in mammals: rats oxidize little L-fucose and rat HSD17B14 has negligible L-fucose dehydrogenase activity. |
Metabolic Pathway | DRAFT | human |
0 | L-fucose catabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 0/2 | 3 | ✗ | modules/mammalian_l_fucose_degradation.yaml | |
L-histidine biosynthesisMODULE:gapmind_his_biosynthesis Imported module for L-histidine biosynthesis, mined from the GapMind amino-acid pathway definition 'his.steps' and grounded against ModelSEED.... [more...][less]Imported module for L-histidine biosynthesis, mined from the GapMind amino-acid pathway definition 'his.steps' and grounded against ModelSEED. Generated by a feasibility-spike importer; GO molecular-function term assignments and biological prose are intentionally left for human/deep-research review and must not be treated as curated. |
Metabolic Pathway | DRAFT | 0 | 12 | 11 | 11 | 0 | 0 | 0 | 0/0 | 9 | ✗ | modules/experimental/gapmind-mining/his-from-gapmind.yaml | |||
L-histidine biosynthesisMODULE:histidine_biosynthesis De novo biosynthesis of L-histidine from PRPP and ATP through the conserved ten-reaction His pathway found in bacteria, archaea, fungi and plants.... [more...][less]De novo biosynthesis of L-histidine from PRPP and ATP through the conserved ten-reaction His pathway found in bacteria, archaea, fungi and plants. The module begins at the first committed ATP phosphoribosyltransferase reaction; PRPP production is shared upstream metabolism and is intentionally outside the module boundary. The pathway returns the ATP-derived purine ring to nucleotide metabolism as AICAR during the imidazole-glycerol-phosphate synthase reaction, which couples histidine and purine biosynthesis. The reaction chain is invariant, but its enzyme architecture varies widely across lineages: ATP phosphoribosyltransferase exists as a short-form catalytic subunit with a separate HisZ regulatory subunit or as a long-form single chain; the phosphoribosyl-ATP diphosphatase and phosphoribosyl-AMP cyclohydrolase can be separate proteins, a bifunctional HisIE protein, or domains of a trifunctional protein that also carries histidinol dehydrogenase (as in budding yeast); the glutaminase and cyclase halves of imidazole-glycerol-phosphate synthase can be separate HisH and HisF subunits or a single fused HisHF chain (as in fungi); and histidinol-phosphate phosphatase activity has arisen in several unrelated families (IMPase-like, HAD and PHP). The terminal histidinol dehydrogenase performs two successive NAD+-dependent oxidations through histidinal to produce L-histidine. |
Metabolic Pathway | DRAFT | 0 | L-histidine biosynthetic process |
21 | 20 | 8 | 5 | 12 | 7 | 27/30 | 0 | ✗ | modules/histidine_biosynthesis.yaml | ||
L-isoleucine biosynthesisMODULE:gapmind_ile_biosynthesis Imported module for L-isoleucine biosynthesis, mined from the GapMind amino-acid pathway definition 'ile.steps' and grounded against ModelSEED.... [more...][less]Imported module for L-isoleucine biosynthesis, mined from the GapMind amino-acid pathway definition 'ile.steps' and grounded against ModelSEED. Generated by a feasibility-spike importer; GO molecular-function term assignments and biological prose are intentionally left for human/deep-research review and must not be treated as curated. |
Metabolic Pathway | DRAFT | 0 | 18 | 13 | 14 | 1 | 3 | 0 | 0/0 | 10 | ✗ | modules/experimental/gapmind-mining/ile-from-gapmind.yaml | |||
L-lysine biosynthesis by the succinylated diaminopimelate pathwayMODULE:lysine_biosynthesis Bacterial L-lysine biosynthesis from L-aspartate 4-semialdehyde and pyruvate through the succinylated diaminopimelate route. DapA and DapB form and... [more...][less]Bacterial L-lysine biosynthesis from L-aspartate 4-semialdehyde and pyruvate through the succinylated diaminopimelate route. DapA and DapB form and reduce the tetrahydrodipicolinate intermediate. DapD masks it by succinylation, DapC introduces the second amino group, and DapE removes the succinyl group. DapF converts LL-diaminopimelate to meso-diaminopimelate, and LysA performs the terminal decarboxylation to L-lysine. Aspartate kinase and aspartate-semialdehyde dehydrogenase provide a shared precursor used by lysine, threonine, and methionine synthesis and are outside the dedicated module boundary. The meso-diaminopimelate product also feeds peptidoglycan assembly before its conversion to lysine. |
Metabolic Pathway | DRAFT | 5 | L-lysine biosynthetic process |
8 | 7 | 7 | 0 | 0 | 6 | 1/7 | 0 | ✗ | modules/lysine_biosynthesis.yaml | ||
L-lysine biosynthesis via alpha-aminoadipateMODULE:lysine_biosynthesis_aminoadipateCONCRETE De novo biosynthesis of L-lysine from 2-oxoglutarate and acetyl-CoA through the C6 intermediate L-2-aminoadipate (alpha-aminoadipate, AAA). This... [more...][less]De novo biosynthesis of L-lysine from 2-oxoglutarate and acetyl-CoA through the C6 intermediate L-2-aminoadipate (alpha-aminoadipate, AAA). This route is chemically unrelated to the diaminopimelate pathway of most bacteria and plants. Its first half extends the carbon chain by one methylene unit through reactions homologous to the citrate-to-2-oxoglutarate segment of the tricarboxylic acid cycle and to leucine biosynthesis: homocitrate synthase condenses acetyl-CoA with 2-oxoglutarate, homocitrate is isomerised to homoisocitrate in two aconitase-family steps (homocitrate dehydration to cis-homoaconitate, then hydration to homoisocitrate), homoisocitrate dehydrogenase oxidatively decarboxylates homoisocitrate to 2-oxoadipate, and a transaminase produces L-2-aminoadipate. The second half diverges by lineage. In fungi, a large phosphopantetheinylated alpha-aminoadipate reductase reduces AAA to its 6-semialdehyde, which is reductively condensed with L-glutamate to saccharopine and then cleaved to L-lysine and 2-oxoglutarate. In Thermus and in Sulfolobus and other archaea, AAA is instead ligated to the C-terminal glutamate of the small carrier protein LysW and converted to lysine by ArgB/C/D-like enzymes before a hydrolase releases free lysine. In fungi the early steps are split between compartments, with homocitrate isomerisation and homoisocitrate oxidation in the mitochondrial matrix and the final steps in the cytosol and peroxisome. |
Metabolic Pathway | DRAFT | Fungi Sulfolobus acidocaldarius Thermus thermophilus |
0 | L-lysine biosynthetic process |
20 | 18 | 15 | 2 | 4 | 12 | 20/38 | 0 | ✗ | modules/lysine_biosynthesis_aminoadipate.yaml | |
L-lysine catabolism (saccharopine pathway to glutaryl-CoA; glutaric aciduria type 1)MODULE:lysine_catabolism The main (saccharopine) pathway of L-lysine degradation in humans, a mitochondrial route that also handles L-hydroxylysine and the final steps of... [more...][less]The main (saccharopine) pathway of L-lysine degradation in humans, a mitochondrial route that also handles L-hydroxylysine and the final steps of L-tryptophan catabolism, converging on glutaryl-CoA and ultimately acetyl-CoA. The bifunctional alpha-aminoadipic semialdehyde synthase (AASS) catalyses the first two committed steps: its lysine-2-oxoglutarate reductase (saccharopine dehydrogenase, NADP+) activity condenses L-lysine with 2-oxoglutarate to saccharopine, and its saccharopine dehydrogenase (NAD+) activity then oxidises saccharopine to L-2-aminoadipate-6-semialdehyde + L-glutamate. Downstream (semialdehyde -> L-2-aminoadipate by ALDH7A1; L-2-aminoadipate -> 2-oxoadipate by the aminotransferase AADAT — not modelled here) yields 2-oxoadipate, which the 2-oxoadipate dehydrogenase complex (OADHC) oxidatively decarboxylates to glutaryl-CoA. The OADHC is a paralogous sibling of the 2-oxoglutarate dehydrogenase complex: a dedicated E1 (DHTKD1, TPP-dependent) plus the shared E2 succinyltransferase core (DLST, acting as a glutaryltransferase here) and the shared E3 (DLD). Finally the FAD-dependent glutaryl-CoA dehydrogenase (GCDH) oxidatively decarboxylates glutaryl-CoA to crotonyl-CoA + CO2, passing electrons to the electron-transfer flavoprotein system (ETF -> ETFDH -> respiratory chain). Inherited defects: AASS deficiency causes (largely benign) hyperlysinemia / saccharopinuria; DHTKD1 deficiency causes 2-aminoadipic/2-oxoadipic aciduria (and is linked to Charcot-Marie-Tooth 2Q); and GCDH deficiency causes glutaric aciduria type 1 (GA1), a serious encephalopathy with striatal injury. |
Metabolic Pathway | DRAFT | 0 | L-lysine catabolic process |
4 | 6 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/lysine_catabolism.yaml | ||
L-lysine catabolism through 5-aminovalerateMODULE:lysine_dav_catabolism A reusable four-reaction Dav pathway that converts L-lysine to glutarate through 5-aminopentanamide, 5-aminopentanoate (5-aminovalerate), and... [more...][less]A reusable four-reaction Dav pathway that converts L-lysine to glutarate through 5-aminopentanamide, 5-aminopentanoate (5-aminovalerate), and 5-oxopentanoate (glutarate semialdehyde). The module represents the DavB, DavA, DavT, and DavD reaction roles independently of genomic organization. Downstream CoA-dependent and CoA-independent routes from glutarate to central metabolism are outside the boundary. |
Metabolic Pathway | DRAFT | 0 | L-lysine catabolic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/6 | 0 | ✗ | modules/lysine_dav_catabolism.yaml | ||
L-methionine biosynthesis (from homoserine)MODULE:methionine_biosynthesis De novo biosynthesis of L-methionine from L-homoserine through three ordered stages: homoserine activation, sulfur incorporation to form... [more...][less]De novo biosynthesis of L-methionine from L-homoserine through three ordered stages: homoserine activation, sulfur incorporation to form L-homocysteine, and methylation of L-homocysteine. Bacteria can activate homoserine with an acetyl or succinyl group, incorporate sulfur through two-step trans-sulfuration or one-step direct sulfhydrylation, and complete the pathway with a cobalamin-independent or cobalamin-dependent methionine synthase. Substrate-matched alternatives are retained explicitly because enzyme-family membership alone does not reliably distinguish acetyl from succinyl chemistry or forward biosynthetic from related PLP-dependent lyase reactions. Fungi such as Saccharomyces cerevisiae and Schizosaccharomyces pombe activate homoserine with an acetyl group, rely mainly on direct sulfhydrylation of O-acetylhomoserine with sulfide from sulfate assimilation, can also make homocysteine from cysteine by trans-sulfuration, and finish with a cobalamin-independent methionine synthase that requires a polyglutamylated 5-methyltetrahydrofolate. Plants use a cobalamin-independent synthase and a trans-sulfuration route whose cystathionine gamma-synthase takes O-phospho-L-homoserine rather than an acylated homoserine. |
Metabolic Pathway | DRAFT | 0 | de novo L-methionine biosynthesis |
13 | 8 | 5 | 3 | 7 | 6 | 13/21 | 0 | ✓ | modules/methionine_biosynthesis.yaml | ||
L-methionine salvage from 5'-methylthioadenosine (MTA cycle)MODULE:methionine_salvage_mta_cycle The methionine salvage pathway, or 5'-methylthioadenosine (MTA) cycle, regenerates L-methionine from MTA, the by-product of S-adenosylmethionine... [more...][less]The methionine salvage pathway, or 5'-methylthioadenosine (MTA) cycle, regenerates L-methionine from MTA, the by-product of S-adenosylmethionine (SAM) use in polyamine synthesis (and, in plants, ethylene synthesis). The methylthio group of MTA and carbons 2-5 of its ribose become the methionine skeleton, so the cycle recovers reduced sulfur that is costly to assimilate, and it also clears MTA, which inhibits spermidine synthase. MTA is first converted to S-methyl-5-thio-alpha-D-ribose 1-phosphate (MTR-1-P), either directly by MTA phosphorylase (eukaryotes and many bacteria) or by MTA nucleosidase followed by ATP-dependent MTR kinase (many bacteria, plants). MTR-1-P isomerase converts MTR-1-P to the ribulose phosphate, which MTRu-1-P dehydratase converts to the 2,3-diketo phosphate. An enolase and a phosphatase then form the acireductone 1,2-dihydroxy-5-(methylthio)pent-1-en-3-one. Fungi and animals do this with one bifunctional enolase-phosphatase (E1); Bacillus uses a RuBisCO-like enolase (MtnW) and a separate phosphatase (MtnX). An Fe(II)-dependent acireductone dioxygenase then oxidises the acireductone to 4-methylthio-2-oxobutanoate (KMTB) and formate. A final transamination converts KMTB to methionine. This step is redundant and is carried out by broad-specificity aromatic and branched-chain amino acid transaminases, not a dedicated enzyme. The cycle needs dioxygen and is largely cytosolic. |
Metabolic Pathway | DRAFT | 0 | L-methionine salvage |
15 | 10 | 10 | 2 | 4 | 7 | 15/27 | 0 | ✗ | modules/methionine_salvage_mta_cycle.yaml | ||
L-methionine salvage pathway in Drosophila melanogasterMODULE:dmel_methionine_salvageCONCRETE The methionine salvage pathway recycles the methylthio group of 5'-methylthioadenosine (MTA), a by-product of polyamine synthesis, back into... [more...][less]The methionine salvage pathway recycles the methylthio group of 5'-methylthioadenosine (MTA), a by-product of polyamine synthesis, back into methionine. MTA phosphorylase (Mtap) cleaves MTA to adenine and 5-methylthioribose-1-phosphate, which is isomerised to methylthioribulose-1-phosphate (Mri1) and dehydrated to a diketo phosphate (CG11134). The bifunctional enolase-phosphatase Enoph converts this to acireductone, which acireductone dioxygenase (Adi1) oxidises to 4-methylthio-2-oxobutanoate. A final transamination regenerates methionine. As in other animals, the pathway in flies lacks the methylthioribose kinase step used by bacteria and plants, because MTA is cleaved phosphorolytically. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | L-methionine salvage |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/dmel_methionine_salvage.yaml | |
L-phenylalanine and L-tyrosine biosynthesis from chorismateMODULE:phenylalanine_tyrosine_biosynthesis Branch of aromatic amino acid biosynthesis that converts chorismate to L-phenylalanine and L-tyrosine in bacteria, fungi and plants. Chorismate... [more...][less]Branch of aromatic amino acid biosynthesis that converts chorismate to L-phenylalanine and L-tyrosine in bacteria, fungi and plants. Chorismate mutase rearranges chorismate to prephenate; this committed step is the main point of feedback control, typically inhibited by tyrosine (and in fungi and plants activated by tryptophan). Prephenate is then converted by one of two routes. In the prephenate route used by fungi and most bacteria, prephenate dehydratase gives phenylpyruvate and prephenate dehydrogenase gives 4-hydroxyphenylpyruvate, and aromatic aminotransferases convert these keto acids to phenylalanine and tyrosine. In the arogenate route that predominates in plants, prephenate aminotransferase first gives arogenate, which arogenate dehydratase and arogenate dehydrogenase convert to phenylalanine and tyrosine. In enteric bacteria chorismate mutase is fused to the dehydratase (P-protein) or the dehydrogenase (T-protein); in fungi and plants it is a separate allosteric enzyme. Synthesis of chorismate, the tryptophan branch and the hydroxylation of phenylalanine to tyrosine are outside this module. |
Metabolic Pathway | DRAFT | bacteria fungi green plants |
0 | L-phenylalanine biosynthetic process L-tyrosine biosynthetic process |
13 | 8 | 8 | 2 | 4 | 5 | 9/15 | 0 | ✗ | modules/phenylalanine_tyrosine_biosynthesis.yaml | |
L-threonine biosynthesis from L-aspartateMODULE:aspartate_family_threonine_biosynthesis L-threonine synthesis from L-aspartate through five successive transformations, represented by bacterial, fungal and plant enzymes and by two... [more...][less]L-threonine synthesis from L-aspartate through five successive transformations, represented by bacterial, fungal and plant enzymes and by two experimentally characterized archaeal steps. Aspartate kinase forms 4-phospho-L-aspartate; NADPH-dependent aspartate-semialdehyde dehydrogenase produces L-aspartate 4-semialdehyde; homoserine dehydrogenase produces L-homoserine; homoserine phosphorylation supplies O-phospho-L-homoserine; and PLP-dependent threonine synthase forms L-threonine. Homoserine phosphorylation can use ATP through a GHMP kinase or phosphoserine through the distinct Pseudomonas ThrH phosphotransferase, which releases serine. In the represented yeasts and E. coli, homoserine is shared with methionine synthesis; in plants the shared intermediate is O-phosphohomoserine, so homoserine kinase does not commit flux exclusively to threonine. Aspartate kinase and homoserine dehydrogenase may be separate proteins or domains of an AK-HSDH fusion. Cofactor preference, feedback sensitivity and oligomeric state are enzyme-specific. Arabidopsis TS1 is activated by S-adenosylmethionine, an allosteric effector rather than a consumed substrate. The aspartate-semialdehyde branch can supply diaminopimelate-pathway lysine synthesis in plants and many prokaryotes; the represented fungi instead use the alpha-aminoadipate lysine pathway. This is a reusable reaction module, not a claim that every member of any named taxon has a complete pathway. |
Metabolic Pathway | DRAFT | Archaea Bacteria Fungi Viridiplantae |
0 | L-threonine biosynthetic process |
16 | 9 | 7 | 4 | 8 | 4 | 24/24 | 0 | ✗ | modules/aspartate_family_threonine_biosynthesis.yaml | |
L-tryptophan biosynthesisMODULE:tryptophan_biosynthesis De novo biosynthesis of L-tryptophan from chorismate, the branch-point precursor of the aromatic amino acids, as found in bacteria, archaea, fungi... [more...][less]De novo biosynthesis of L-tryptophan from chorismate, the branch-point precursor of the aromatic amino acids, as found in bacteria, archaea, fungi and plants. Five ordered reactions convert chorismate to L-tryptophan, drawing in L-glutamine (amide nitrogen), PRPP (5-phospho-alpha-D-ribose 1-diphosphate) and L-serine, and releasing pyruvate, CO2 and glyceraldehyde 3-phosphate along the way. The reaction chain is invariant, but the enzymes that carry it out are fused in different combinations in different lineages. Anthranilate synthase is a glutamine amidotransferase built from a synthase component (TrpE) and a glutaminase component (TrpG); TrpG can be a separate protein, fused to anthranilate phosphoribosyltransferase (TrpGD of enteric bacteria), fused to indole-3-glycerol-phosphate synthase (budding yeast TRP3, TrpG-TrpC), or the first domain of a trifunctional TrpG-TrpC-TrpF protein (Neurospora trp-1, fission yeast trp1). Phosphoribosylanthranilate isomerase (TrpF) is a standalone enzyme in many bacteria and in budding yeast, but is fused to indole-3-glycerol-phosphate synthase in TrpCF proteins and in the fungal trifunctional protein. The terminal tryptophan synthase is an alpha-2-beta-2 complex of TrpA and TrpB in bacteria and plants and a single fused TrpA-TrpB chain in fungi; in both forms indole made at the TrpA (alpha) active site is channelled through an intramolecular tunnel to the PLP-dependent TrpB (beta) site, where it condenses with L-serine, so free indole is not released. The pathway is feedback-regulated by L-tryptophan at anthranilate synthase and, in many bacteria, also transcriptionally by attenuation and the TrpR repressor. |
Metabolic Pathway | DRAFT | 0 | L-tryptophan biosynthetic process |
15 | 13 | 5 | 4 | 9 | 4 | 16/19 | 0 | ✓ | modules/tryptophan_biosynthesis.yaml | ||
L-tyrosine catabolism (hepatic tyrosine degradation to fumarate + acetoacetate)MODULE:tyrosine_catabolism The main pathway of L-tyrosine degradation, a five-step cytosolic route operating chiefly in the liver (and kidney) that converts tyrosine —... [more...][less]The main pathway of L-tyrosine degradation, a five-step cytosolic route operating chiefly in the liver (and kidney) that converts tyrosine — including the tyrosine produced from phenylalanine by phenylalanine hydroxylase — to the central-metabolism end-products fumarate and acetoacetate, thereby feeding the carbon skeleton into the TCA cycle and ketone-body pool. Tyrosine aminotransferase (TAT) first transaminates tyrosine with 2-oxoglutarate to 4-hydroxyphenylpyruvate; 4-hydroxyphenylpyruvate dioxygenase (HPD/HPPD) then carries out an unusual oxidative decarboxylation, ring-hydroxylation and side-chain migration to give homogentisate; homogentisate 1,2-dioxygenase (HGD) cleaves the aromatic ring to 4-maleylacetoacetate; maleylacetoacetate isomerase (GSTZ1/MAAI) isomerises this to 4-fumarylacetoacetate; and fumarylacetoacetate hydrolase (FAH) hydrolyses the C-C bond to release fumarate and acetoacetate. Every step has a corresponding inborn error of metabolism: TAT deficiency causes tyrosinemia type II (Richner-Hanhart, oculocutaneous); HPD deficiency causes tyrosinemia type III and hawkinsinuria; HGD deficiency causes alkaptonuria (homogentisate accumulates and its oxidised polymer deposits as ochronotic pigment); GSTZ1/MAAI deficiency is biochemically mild; and FAH deficiency causes the severe hepatorenal tyrosinemia type I, in which the blocked terminal step causes accumulation of the upstream reactive intermediates maleyl-/fumarylacetoacetate and the toxin succinylacetone. Pharmacologically, the herbicide-derived HPD inhibitor nitisinone (NTBC) is the mainstay treatment of tyrosinemia type I: by blocking HPD (the second step) it prevents formation of the toxic downstream metabolites that accumulate when FAH is deficient, and it is also used in alkaptonuria to lower homogentisate. |
Metabolic Pathway | DRAFT | 0 | L-tyrosine catabolic process L-phenylalanine catabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/tyrosine_catabolism.yaml | ||
L-valine, L-leucine, and L-isoleucine biosynthesisMODULE:branched_chain_amino_acid_biosynthesis De novo biosynthesis of the three branched-chain amino acids in bacteria, archaea, fungi and plants; the pathway is absent from animals.... [more...][less]De novo biosynthesis of the three branched-chain amino acids in bacteria, archaea, fungi and plants; the pathway is absent from animals. L-isoleucine synthesis begins with threonine deamination to 2-oxobutanoate. An acetohydroxy-acid synthase (a catalytic large subunit with a regulatory small subunit), ketol-acid reductoisomerase and dihydroxy-acid dehydratase then form a shared catalytic trunk that processes either the valine precursor derived from two pyruvate molecules or the isoleucine precursor derived from pyruvate plus 2-oxobutanoate. The valine intermediate 2-oxoisovalerate also enters a three-reaction leucine extension (2-isopropylmalate synthase, isopropylmalate isomerase and 3-isopropylmalate dehydrogenase). A branched-chain amino-acid aminotransferase performs the terminal transamination for all three products. The reaction chain is conserved, but two features vary by lineage. First, isopropylmalate isomerase is a heteromeric LeuC-LeuD enzyme in bacteria and plants but a single fused polypeptide in fungi. Second, in fungi the pathway is split between compartments: threonine deaminase, the shared trunk, most 2-isopropylmalate synthase and a biosynthetic aminotransferase are in the mitochondrial matrix, 2-isopropylmalate is exported to the cytosol by a mitochondrial carrier, and the isomerase and dehydrogenase are cytosolic. In budding yeast, mitochondrial BAT1 and cytosolic BAT2 are paralogous aminotransferases, with BAT1 favoured for biosynthesis and BAT2 for catabolism. |
Metabolic Pathway | DRAFT | 4 | branched-chain amino acid biosynthetic process L-valine biosynthetic process L-isoleucine biosynthetic process L-leucine biosynthetic process |
13 | 12 | 10 | 1 | 2 | 10 | 33/42 | 0 | ✗ | modules/branched_chain_amino_acid_biosynthesis.yaml | ||
LDL receptor-mediated endocytic uptake — apoB-100 ligand, LDLR internalization and recycling, PCSK9 degradation controlMODULE:ldl_receptor_mediated_endocytosis Low-density lipoprotein (LDL) carries most plasma cholesterol and is cleared mainly by hepatocyte LDL receptors. Each LDL particle contains one... [more...][less]Low-density lipoprotein (LDL) carries most plasma cholesterol and is cleared mainly by hepatocyte LDL receptors. Each LDL particle contains one apolipoprotein B-100 molecule, whose receptor-binding region is the ligand for the cysteine-rich ligand-binding repeats of the LDL receptor (LDLR) at the cell surface. LDLR-LDL complexes cluster in clathrin-coated pits through the LDLR cytoplasmic NPxY motif (with the adaptor LDLRAP1/ARH in liver) and are internalized by receptor-mediated endocytosis. In the acidic early endosome the receptor releases LDL, which proceeds to lysosomes where cholesteryl esters are hydrolysed and free cholesterol is delivered to the cell; the empty receptor recycles to the plasma membrane for further rounds. Secreted PCSK9 binds the LDLR EGF-A repeat and, after co-internalization, prevents the receptor's acid-induced conformational change so that it is routed to lysosomes and degraded instead of recycling, lowering receptor number and LDL clearance (IDOL/MYLIP provides an intracellular, ubiquitin-dependent degradation route). Loss of LDLR, of the apoB-100 receptor-binding region, or of LDLRAP1, or gain of function of PCSK9, causes familial hypercholesterolaemia; PCSK9 loss of function lowers LDL cholesterol and is the target of PCSK9-inhibitor therapy. |
Transport Step | DRAFT | 0 | receptor-mediated endocytosis involved in cholesterol transport low-density lipoprotein particle clearance |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | Agent Based | modules/ldl_receptor_mediated_endocytosis.yaml | |
LINC complex (SUN-KASH nuclear envelope bridge) moduleMODULE:linc_complexABSTRACT The LINC (linker of nucleoskeleton and cytoskeleton) complex is a transmembrane bridge across the nuclear envelope. It connects the cytoskeleton to... [more...][less]The LINC (linker of nucleoskeleton and cytoskeleton) complex is a transmembrane bridge across the nuclear envelope. It connects the cytoskeleton to the nuclear interior. Inner-nuclear-membrane SUN-domain proteins form trimers whose C-terminal SUN domains project into the perinuclear space. Each trimer binds the C-terminal KASH peptides of three outer-nuclear-membrane KASH proteins, and the pair is reinforced by a conserved intermolecular disulfide. On the nucleoplasmic side, SUN proteins bind the nuclear lamina and, in meiosis, telomeres. On the cytoplasmic side, different KASH proteins engage different cytoskeletal systems: nesprin-1 and nesprin-2 bind actin through calponin-homology domains and bind microtubule motors (dynein-dynactin through BICD2, and kinesin-1); nesprin-3 binds plectin and so intermediate filaments; nesprin-4 binds kinesin-1; and the meiosis-specific KASH5 recruits dynein-dynactin. The bridge transmits force for nuclear migration and anchorage, centrosome-nucleus coupling, meiotic telomere-led chromosome movement, and sperm head-tail attachment. Disruption causes muscular dystrophy, cerebellar ataxia, hearing loss, infertility and neuronal migration defects. |
Protein Complex | DRAFT | Eukaryota |
3 | LINC complex |
16 | 14 | 3 | 2 | 12 | 2 | 16/17 | 0 | ✓ | modules/linc_complex.yaml | |
LKB1-STRAD-MO25 kinase complex in Drosophila melanogasterMODULE:dmel_lkb1_strad_mo25_complexCONCRETE LKB1 is a serine/threonine kinase that is active only when bound to the pseudokinase STRAD (Stlk in Drosophila) and the scaffold MO25. The trimeric... [more...][less]LKB1 is a serine/threonine kinase that is active only when bound to the pseudokinase STRAD (Stlk in Drosophila) and the scaffold MO25. The trimeric complex phosphorylates the activation loop of AMPK and of AMPK-related kinases such as Par-1, and so acts as a master upstream kinase. In Drosophila, Lkb1 is required for anterior-posterior polarity of the oocyte, for epithelial polarity under energy stress, and for asymmetric division of neuroblasts. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | serine/threonine protein kinase complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_lkb1_strad_mo25_complex.yaml | |
Lactate fermentation and the Rapoport-Luebering (2,3-BPG) shunt — GSD XI, BPGM deficiencyMODULE:lactate_fermentation_and_bpg_shunt Two branch reactions of glycolysis, prominent in anaerobic tissue and in erythrocytes (which depend entirely on glycolysis and lack mitochondria).... [more...][less]Two branch reactions of glycolysis, prominent in anaerobic tissue and in erythrocytes (which depend entirely on glycolysis and lack mitochondria). (1) Lactate fermentation: lactate dehydrogenase (a tetramer of the LDHA/M and LDHB/H subunits) reduces the glycolytic end-product pyruvate to L-lactate using NADH, regenerating the NAD+ that glyceraldehyde-3-phosphate dehydrogenase needs to sustain glycolytic flux when oxidative phosphorylation is unavailable or saturated; the LDHA-rich isoenzymes favour pyruvate to lactate (anaerobic/glycolytic tissue) while LDHB-rich isoenzymes favour the reverse oxidation of lactate to pyruvate (oxidative tissue). (2) The Rapoport-Luebering shunt: bisphosphoglycerate mutase (BPGM) diverts 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate (and hydrolyses it onward to 3-phosphoglycerate), bypassing the ATP-generating phosphoglycerate-kinase step; 2,3-bisphosphoglycerate is the principal allosteric effector that binds deoxyhemoglobin and lowers its oxygen affinity, tuning O2 delivery to tissues. Both branches feed off glycolytic intermediates (pyruvate and 1,3-bisphosphoglycerate respectively). Inherited defects: LDHA deficiency causes glycogen storage disease type XI (exertional myopathy, myoglobinuria, skin lesions); LDHB deficiency is usually clinically silent; and BPGM deficiency lowers 2,3-BPG, raising hemoglobin oxygen affinity and causing secondary erythrocytosis. |
Metabolic Pathway | DRAFT | 0 | glycolytic process |
3 | 2 | 2 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/lactate_fermentation_and_bpg_shunt.yaml | ||
Lambdoid phage ori-theta to rolling-circle DNA replication and Red homologous recombinationMODULE:phage_lambda_red_recombination_replicationCONCRETE A coupled biphasic DNA replication and homologous recombination module conserved across lambdoid bacteriophages, exemplified by Escherichia phage... [more...][less]A coupled biphasic DNA replication and homologous recombination module conserved across lambdoid bacteriophages, exemplified by Escherichia phage lambda (NCBITaxon:2681611). During early lytic infection, the phage origin-binding initiator protein O binds four 18-bp iteron repeats within ori-lambda (located inside the O coding sequence) to assemble the O-some nucleoprotein complex and unwind the adjacent AT-rich DNA unwinding element. The phage helicase loader P captures the hexameric host replicative helicase DnaB in a DnaB6:P5 open-spiral complex, suppressing premature ATPase and helicase activity while delivering DnaB to the ori-lambda O-some; remodeling by the host DnaK-DnaJ-GrpE chaperone machinery ejects P and activates bidirectional theta replication. Transition to late rolling-circle replication producing linear concatemeric substrates for cos packaging depends on the pL-transcribed Red/Gam and nin-region recombination machinery. The homodimeric DNA-mimic protein Gam inserts into the DNA-binding channel of host RecBCD exonuclease V, preventing RecBCD-mediated degradation of rolling-circle tails. Concurrently, the homotrimeric toroidal 5'-to-3' exonuclease Exo (Red-alpha) resects double-stranded DNA ends to generate 3' single-stranded overhangs and loads the single-strand DNA annealing recombinase Bet (Red-beta) onto the nascent 3' ssDNA tail, while accessory nin-region factors NinB (Orf) and NinG (Rap) mediate SSB/ssDNA loading and Holliday junction resolution. |
Biological Process | COMPLETE | Caudoviricetes Escherichia phage lambda |
0 | bidirectional double-stranded viral DNA replication rolling circle double-stranded viral DNA replication DNA recombination |
6 | 7 | 5 | 0 | 0 | 4 | 7/7 | 0 | ✗ | modules/phage_lambda_red_recombination_replication.yaml | |
Larval salivary glue proteins and puparial adhesion in Drosophila melanogasterMODULE:dmel_salivary_glue_secretionCONCRETE At the end of the third larval instar, the larval salivary glands make large amounts of glue glycoproteins in response to the ecdysone pulse, store... [more...][less]At the end of the third larval instar, the larval salivary glands make large amounts of glue glycoproteins in response to the ecdysone pulse, store them in secretory granules and release them into the gland lumen. At pupariation the larva expectorates the glue, which spreads over the body and hardens, fixing the puparium to the substrate for metamorphosis. The glue is a mixture of unrelated proteins: long, repeat-rich, heavily glycosylated mucin-like proteins (Sgs1, Sgs3, Sgs4 and the mucin Eig71Ee/gp150), small cysteine-rich proteins (Sgs7, Sgs8) and Sgs5 and Sgs5bis, whose role in the glue is not known. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | puparial adhesion |
4 | 8 | 3 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_salivary_glue_secretion.yaml | |
Larval serum protein hexamerins in Drosophila melanogasterMODULE:dmel_larval_serum_protein_hexamersCONCRETE Larval serum proteins (LSPs) are hexamerins, storage proteins related to arthropod hemocyanins that have lost the copper-binding oxygen-carrying... [more...][less]Larval serum proteins (LSPs) are hexamerins, storage proteins related to arthropod hemocyanins that have lost the copper-binding oxygen-carrying function. They are made in large amounts by the larval fat body, secreted into the hemolymph, and taken back up by the fat body at the end of the third instar, where they are stored in granules and broken down to supply amino acids for metamorphosis. Lsp1 hexamers are made of the alpha, beta and gamma chains (Lsp1alpha, Lsp1beta, Lsp1gamma) in various combinations, and Lsp2 forms a separate hexamer. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | protein storage |
3 | 2 | 2 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/dmel_larval_serum_protein_hexamers.yaml | |
Leaf trichome initiation and patterning by the MYB-bHLH-WD40 activator complex and R3 MYB lateral inhibitorsMODULE:trichome_initiation_mbwCONCRETE Arabidopsis leaf trichomes (unicellular epidermal hairs) are spaced by a cell-autonomous activator complex and mobile inhibitors. In the leaf... [more...][less]Arabidopsis leaf trichomes (unicellular epidermal hairs) are spaced by a cell-autonomous activator complex and mobile inhibitors. In the leaf primordium epidermis an MYB-bHLH-WD40 (MBW) activator complex forms from the R2R3-MYB GLABRA1 (GL1; MYB23 acts partially redundantly), the redundant bHLH proteins GLABRA3 (GL3) and ENHANCER OF GLABRA3 (EGL3), and the WD40-repeat protein TRANSPARENT TESTA GLABRA1 (TTG1); GL3/EGL3 bridge GL1 and TTG1. The active complex binds and activates the promoters of the HD-ZIP IV transcription factor GLABRA2 (GL2), which executes trichome differentiation, and of the single-repeat R3 MYB inhibitors CAPRICE (CPC), ENHANCER OF TRY AND CPC1 (ETC1) and TRIPTYCHON (TRY). The R3 MYB proteins lack an activation domain; they move into neighbouring epidermal cells, bind GL3/EGL3 and compete with GL1, so that inactive complexes form there and those cells remain pavement cells (lateral inhibition). TRY also represses its own promoter, and TTG1 depletion from cells surrounding a trichome by GL3-dependent trapping contributes a second, trapping/depletion patterning mechanism. TRY suppresses trichome clustering, CPC mainly sets trichome density, and try cpc double mutants convert all cells contacting a trichome into trichomes. Jasmonate (JAZ) and gibberellin (DELLA) repressors bind GL1 and GL3/EGL3 and modulate the complex; these hormone inputs, the root epidermis WER-GL3/EGL3-TTG1 module that specifies non-hair cells, and the seed coat/anthocyanin MBW complexes built on TT8 and TT2/PAP MYBs share components with this module but are outside its boundary. |
Developmental Process | DRAFT | Arabidopsis thaliana |
0 | trichome patterning trichome differentiation |
6 | 7 | 3 | 1 | 2 | 3 | 7/7 | 0 | ✗ | modules/trichome_initiation_mbw.yaml | |
Lipid droplet lifecycleMODULE:lipid_droplet_lifecycleCONCRETE Lipid droplets store neutral lipids. They are born in the endoplasmic reticulum when triacylglycerol and sterol esters made in the membrane... [more...][less]Lipid droplets store neutral lipids. They are born in the endoplasmic reticulum when triacylglycerol and sterol esters made in the membrane coalesce at seipin-marked sites and bud toward the cytosol; they grow by local synthesis, by transfer of lipid from the ER and by fusion; and they are consumed by lipases on their surface or by lipophagy, releasing fatty acids for energy and membrane synthesis. This umbrella module composes the modules for those stages by reference. Triacylglycerol synthesis by a DGAT is required in every eukaryote; the pathway and lipolysis descriptions are optional. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | lipid droplet organization lipid droplet |
5 | 0 | 4 | 0 | 0 | 1 | 0/0 | 0 | ✗ | modules/lipid_droplet_lifecycle.yaml | |
Low-molecular-mass PBP peptidoglycan hydrolysisMODULE:low_molecular_mass_pbp_peptidoglycan_hydrolysisCONCRETE A reusable bacterial module for two distinct hydrolytic reactions performed by low-molecular-mass penicillin-binding proteins during peptidoglycan... [more...][less]A reusable bacterial module for two distinct hydrolytic reactions performed by low-molecular-mass penicillin-binding proteins during peptidoglycan maturation. D,D-carboxypeptidases trim terminal D-alanine from uncrosslinked pentapeptide stems, whereas D,D-endopeptidases cleave D-Ala-mDAP 4-3 crosslinks between stems. Individual enzymes may catalyze one or both reactions; neither reaction represents protein proteolysis or crosslink formation. |
Biological Process | COMPLETE | bacteria |
0 | peptidoglycan metabolic process |
6 | 3 | 2 | 2 | 3 | 0 | 5/5 | 0 | ✗ | modules/low_molecular_mass_pbp_peptidoglycan_hydrolysis.yaml | |
Lysine catabolism (saccharopine pathway; AASS/ALDH7A1/AADAT/DHTKD1/GCDH)MODULE:lysine_catabolism_saccharopine The saccharopine pathway is the main route of L-lysine degradation in mammals, converting lysine to acetyl-CoA through 2-aminoadipate and... [more...][less]The saccharopine pathway is the main route of L-lysine degradation in mammals, converting lysine to acetyl-CoA through 2-aminoadipate and glutaryl-CoA, predominantly in liver and brain mitochondria. The bifunctional enzyme AASS (2-aminoadipic-6-semialdehyde synthase) catalyses the first two steps: its lysine-ketoglutarate reductase domain condenses L-lysine with 2-oxoglutarate to saccharopine, and its saccharopine dehydrogenase domain then cleaves saccharopine to L-2-aminoadipate 6-semialdehyde (AASA) plus L-glutamate. AASA (in equilibrium with delta-1-piperideine-6-carboxylate, P6C) is oxidised to L-2-aminoadipate by the NAD-dependent aldehyde dehydrogenase ALDH7A1 (antiquitin); a block here causes accumulation of P6C, which inactivates pyridoxal-5'-phosphate and produces pyridoxine-dependent epilepsy. The PLP-dependent aminotransferase AADAT (KAT2) then transaminates 2-aminoadipate with 2-oxoglutarate to 2-oxoadipate (AADAT is also kynurenine aminotransferase II, linking to tryptophan metabolism). 2-oxoadipate is oxidatively decarboxylated to glutaryl-CoA by the 2-oxoadipate dehydrogenase DHTKD1 (with DLST and DLD), and glutaryl-CoA is dehydrogenated/decarboxylated to crotonyl-CoA by GCDH (glutaryl-CoA dehydrogenase), which continues to two acetyl-CoA. Inherited defects cause aminoadipic/oxoadipic aciduria (DHTKD1), pyridoxine-dependent epilepsy (ALDH7A1) and glutaric aciduria type 1 (GCDH). |
Metabolic Pathway | DRAFT | 0 | L-lysine catabolic process |
4 | 5 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/lysine_catabolism_saccharopine.yaml | ||
Lysosomal glycogen degradation (acid alpha-glucosidase) — Pompe disease (GSD II)MODULE:lysosomal_glycogen_degradation Lysosomal glycogen degradation is the acid-hydrolase route for breaking down the glycogen that is delivered to lysosomes by autophagy (glycophagy),... [more...][less]Lysosomal glycogen degradation is the acid-hydrolase route for breaking down the glycogen that is delivered to lysosomes by autophagy (glycophagy), complementing the cytosolic glycogenolysis pathway (phosphorylase/debranching). Its single enzyme is lysosomal acid alpha-glucosidase (GAA, acid maltase), a glycoside-hydrolase-family-31 enzyme that works at the acidic pH of the lysosomal lumen to completely hydrolyse glycogen to free glucose, cleaving the alpha-1,4-glucosidic bonds (and, more slowly, the alpha-1,6 branch linkages). GAA is synthesised as a precursor, N-glycosylated and mannose-6-phosphate-tagged for delivery to the lysosome, and proteolytically matured to its active forms. Because this route continuously clears autophagocytosed glycogen, its loss is not compensated by cytosolic glycogenolysis: inherited GAA deficiency causes Pompe disease (glycogen storage disease type II) — lysosomal glycogen accumulation producing hypertrophic cardiomyopathy and profound hypotonia in the infantile-onset form, and a progressive limb-girdle and respiratory myopathy in late-onset disease. It is one of the few glycogenoses treatable by enzyme replacement therapy (recombinant human GAA, e.g. alglucosidase/avalglucosidase alfa). |
Metabolic Pathway | DRAFT | 0 | glycogen catabolic process |
2 | 1 | 1 | 0 | 0 | 0 | 1/1 | 0 | ✗ | modules/lysosomal_glycogen_degradation.yaml | ||
Lysosomal glycoprotein (N-glycan) degradation; NEU1/GLB1/HEX/MAN2B1/MANBA/FUCA1/AGA/NAGAMODULE:lysosomal_glycoprotein_degradation Glycoproteins delivered to the lysosome are proteolysed to glycopeptides whose glycans are then dismantled by lumenal exoglycosidases working from... [more...][less]Glycoproteins delivered to the lysosome are proteolysed to glycopeptides whose glycans are then dismantled by lumenal exoglycosidases working from both ends. From the non-reducing end, N-glycan antennae are trimmed residue by residue: capping sialic acid (NEU1), terminal galactose (GLB1), antennal N-acetylglucosamine (beta-hexosaminidase, HEXA/HEXB), alpha-linked mannoses (MAN2B1) and the core beta-mannose (MANBA); terminal alpha-N-acetylgalactosamine of blood group A and mucin-type determinants is removed by NAGA. From the reducing end, the core alpha1,6-fucose is removed by FUCA1, which is required because core fucosylation blocks aspartylglucosaminidase (AGA); AGA then cleaves the N-glycosidic GlcNAc-Asn bond, separating the glycan from the asparagine residue. Loss of any step causes a glycoproteinosis (oligosaccharidosis) with lysosomal storage and urinary excretion of the corresponding oligosaccharides or glycoasparagines: sialidosis, GM1 gangliosidosis, Sandhoff disease, alpha- and beta-mannosidosis, fucosidosis, aspartylglucosaminuria and NAGA deficiency. |
Metabolic Pathway | DRAFT | 0 | glycoprotein catabolic process |
9 | 8 | 8 | 0 | 0 | 5 | 6/8 | 0 | ✗ | modules/lysosomal_glycoprotein_degradation.yaml | ||
Lysosome and lytic vacuole lifecycleMODULE:lysosome_lifecycleCONCRETE Lysosomes in animals and lytic vacuoles in fungi and plants are the acidic, hydrolase-filled compartments where the endocytic, autophagic and... [more...][less]Lysosomes in animals and lytic vacuoles in fungi and plants are the acidic, hydrolase-filled compartments where the endocytic, autophagic and biosynthetic routes end. They form by maturation of endosomes, which turn membrane cargo into intralumenal vesicles and fuse with existing lysosomes; they receive hydrolases from the Golgi; they degrade macromolecules in an acidified lumen; and damaged lysosomes are repaired or removed by lysophagy. This umbrella module composes the modules for those stages by reference. Lumen acidification and ESCRT-III membrane scission are required in every eukaryote; hydrolase delivery and the degradative pathways are optional because the modelled routes are animal-specific. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | lytic vacuole organization lytic vacuole |
10 | 0 | 9 | 0 | 0 | 3 | 0/0 | 0 | ✗ | modules/lysosome_lifecycle.yaml | |
Lysosome-to-nucleus lipid signaling in Caenorhabditis elegansMODULE:c_elegans_lysosomal_lipid_signalingCONCRETE In the Caenorhabditis elegans intestine, lysosomes send lipid signals to the nucleus that adjust fat metabolism and extend lifespan. The TFEB... [more...][less]In the Caenorhabditis elegans intestine, lysosomes send lipid signals to the nucleus that adjust fat metabolism and extend lifespan. The TFEB ortholog HLH-30 is a basic helix-loop-helix transcription factor that moves into the nucleus during fasting, after germline loss or when TOR signalling falls. It turns on autophagy and lysosome genes, and with the Max-like factor MXL-3 it links lysosomal lipolysis to nutrient supply. The lysosomal acid lipase LIPL-4, a homolog of human LIPA, is induced in these conditions and hydrolyses lipids at acidic pH inside the lysosome. Its activity raises the levels of omega-6 polyunsaturated fatty acids, which promote autophagy, and of the N-acylethanolamine oleoylethanolamide (OEA). The intestinal fatty acid-binding protein LBP-8 sits on lysosomes and binds OEA and oleic acid with high affinity. When LIPL-4 activity is high, LBP-8 enters the nucleus through an N-terminal nuclear localization signal. There, OEA binds the HNF4-family nuclear receptor NHR-80 directly. NHR-80 works with its partner NHR-49, which does not bind OEA, to switch on genes for fatty acid desaturation (fat-5, fat-6, fat-7) and mitochondrial beta-oxidation (acs-2), as well as lbp-8 itself. The pathway is needed for the long life of animals that overexpress LIPL-4 or LBP-8. It is independent of dietary restriction. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | determination of adult lifespan |
5 | 5 | 4 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/c_elegans_lysosomal_lipid_signaling.yaml | |
MEP isoprenoid precursor biosynthesisMODULE:mep_isoprenoid_precursor_biosynthesis The methylerythritol phosphate (MEP/DOXP) route converts pyruvate and glyceraldehyde 3-phosphate through seven reactions into isopentenyl... [more...][less]The methylerythritol phosphate (MEP/DOXP) route converts pyruvate and glyceraldehyde 3-phosphate through seven reactions into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). DXS forms the shared branch-point metabolite DXP, Dxr commits DXP to the MEP route, IspD-IspG build HMBPP, and IspH produces the two universal five-carbon isoprenoid precursors. DXP use in thiamine or pyridoxal-phosphate biosynthesis and downstream prenyl-diphosphate elongation are outside this module. |
Metabolic Pathway | DRAFT | 6 | isopentenyl diphosphate biosynthetic process, methylerythritol 4-phosphate pathway dimethylallyl diphosphate biosynthetic process |
12 | 9 | 7 | 2 | 4 | 6 | 7/16 | 0 | ✓ | modules/mep_isoprenoid_precursor_biosynthesis.yaml | ||
MICOS complex in Drosophila melanogasterMODULE:dmel_micos_complexCONCRETE The mitochondrial contact site and cristae organizing system (MICOS) is an inner membrane complex enriched at crista junctions. It stabilises... [more...][less]The mitochondrial contact site and cristae organizing system (MICOS) is an inner membrane complex enriched at crista junctions. It stabilises crista junctions, shapes cristae and links the inner membrane to the outer membrane. MICOS is made of two subcomplexes: a Mic60 subcomplex, built on Mitofilin (Mic60) with the CHCH-domain protein Chchd3 (Mic19), and a Mic10 subcomplex containing the membrane-bending protein Mic10 together with QIL1 (Mic13) and the apolipoprotein-domain protein Mic26-27. Drosophila has three Mic10 paralogs: Mic10b is broadly expressed, whereas Mic10a and Mic10c are testis-specific. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | MICOS complex |
7 | 5 | 3 | 1 | 3 | 0 | 0/7 | 0 | ✗ | modules/dmel_micos_complex.yaml | |
MIF signaling pathway moduleMODULE:mif_signalingABSTRACT Macrophage migration inhibitory factor (MIF) and its paralog D-dopachrome tautomerase (DDT, also called MIF-2) are secreted homotrimeric cytokines... [more...][less]Macrophage migration inhibitory factor (MIF) and its paralog D-dopachrome tautomerase (DDT, also called MIF-2) are secreted homotrimeric cytokines that bind the cell-surface receptor CD74 (the MHC class II invariant chain) in complex with the signaling co-receptor CD44 on responding immune and parenchymal cells, initiating SRC-family kinase and ERK1/2 MAP kinase signaling cascades that regulate leukocyte activation, inflammatory cytokine production and cell survival. |
Signaling Pathway | DRAFT | Euteleostomi |
4 | macrophage migration inhibitory factor signaling pathway |
3 | 2 | 2 | 0 | 0 | 1 | 2/8 | 0 | ✗ | modules/mif_signaling.yaml | |
MSL dosage compensation complex in Drosophila melanogasterMODULE:dmel_msl_dosage_compensation_complexCONCRETE The male-specific lethal (MSL) complex doubles transcription of the single X chromosome in males. It contains five proteins, MSL1, MSL2, MSL3, the... [more...][less]The male-specific lethal (MSL) complex doubles transcription of the single X chromosome in males. It contains five proteins, MSL1, MSL2, MSL3, the acetyltransferase MOF and the RNA helicase MLE, and one of two long noncoding RNAs, roX1 or roX2, which are redundant. MSL2 is made only in males and nucleates assembly; MLE remodels the roX RNAs to incorporate them. The complex binds high-affinity sites on the X and spreads to active genes, where MOF acetylates histone H4 lysine 16 to raise transcription. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | MSL complex |
5 | 3 | 2 | 1 | 2 | 0 | 5/5 | 0 | ✗ | modules/dmel_msl_dosage_compensation_complex.yaml | |
Major (U2-type) spliceosome in Drosophila melanogasterMODULE:dmel_spliceosomeCONCRETE The major spliceosome removes U2-type introns from nuclear pre-mRNAs. It is assembled stepwise on each intron from the U1, U2, U4/U6 and U5 small... [more...][less]The major spliceosome removes U2-type introns from nuclear pre-mRNAs. It is assembled stepwise on each intron from the U1, U2, U4/U6 and U5 small nuclear ribonucleoprotein particles (snRNPs) and many non-snRNP proteins. Each snRNP contains a small nuclear RNA; the U1, U2, U4 and U5 snRNAs carry a heptameric ring of Sm proteins, whereas U6 snRNA binds the related LSm proteins. U1 snRNP recognizes the 5' splice site, and the U2 snRNP auxiliary factor (U2AF) together with SF1 recognizes the 3' splice site region, allowing U2 snRNP to pair with the branch site (complex A). Joining of the U4/U6.U5 tri-snRNP forms the precatalytic complex B; release of U1 and U4 and recruitment of the Prp19 complex and associated proteins create the catalytic spliceosome, which carries out the two transesterification steps (complex C) and then releases the spliced mRNA (post-catalytic complex P) with an exon junction complex deposited upstream of the exon-exon junction. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | spliceosomal complex mRNA splicing, via spliceosome |
18 | 13 | 15 | 1 | 2 | 5 | 0/124 | 0 | ✗ | modules/dmel_spliceosome.yaml | |
Malate-aspartate shuttle (MDH1/MDH2/GOT1/GOT2 + SLC25A11/SLC25A12)MODULE:malate_aspartate_shuttle The malate-aspartate shuttle is the principal mechanism by which reducing equivalents (cytosolic NADH generated in glycolysis) are transferred into... [more...][less]The malate-aspartate shuttle is the principal mechanism by which reducing equivalents (cytosolic NADH generated in glycolysis) are transferred into the mitochondrial matrix for oxidation by the respiratory chain, in tissues such as heart, liver and brain. Because NADH itself cannot cross the inner mitochondrial membrane, the shuttle moves the electrons as malate: in the cytosol, malate dehydrogenase 1 (MDH1) reduces oxaloacetate to malate, consuming a cytosolic NADH; the malate is imported by the oxoglutarate/malate carrier (SLC25A11, OGC) in exchange for 2-oxoglutarate; in the matrix, malate dehydrogenase 2 (MDH2) re-oxidises malate to oxaloacetate, regenerating matrix NADH that feeds Complex I. Oxaloacetate cannot cross the membrane either, so it is transaminated with glutamate to aspartate by mitochondrial aspartate aminotransferase (GOT2, PLP-dependent); the aspartate is exported by the Ca2+-regulated aspartate-glutamate carrier (SLC25A12, AGC1/aralar) in exchange for cytosolic glutamate, and cytosolic aspartate aminotransferase (GOT1) regenerates oxaloacetate and 2-oxoglutarate to close the cycle. The AGC1 antiport, being electrogenic and effectively unidirectional, gives the shuttle its net direction. Defects in these components cause disease: SLC25A12/AGC1 deficiency causes a hypomyelinating encephalopathy (global cerebral hypomyelination / epilepsy), MDH2 and GOT2 deficiencies cause early infantile epileptic encephalopathy, and the shuttle is a key node in cancer redox metabolism. |
Metabolic Pathway | DRAFT | 0 | malate-aspartate shuttle |
4 | 6 | 3 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/malate_aspartate_shuttle.yaml | ||
Mammalian apoptotic execution: proteolysis, ICAD/CAD and contextual nuclear branchesMODULE:apoptotic_execution_phaseABSTRACT Mammalian executioner caspases cleave distinct sets of cellular substrates. CASP3 cleavage of ICAD relieves inhibition of the CAD nuclease after... [more...][less]Mammalian executioner caspases cleave distinct sets of cellular substrates. CASP3 cleavage of ICAD relieves inhibition of the CAD nuclease after ICAD-supported folding, enabling chromatin DNA fragmentation; mouse CASP7 provides a supported alternative ICAD-cleaving activity. XIAP and mitochondrial SMAC regulate execution in a cell-dependent manner. CASP6 proteolysis, Acinus-associated nuclear remodeling and AIF chromatin engagement are separately qualified branches, not an obligatory sequence shared by every dying cell. The template starts downstream of initiation and excludes a complete substrate inventory and phagocyte-mediated disposal. |
Biological Process | DRAFT | Homo sapiens Mammalia Mus musculus |
0 | execution phase of apoptosis |
12 | 10 | 9 | 1 | 2 | 10 | 16/16 | 0 | ✗ | modules/apoptotic_execution_phase.yaml | |
Mammalian cerebellum development moduleMODULE:cerebellum_developmentCONCRETE A mammalian developmental program that builds the cerebellum from dorsal rhombomere 1. The program begins with allocation of the cerebellar anlage... [more...][less]A mammalian developmental program that builds the cerebellum from dorsal rhombomere 1. The program begins with allocation of the cerebellar anlage by the midbrain-hindbrain (isthmic) organizer, followed by segregation of two principal germinal-zone programs: an ATOH1-positive rhombic-lip program that generates glutamatergic lineages and a PTF1A-positive ventricular-zone program that generates GABAergic lineages. Reelin-dependent reorientation of an early/posterior-born Purkinje-cell subset initiates early plate formation. As Purkinje cells differentiate, they provide Sonic hedgehog (SHH) to expand granule-cell precursors in the transient external granule layer. Partly overlapping granule-neuron migration and Bergmann-glial differentiation assemble the cortical layers, while Engrailed-dependent regional patterning coordinates foliation of the vermis and hemispheres. The module ends with formation of the layered, foliated cerebellum; mature synaptic physiology, motor learning, adult homeostasis, and tumorigenesis are outside its boundary. |
Developmental Process | DRAFT | mammals |
0 | cerebellum development |
14 | 12 | 11 | 1 | 2 | 12 | 13/13 | 0 | ✗ | modules/cerebellum_development.yaml | |
Mammalian nucleotide excision repair — GG-NER (XPC-RAD23B-CETN2, UV-DDB/CRL4-DDB2) and TC-NER (stalled RNA Pol II, CSB, CRL4-CSA, UVSSA, ELOF1) damage recognition, TFIIH opening, XPA-RPA verification, XPF-ERCC1 and XPG dual incision, PCNA/RFC-dependent repair synthesis by Pol delta, epsilon or kappa, and ligation by LIG1 or LIG3-XRCC1MODULE:nucleotide_excision_repairCONCRETE Nucleotide excision repair (NER) removes a wide range of structurally unrelated, helix-distorting DNA lesions, most prominently the UV... [more...][less]Nucleotide excision repair (NER) removes a wide range of structurally unrelated, helix-distorting DNA lesions, most prominently the UV photoproducts (cyclobutane pyrimidine dimers and 6-4 photoproducts) and bulky chemical adducts, by excising a 24-32 nucleotide single-stranded oligonucleotide containing the lesion and resynthesising the gap. Mammalian NER has two damage-recognition sub-pathways that converge on a common core. In global genome NER (GG-NER), the XPC-RAD23B-centrin 2 complex detects the unpaired bases opposite a lesion anywhere in the genome; for CPDs, which distort the helix only slightly, the UV-DDB complex (DDB2 within the DDB1-CUL4-RBX1 ubiquitin ligase) binds the lesion first, ubiquitylates XPC, histones and itself, and hands the lesion over to XPC. In transcription-coupled NER (TC-NER), RNA polymerase II stalled at a lesion in the transcribed strand is the sensor: CSB (ERCC6), a SWI2/SNF2-family DNA translocase, binds the arrested polymerase and recruits the CSA (ERCC8) substrate receptor of a second DDB1-CUL4-RBX1 ligase (CRL4-CSA); CSA brings UVSSA, and ELOF1 positions UVSSA and CRL4-CSA so that RPB1 is ubiquitylated on Lys1268. Both sub-pathways then recruit the ten-subunit transcription factor TFIIH, in GG-NER through XPC and in TC-NER through UVSSA. The XPB (ERCC3) ATPase anchors TFIIH and opens the DNA, and the XPD (ERCC2) 5'-3' helicase extends the bubble to about 30 nucleotides and scans the strand to verify the lesion; the CDK-activating kinase subcomplex leaves TFIIH during this step. XPA and the single-stranded DNA-binding protein RPA bind the opened intermediate, verify the damaged strand and position the two structure-specific endonucleases: XPF-ERCC1 incises 5' to the lesion and XPG incises 3' to it. The 5' incision lets RFC load PCNA, and DNA polymerase delta, epsilon or kappa fills the gap; the 3' incision by XPG then releases the excised oligonucleotide. DNA ligase I or the DNA ligase III-XRCC1 complex seals the remaining nick. Inherited defects in NER proteins cause xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy and UV-sensitive syndrome. |
Biological Process | DRAFT | Homo sapiens |
0 | nucleotide-excision repair |
14 | 19 | 6 | 3 | 7 | 9 | 13/45 | 0 | ✗ | modules/nucleotide_excision_repair.yaml | |
Mannose 6-phosphate tagging of lysosomal hydrolases — Golgi GlcNAc-1-phosphotransferase (GNPTAB) and its retention factor LYSETMODULE:mannose_6_phosphate_lysosomal_targeting Newly synthesised soluble lysosomal acid hydrolases are sorted away from the secretory pathway by a mannose 6-phosphate (M6P) recognition marker on... [more...][less]Newly synthesised soluble lysosomal acid hydrolases are sorted away from the secretory pathway by a mannose 6-phosphate (M6P) recognition marker on their N-glycans. In the cis-Golgi the GlcNAc-1-phosphotransferase complex (alpha2beta2gamma2; catalytic alpha/beta subunits encoded by GNPTAB, gamma by GNPTG) recognises a conformational protein determinant shared by lysosomal hydrolases and transfers GlcNAc-1-phosphate from UDP-GlcNAc to C6 hydroxyls of mannose residues of their high-mannose N-glycans. The Golgi membrane protein LYSET (TMEM251) binds the GlcNAc-1-phosphotransferase, stabilising it and supporting its site-1 protease activation and Golgi retention, and is required for M6P tagging. In the trans-Golgi network the uncovering enzyme NAGPA removes the covering GlcNAc to expose M6P, and the M6P receptors (cation-dependent M6PR and cation-independent IGF2R) bind the tagged hydrolases and deliver them to endosomes, from which the receptors recycle. Loss of GNPTAB causes mucolipidosis II (I-cell disease) and MLIII alpha/beta, GNPTG loss causes MLIII gamma, and LYSET deficiency causes a mucolipidosis-like disorder, all with hypersecretion of lysosomal enzymes and lysosomal storage. |
Biological Process | DRAFT | 0 | N-glycan processing to lysosome |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/mannose_6_phosphate_lysosomal_targeting.yaml | ||
Maternal-to-zygotic transition moduleMODULE:maternal_to_zygotic_transition The earliest developmental hand-off in metazoan embryos, in which control of development passes from maternally deposited factors to the embryo's... [more...][less]The earliest developmental hand-off in metazoan embryos, in which control of development passes from maternally deposited factors to the embryo's own genome. The module has two coupled, ordered arms: (1) clearance of maternal mRNAs and proteins, executed by sequence-specific RNA-binding factors and maternal/zygotic small RNAs that target maternal transcripts for deadenylation and decay; and (2) zygotic genome activation (ZGA), in which pioneer and pluripotency transcription factors (e.g. POU5F1/Oct4, Nanog/NANOG, SOX2, and lineage-specific activators such as DUX/DUX4 and Nr5a2) open embryonic chromatin and switch on the first zygotic transcripts. In insects the transition coincides with cellularization of the syncytial blastoderm, modelled here as a taxon-restricted variant part. Grounded in GO:0141064 (zygotic genome activation) within GO:0009790 (embryo development). Maternal patterning determinants deposited during this window feed forward into modules/body_axis_specification.yaml. |
Developmental Process | DRAFT | insects metazoa |
0 | zygotic genome activation embryo development |
6 | 4 | 3 | 1 | 2 | 2 | 1/3 | 3 | ✗ | modules/maternal_to_zygotic_transition.yaml | |
Mediator complex in Drosophila melanogasterMODULE:dmel_mediator_complexCONCRETE Mediator is a large multisubunit coactivator that bridges DNA-bound transcription factors and RNA polymerase II, helping assemble and activate the... [more...][less]Mediator is a large multisubunit coactivator that bridges DNA-bound transcription factors and RNA polymerase II, helping assemble and activate the preinitiation complex. The core Mediator (head, middle and tail modules, with MED14 as a central scaffold) binds the polymerase, while tail subunits contact activators. The CDK8 kinase module (CKM), consisting of Cdk8, CycC, MED12 (kto) and MED13 (skd), associates reversibly with core Mediator and generally restrains its interaction with polymerase; Drosophila kto and skd were identified through their roles in imaginal disc patterning. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | mediator complex |
3 | 2 | 2 | 0 | 0 | 1 | 0/30 | 0 | ✗ | modules/dmel_mediator_complex.yaml | |
Metaphase/anaphase transition and mitotic exit (APC/C-driven)MODULE:metaphase_anaphase_transition_and_mitotic_exitCONCRETE A taxon-neutral decomposition of the two coupled proteolytic switches that end mitosis. (1) The anaphase-promoting complex/cyclosome (APC/C), a... [more...][less]A taxon-neutral decomposition of the two coupled proteolytic switches that end mitosis. (1) The anaphase-promoting complex/cyclosome (APC/C), a cullin-RING ubiquitin ligase, is activated by CDK1 phosphorylation and by binding of its substrate-adaptor coactivator Cdc20 (Slp1). (2) Until every kinetochore is attached, the spindle assembly checkpoint (SAC) - Mps1/Mph1 kinase at unattached kinetochores, Mad1-Mad2 templating, and the Bub1/Bub3 scaffold - assembles the mitotic checkpoint complex (Mad2-BubR1/Mad3-Bub3-Cdc20) that sequesters and inhibits APC/C-Cdc20. (3) Once the SAC is satisfied, APC/C-Cdc20 ubiquitinates securin (PTTG1, Pds1, Cut2), releasing separase (ESPL1, Esp1, Cut1) to cleave the cohesin kleisin subunit (RAD21, Scc1/Mcd1, Rad21) and trigger sister-chromatid separation, the metaphase/anaphase transition proper. (4) APC/C-Cdc20 and then APC/C-Cdh1 (FZR1, Hct1/Cdh1, Ste9/Srw1) ubiquitinate the mitotic cyclins, extinguishing CDK1 activity. (5) A CDK-counteracting phosphatase - Cdc14 released by the mitotic exit network in budding yeast, Clp1/Flp1 and the septation initiation network in fission yeast, and reactivated PP2A-B55 in metazoa - reverses CDK phosphorylation to complete mitotic exit and reset G1. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0007091 (metaphase/anaphase transition of mitotic cell cycle) and GO:0010458 (exit from mitosis). |
Biological Process | DRAFT | Eukaryota Metazoa Saccharomyces cerevisiae Schizosaccharomyces pombe |
10 | metaphase/anaphase transition of mitotic cell cycle exit from mitosis |
9 | 14 | 5 | 1 | 3 | 13 | 46/46 | 0 | ✗ | modules/metaphase_anaphase_transition_and_mitotic_exit.yaml | |
Metazoan NLR signaling pathway moduleMODULE:nlr_signaling Metazoan nucleotide-binding leucine-rich-repeat receptors detect intracellular perturbations and assemble RIPK-, ASC-, or caspase-containing... [more...][less]Metazoan nucleotide-binding leucine-rich-repeat receptors detect intracellular perturbations and assemble RIPK-, ASC-, or caspase-containing signaling platforms for inflammatory and antimicrobial responses. Scope is deliberately metazoan; plant NB-LRR receptors share the NB-ARC/LRR architecture but signal through resistosomes rather than through these platforms, and are modelled separately in modules/plant_nlr_resistosome_signaling.yaml. |
Signaling Pathway | DRAFT | metazoa |
8 | nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway |
5 | 7 | 4 | 0 | 0 | 3 | 6/9 | 0 | ✓ | modules/nlr_signaling.yaml | |
Metazoan autophagosome biogenesis and maturationMODULE:metazoan_autophagosome_biogenesisCONCRETE In animals, macroautophagy builds a double-membrane autophagosome around cytoplasmic cargo and delivers it to lysosomes. The core steps are shared... [more...][less]In animals, macroautophagy builds a double-membrane autophagosome around cytoplasmic cargo and delivers it to lysosomes. The core steps are shared with yeast, but several are wired differently. An initiation complex of the Atg1/ULK kinase, ATG13 and ATG101 marks the site of formation, which in animals lies on endoplasmic reticulum (ER) subdomains called omegasomes. The class III phosphatidylinositol 3-kinase complex I (VPS34, the pseudokinase VPS15, Beclin 1 and ATG14) makes phosphatidylinositol 3-phosphate (PI3P) on this membrane. Two kinds of WD40 PROPPIN read PI3P. WIPI1/2-type proteins recruit the conjugation machinery, and WIPI3/4-type proteins partner the ATG2 rod in an ATG2-ATG18 complex. ATG2 carries lipids from the ER to the growing phagophore, and the ATG9 scramblase spreads them between the two leaflets. Atg8-family proteins are primed by ATG4 and conjugated to phosphatidylethanolamine by the E1 ATG7, the E2 ATG3 and the E3-like ATG12-ATG5-ATG16 complex, with ATG16 setting where conjugation happens. Animals have two Atg8 subfamilies, GABARAP-type and LC3-type, and the stage at which each acts differs between lineages: in nematodes the GABARAP-type protein acts early and the LC3-type protein late, whereas in mammalian cells the GABARAP subfamily dominates autophagosome-lysosome fusion. Cargo receptors such as p62/SQSTM1 link ubiquitinated cargo to Atg8-family proteins. Fusion with late endosomes and lysosomes needs EPG5, a metazoan-specific RAB7 effector that binds Atg8-family proteins and SNAREs and makes sure autophagosomes fuse with the correct partner. |
Biological Process | DRAFT | Metazoa |
0 | macroautophagy |
11 | 21 | 8 | 1 | 2 | 9 | 34/34 | 0 | ✗ | modules/metazoan_autophagosome_biogenesis.yaml | |
Methionine (S-adenosylmethionine) cycle moduleMODULE:methionine_cycle A taxon-neutral decomposition of the methionine / S-adenosylmethionine (SAM) cycle, the core methyl-group-cycling pathway that interconverts... [more...][less]A taxon-neutral decomposition of the methionine / S-adenosylmethionine (SAM) cycle, the core methyl-group-cycling pathway that interconverts methionine, S-adenosyl-L-methionine, S-adenosyl-L-homocysteine, and homocysteine, with exits to transsulfuration (via cystathionine beta-synthase) and remethylation inputs from folate (via methionine synthase) and choline/betaine (via BHMT). This module is intentionally structured in two layers. The CATALYTIC layer (enzymatic steps) grounds each step to a GO molecular-function term, the same EC <-> GO MF alignment used by the gluconeogenesis module. The REGULATORY layer is captured as connections of type POSITIVELY_REGULATES / NEGATIVELY_REGULATES whose predicate is grounded to a Systems Biology Ontology (SBO) term that distinguishes the MECHANISM (competitive vs allosteric), with the effector represented as a ChEBI-grounded metabolite-pool node. This regulatory wiring (small-molecule effector -> enzyme, with mechanism and sign) is information GO cannot express: GO annotations attach to gene products, the effectors here are metabolites, and GO has no competitive-vs-allosteric distinction. The regulatory structure is transcribed from the biosustain Maud kinetic model `data/methionine/methionine_cycle.toml`. A notable showcase is METAT, where two isozyme forms of methionine adenosyltransferase catalyse the SAME reaction but are OPPOSITELY regulated by SAM: MAT-I is competitively product-inhibited by SAM, whereas MAT-III is allosterically activated by SAM. Isozyme-specific regulation of this kind is the central thing GO flattens away. The core chemistry (SAM synthesis, transmethylation, SAH hydrolysis, homocysteine remethylation) is universal; the lineage-specific pieces are modelled as optional parts or variants. Fungi such as budding and fission yeast run the cycle with single-chain SAM synthetases (two paralogues in S. cerevisiae), a single adenosylhomocysteinase, and a cobalamin-independent (MetE-type) methionine synthase that uses 5-methyltetrahydropteroyl triglutamate; they have no glycine N-methyltransferase or betaine-homocysteine methyltransferase, whereas mammals use the cobalamin-dependent MetH-type enzyme plus hepatic BHMT and GNMT. The 5'-methylthioadenosine (MTA) salvage route back to methionine is a separate module (methionine_salvage_mta_cycle). |
Metabolic Pathway | DRAFT | 0 | methionine cycle |
19 | 11 | 11 | 2 | 7 | 23 | 17/21 | 7 | ✗ | Kinetic | modules/methionine_cycle.yaml | |
Mettl1-Wuho tRNA m7G46 methyltransferase in Drosophila melanogasterMODULE:dmel_mettl1_wuho_methyltransferaseCONCRETE The METTL1-WDR4 complex (Trm8-Trm82 in yeast) methylates guanosine 46 in the variable loop of many tRNAs at the N7 position, forming m7G46, which... [more...][less]The METTL1-WDR4 complex (Trm8-Trm82 in yeast) methylates guanosine 46 in the variable loop of many tRNAs at the N7 position, forming m7G46, which stabilizes tRNA structure. METTL1 is the S-adenosylmethionine-dependent catalytic subunit and the WD40-repeat protein WDR4 is required for its stability and activity. In Drosophila, the WDR4 ortholog is wuho (wh), which binds Mettl1 and is required for male and female germline development. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | tRNA (m7G46) methyltransferase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_mettl1_wuho_methyltransferase.yaml | |
Mevalonate pathway (acetyl-CoA -> isopentenyl diphosphate)MODULE:mevalonate_pathwayCONCRETE The eukaryotic (classical) mevalonate pathway converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl diphosphate... [more...][less]The eukaryotic (classical) mevalonate pathway converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl diphosphate (IPP), the precursor of sterols (cholesterol in animals, ergosterol in fungi), dolichol, ubiquinone (CoQ), heme A and the farnesyl/geranylgeranyl groups used for protein prenylation. A cytosolic acetoacetyl-CoA thiolase condenses two acetyl-CoA to acetoacetyl-CoA; HMG-CoA synthase adds a third acetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA reductase, the rate-limiting, sterol-feedback-regulated enzyme and target of the statin drugs, reduces HMG-CoA to mevalonate with two NADPH on the endoplasmic-reticulum membrane; mevalonate kinase and phosphomevalonate kinase then doubly phosphorylate mevalonate to mevalonate 5-diphosphate; and diphosphomevalonate decarboxylase decarboxylates it to IPP in an ATP-dependent reaction. The reaction chain is conserved across animals, fungi and plants, but the phosphomevalonate kinase step is carried out by two unrelated protein families: a GHMP-kinase-type enzyme (ERG8 type) in fungi, plants and bacteria, and a small P-loop kinase (PMVK type) that displaced it early in animal evolution. Fungi may carry two HMG-CoA reductase isozymes (budding yeast HMG1 and HMG2). Mevalonate kinase is a second, metabolite-level control point, competitively feedback-inhibited by downstream prenyl diphosphates. In humans, inherited defects cause mevalonate kinase deficiency (MVK; hyper-IgD/periodic fever syndrome to mevalonic aciduria) and porokeratosis (MVD and MVK); HMGCR and HMGCS1 are pharmacologic (statin), autoimmune and rare-myopathy loci rather than classic enzymopathies. |
Metabolic Pathway | DRAFT | 0 | isopentenyl diphosphate biosynthetic process, mevalonate pathway |
9 | 7 | 6 | 1 | 2 | 6 | 18/19 | 0 | ✗ | modules/mevalonate_pathway.yaml | ||
Microsomal fatty-acid elongation cycle (ELOVL or KCS -> KAR -> HACD -> ECR)MODULE:fatty_acid_elongation_cycle Most fatty acids longer than the C16 palmitate made by cytosolic fatty-acid synthase are produced by the microsomal elongation system, a... [more...][less]Most fatty acids longer than the C16 palmitate made by cytosolic fatty-acid synthase are produced by the microsomal elongation system, a four-reaction cycle on the cytosolic face of the endoplasmic-reticulum membrane that adds two carbons per turn. Each round begins with the rate-limiting, substrate-selective condensation of an acyl-CoA with malonyl-CoA to a 3-oxoacyl-CoA (releasing CO2), catalysed by one of seven fatty-acid elongases (ELOVL1-7) whose chain-length and saturation preferences define which fatty acids a cell makes: ELOVL1/3/6 handle saturated and monounsaturated substrates (ELOVL6 the C16->C18 lipogenic step, ELOVL1 the C22->C26 very-long-chain step for sphingolipids/myelin, ELOVL3 skin/brown-fat lipids), ELOVL2/5 the C20/C22 polyunsaturated fatty acids en route to DHA, ELOVL7 C18-C20 substrates, and ELOVL4 the unique ultra-long-chain (C26-C38) fatty acids of retina, skin and brain. The 3-oxoacyl-CoA is then reduced by the NADPH-dependent 3-ketoacyl-CoA reductase HSD17B12 (KAR) to (3R)-3-hydroxyacyl-CoA, dehydrated by the 3-hydroxyacyl-CoA dehydratases HACD1/HACD2 to (2E)-enoyl-CoA, and reduced by the NADPH-dependent trans-2-enoyl-CoA reductase TECR to the two-carbon-extended saturated acyl-CoA, which re-enters the cycle. The reductase/dehydratase/reductase enzymes are shared across all ELOVLs; substrate specificity resides in the elongase. Inherited defects span the products: ELOVL1 (IKSHD ichthyosis/spastic quadriplegia), ELOVL4 (Stargardt-like macular dystrophy, SCA34, ichthyosis), HACD1 (congenital myopathy), TECR (intellectual disability), reflecting the roles of very-long-chain and ultra-long-chain fatty acids in skin barrier, myelin, retina and muscle. Fungi use ELO-family elongases homologous to the ELOVLs, whose paralogs divide the chain-length range from medium-chain (C12-C14) to C26 substrates, together with orthologous reductase, dehydratase and enoyl reductase; the C26 product is the fatty acid of fungal sphingolipids. Plants run the same four-step cycle but use an unrelated condensing enzyme, the thiolase-fold 3-ketoacyl-CoA synthases (KCS; e.g. FAE1/KCS18 for seed erucic acid, CER6/KCS6 for cuticular wax), while the downstream steps are carried out by orthologs of the animal enzymes (KCR1, PAS2, ECR/CER10 in Arabidopsis). The condensation step is therefore modelled as alternative enzyme families, and the three shared steps list animal and plant exemplars. |
Metabolic Pathway | DRAFT | 1 | fatty acid elongation very long-chain fatty acid biosynthetic process |
7 | 5 | 4 | 1 | 2 | 4 | 27/30 | 0 | ✗ | modules/fatty_acid_elongation_cycle.yaml | ||
Mitochondrial ADP/ATP and phosphate carriers (ATP synthasome substrate carriers); SLC25A4/A5/A6 + SLC25A3MODULE:oxphos_adenine_nucleotide_phosphate_carriers Oxidative phosphorylation is completed not only by the five respiratory complexes but by the inner-membrane carriers that supply ATP synthase... [more...][less]Oxidative phosphorylation is completed not only by the five respiratory complexes but by the inner-membrane carriers that supply ATP synthase (Complex V) with its substrates and export its product. Because the inner membrane is impermeable to adenine nucleotides and phosphate, two SLC25 mitochondrial-carrier activities are essential: the ADP/ATP translocase (adenine nucleotide translocator, ANT) and the phosphate carrier (PiC). The ADP/ATP translocase is an electrogenic antiporter that imports cytosolic ADP into the matrix in exchange for newly synthesised ATP, exporting the ATP made by Complex V; humans express three near-identical isoforms with tissue-specific distribution — ANT1/SLC25A4 (heart and skeletal muscle), ANT2/SLC25A5 (proliferative and glycolytic tissues) and ANT3/SLC25A6 (ubiquitous). The phosphate carrier SLC25A3 (PiC) imports inorganic phosphate into the matrix in symport with a proton, providing the Pi consumed by ATP synthase. ANT, PiC and ATP synthase physically associate as the "ATP synthasome", coupling substrate delivery to ATP synthesis. The ADP/ATP translocase also forms part of the mitochondrial permeability transition pore and participates in apoptosis (curated as non-core roles). Disorders: ANT1 (SLC25A4) mutations cause autosomal-dominant progressive external ophthalmoplegia and mitochondrial myopathy/cardiomyopathy; SLC25A3 defects cause a mitochondrial phosphate-carrier deficiency with lactic acidosis and hypertrophic cardiomyopathy. |
Metabolic Pathway | DRAFT | 0 | oxidative phosphorylation |
3 | 4 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/oxphos_adenine_nucleotide_phosphate_carriers.yaml | ||
Mitochondrial ClpXP protease in Drosophila melanogasterMODULE:dmel_mitochondrial_clpxpCONCRETE ClpXP is an ATP-dependent protease of the mitochondrial matrix. Hexameric rings of the AAA+ unfoldase ClpX recognise substrates, unfold them and... [more...][less]ClpXP is an ATP-dependent protease of the mitochondrial matrix. Hexameric rings of the AAA+ unfoldase ClpX recognise substrates, unfold them and thread them into the barrel formed by two heptameric rings of the serine peptidase ClpP, where they are degraded. ClpXP contributes to matrix protein quality control and to the mitochondrial unfolded protein response. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | endopeptidase Clp complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_mitochondrial_clpxp.yaml | |
Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) accessory/supernumerary subunits; NDUFA1/2/5/6/8/10/11/12/13, NDUFB3/7/8/9/10/11, NDUFC2MODULE:complex_i_accessory_subunits Beyond its 14 conserved "core" subunits, mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase) carries ~30 nuclear-encoded accessory... [more...][less]Beyond its 14 conserved "core" subunits, mitochondrial respiratory Complex I (NADH:ubiquinone oxidoreductase) carries ~30 nuclear-encoded accessory (supernumerary) subunits that form a shell around the core L-shaped enzyme. These subunits are stable constituents of the mature holoenzyme (unlike the transient assembly factors) but are non-catalytic — they carry no redox cofactor and do not themselves perform the NADH:ubiquinone reaction. Their roles are structural: they stabilise and shield the core, seal the membrane arm, and are required for assembly and stability of a fully active complex. This module groups the human accessory subunits by which arm they decorate. The peripheral (matrix) arm accessory subunits — NDUFA2 (thioredoxin-fold), NDUFA5, NDUFA6, NDUFA12 (near the N/Q junction) and NDUFA13/GRIM-19 — buttress the flavoprotein and Q modules; NDUFA13 additionally has a well-documented moonlighting role as a negative regulator of STAT3 signalling and in apoptosis, curated separately from its structural role. The membrane arm accessory subunits — NDUFA1 (MWFE), NDUFA8 (twin-CX9C), NDUFA10, NDUFA11 (Tim17-like fold), NDUFB3, NDUFB7, NDUFB8, NDUFB9, NDUFB10 and NDUFB11 (several imported and disulfide-folded by the MIA40/CHCHD4 relay), and NDUFC2 — clamp the hydrophobic ND subunits. Loss of individual accessory subunits destabilises the holoenzyme and causes isolated mitochondrial complex I deficiency (Leigh syndrome, cardiomyopathy, leukoencephalopathy; NDUFB11 is X-linked, causing histiocytoid cardiomyopathy / MLS-like disease). |
Protein Complex | DRAFT | 0 | mitochondrial electron transport, NADH to ubiquinone |
3 | 16 | 2 | 0 | 0 | 1 | 16/16 | 0 | ✗ | modules/complex_i_accessory_subunits.yaml | ||
Mitochondrial Complex I (NADH:ubiquinone oxidoreductase) assembly factors; NDUFAF1-8/NUBPL/FOXRED1/TIMMDC1MODULE:complex_i_assembly_factors Biogenesis of respiratory Complex I (NADH:ubiquinone oxidoreductase) is the most factor-dependent of all OXPHOS assembly pathways: its ~45 subunits... [more...][less]Biogenesis of respiratory Complex I (NADH:ubiquinone oxidoreductase) is the most factor-dependent of all OXPHOS assembly pathways: its ~45 subunits (7 mtDNA-encoded membrane ND subunits and ~38 nuclear-encoded) are built as preassembled modules (N/Q/ND1/ND2/ND4/ND5) that are then joined, and this ordered process requires at least a dozen dedicated assembly factors that are not part of the mature holoenzyme. This module groups the human Complex I assembly factors by the step they serve. The membrane-arm (MCIA) machinery — NDUFAF1 (CIA30) together with ACAD9/ECSIT/ TMEM126B (reviewed with the core) and the multi-pass insertase-like scaffold TIMMDC1 — builds the ND2/membrane intermediates. The Q-module/mid-stage intermediate is chaperoned by the NDUFAF3– NDUFAF4 pair and by NDUFAF6. A set of factors covalently modify or metallate specific core subunits before they can be incorporated: NDUFAF5 hydroxylates a conserved arginine of NDUFS7, NDUFAF7 symmetrically dimethylates an arginine of NDUFS2, NUBPL (IND1) delivers the [4Fe-4S] clusters, and the FAD-dependent oxidoreductase-fold protein FOXRED1 is required for maturation of the late ~815 kDa intermediate (its substrate, if any, is unknown). Finally the late N-module is stabilised by NDUFAF2 (NDUFA12L) — a paralogue of the structural subunit NDUFA12 that binds transiently and is released from the mature enzyme — together with NDUFAF8, which is imported by the MIA40 disulfide relay and cooperates with NDUFAF5. Loss of any of these factors causes mitochondrial complex I deficiency, the commonest inborn OXPHOS defect — Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis, hypertrophic cardiomyopathy and encephalopathy. |
Metabolic Pathway | DRAFT | 0 | mitochondrial respiratory chain complex I assembly |
5 | 11 | 4 | 0 | 0 | 3 | 11/11 | 0 | ✗ | modules/complex_i_assembly_factors.yaml | ||
Mitochondrial Complex IV (cytochrome c oxidase) assembly factors; TACO1/COA3/COX11/SCO1/COA6/COX16/COA5/COX18/COA7/PET100/PET117MODULE:complex_iv_assembly_factors Assembly of cytochrome c oxidase (Complex IV) around its three mtDNA-encoded catalytic subunits (MT-CO1, MT-CO2, MT-CO3) is a highly ordered,... [more...][less]Assembly of cytochrome c oxidase (Complex IV) around its three mtDNA-encoded catalytic subunits (MT-CO1, MT-CO2, MT-CO3) is a highly ordered, factor-dependent process, because the copper and heme redox centres must be built into hydrophobic membrane proteins in the correct sequence. This module groups the dedicated assembly factors by the step they serve. Synthesis of the central MT-CO1 subunit is activated by the matrix RNA-binding translational activator TACO1 (which binds the MT-CO1 mRNA on the mitoribosome), and the nascent MT-CO1 is captured and stabilised by the MITRAC module (COA3/CCDC56 with COX14) that couples its translation to assembly. The MT-CO1 CuB site is metallated by the copper chaperone COX11, while the MT-CO2 CuA site is built by an intermembrane-space copper-relay/thiol-redox system — COA6 and COA7 (twin CX9C protein-disulfide reductases), COX16 and COA5 — acting with the SCO1/SCO2 metallochaperones (reviewed elsewhere). MT-CO2 itself is threaded into the membrane by the OXA1L-family insertase COX18 (with COX20). Finally, PET100 and PET117 are small chaperones that promote incorporation of the early nuclear-encoded subunits (COX7/COX8) to complete the holoenzyme. Loss of any factor causes mitochondrial complex IV (cytochrome c oxidase) deficiency — Leigh syndrome, fatal infantile cardioencephalomyopathy (COA5/COA6), axonal neuropathy with leukoencephalopathy (COA7) and other encephalopathies. |
Metabolic Pathway | DRAFT | 0 | mitochondrial respiratory chain complex IV assembly |
6 | 11 | 5 | 0 | 0 | 4 | 11/11 | 0 | ✗ | modules/complex_iv_assembly_factors.yaml | ||
Mitochondrial DNA replisome in Drosophila melanogasterMODULE:dmel_mitochondrial_dna_replisomeCONCRETE Mitochondrial DNA is copied by a dedicated replisome in the mitochondrial matrix that is separate from the nuclear replication machinery. DNA... [more...][less]Mitochondrial DNA is copied by a dedicated replisome in the mitochondrial matrix that is separate from the nuclear replication machinery. DNA polymerase gamma, a heterodimer of the catalytic subunit PolG1 and the accessory subunit PolG2, synthesizes DNA and proofreads it. The mitochondrial replicative helicase (mtDNA-helicase, the ortholog of human Twinkle) unwinds the duplex ahead of the polymerase, and the mitochondrial single-stranded DNA-binding protein mtSSB coats the displaced strand and stimulates both enzymes. Mutations in these genes in Drosophila reduce mtDNA copy number. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | replisome |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/dmel_mitochondrial_dna_replisome.yaml | |
Mitochondrial aminoacyl-tRNA charging and initiator Met-tRNA formylation (human); AARS2/DARS2/TARS2 + MTFMTMODULE:mitochondrial_trna_charging_and_initiator_formylation Translation in mitochondria uses the 22 tRNAs encoded by mitochondrial DNA, which are charged with their amino acids in the mitochondrial matrix by... [more...][less]Translation in mitochondria uses the 22 tRNAs encoded by mitochondrial DNA, which are charged with their amino acids in the mitochondrial matrix by a separate set of nuclear-encoded aminoacyl-tRNA synthetases (the "2" synthetases, for example AARS2, DARS2 and TARS2). Each synthetase activates its amino acid with ATP and transfers it to the cognate mitochondrial tRNA. A single mitochondrial tRNA(Met) serves both initiation and elongation; the fraction destined for initiation is formylated on its methionyl group by methionyl-tRNA formyltransferase (MTFMT), using 10-formyltetrahydrofolate, to give fMet-tRNA(Met), which is recognized by the mitochondrial initiation factor and used to start synthesis of the 13 mtDNA-encoded respiratory-chain subunits. Biallelic variants in the mitochondrial synthetases cause tissue-selective disorders (for example DARS2 leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation, AARS2 infantile cardiomyopathy or adult leukoencephalopathy with ovarian failure, TARS2 combined oxidative phosphorylation deficiency), and MTFMT variants cause Leigh syndrome and combined oxidative phosphorylation deficiency 15. |
Biological Process | DRAFT | Homo sapiens |
0 | tRNA aminoacylation for mitochondrial protein translation conversion of methionyl-tRNA to N-formyl-methionyl-tRNA |
6 | 4 | 2 | 1 | 3 | 1 | 4/4 | 0 | ✗ | modules/mitochondrial_trna_charging_and_initiator_formylation.yaml | |
Mitochondrial and cytosolic iron-sulfur cluster assembly in Drosophila melanogasterMODULE:dmel_iron_sulfur_cluster_assemblyCONCRETE Iron-sulfur (Fe-S) clusters are cofactors of respiratory complexes, the TCA cycle, DNA replication and repair enzymes and many other proteins. In... [more...][less]Iron-sulfur (Fe-S) clusters are cofactors of respiratory complexes, the TCA cycle, DNA replication and repair enzymes and many other proteins. In eukaryotes all clusters depend on the mitochondrial iron-sulfur cluster (ISC) machinery. In the matrix, the cysteine desulfurase Nfs1, stabilised by Isd11 (bcn92) and acyl-ND-ACP, supplies sulfur and frataxin (fh) stimulates assembly of a [2Fe-2S] cluster on the scaffold IscU, with electrons from ferredoxin (Fdx1) and ferredoxin reductase (dare). The Hsc20-Hsc70-5 chaperone pair with glutaredoxin 5 transfers the cluster to client proteins, and the ISA proteins (MagR, CG13623) with IBA57 (CG8043) convert [2Fe-2S] into [4Fe-4S] clusters for mitochondrial targets. A sulfur-containing compound made by the ISC machinery is exported by the ABC transporter Abcb7 and used by the cytosolic iron-sulfur protein assembly (CIA) system: the diflavin reductase CG13667 and anamorsin (Ciapin1) supply electrons, the Nubp1-Nubp2 scaffold builds [4Fe-4S] clusters, and the CIA targeting complex (Ciao1, CG17683, galla2 and Mms19) inserts them into cytosolic and nuclear apoproteins. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | iron-sulfur cluster assembly |
11 | 13 | 10 | 0 | 0 | 7 | 0/22 | 0 | ✗ | modules/dmel_iron_sulfur_cluster_assembly.yaml | |
Mitochondrial calcium uniporter complex in Drosophila melanogasterMODULE:dmel_mitochondrial_calcium_uniporterCONCRETE The mitochondrial calcium uniporter carries Ca2+ across the inner mitochondrial membrane, driven by the membrane potential. The pore is formed by... [more...][less]The mitochondrial calcium uniporter carries Ca2+ across the inner mitochondrial membrane, driven by the membrane potential. The pore is formed by MCU together with the small single-pass protein EMRE, which is required for uniporter activity in animals. On the intermembrane space side, the EF-hand proteins of the MICU family act as Ca2+-sensing gatekeepers that keep the channel closed at resting Ca2+ and open it when Ca2+ rises. FlyBase defines a complex with MICU1 and MICU3 and a variant in which the EF-hand protein CG4704 takes the place of MICU1. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | uniplex complex |
5 | 3 | 2 | 1 | 2 | 0 | 5/5 | 0 | ✗ | modules/dmel_mitochondrial_calcium_uniporter.yaml | |
Mitochondrial cofactor/coenzyme carriers (SLC25A19 ThPP, SLC25A26 SAM, SLC25A32 FAD, SLC25A42 CoA)MODULE:mitochondrial_cofactor_carriers Many essential enzyme cofactors and coenzymes are synthesised (wholly or partly) in the cytosol but are required by enzymes inside the... [more...][less]Many essential enzyme cofactors and coenzymes are synthesised (wholly or partly) in the cytosol but are required by enzymes inside the mitochondrial matrix, which the inner membrane keeps impermeable. A set of SLC25 mitochondrial-carrier proteins solves this by importing specific cofactors into the matrix. This module groups the human cofactor/coenzyme carriers. SLC25A19 imports thiamine pyrophosphate (ThPP), the cofactor of the matrix 2-oxo-acid dehydrogenases (pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain ketoacid dehydrogenase) and transketolase-like enzymes; SLC25A26 is the only carrier that imports S-adenosylmethionine (SAM), the methyl donor for matrix methyltransferases (mtDNA/RNA methylation and cofactor maturation), exchanging it for the product S-adenosylhomocysteine; SLC25A32 imports FAD (and is linked to mitochondrial folate/one-carbon metabolism); and SLC25A42 imports coenzyme A (CoA), needed for matrix acyl-CoA metabolism (fatty-acid oxidation and the TCA cycle), in exchange for intramitochondrial adenine nucleotides. Loss-of-function of these carriers causes cofactor-specific mitochondrial diseases: SLC25A19 — Amish lethal microcephaly and bilateral striatal necrosis/polyneuropathy (THMD3/4); SLC25A26 — combined oxidative phosphorylation deficiency 28; SLC25A32 — riboflavin/folate-responsive exercise intolerance and myopathy; SLC25A42 — a mitochondrial myopathy with episodic metabolic crises. |
Metabolic Pathway | DRAFT | 0 | thiamine pyrophosphate transmembrane transport mitochondrial S-adenosyl-L-methionine transmembrane transport mitochondrial FAD transmembrane transport mitochondrial coenzyme A transmembrane transport |
2 | 4 | 1 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/mitochondrial_cofactor_carriers.yaml | ||
Mitochondrial dNTP supply for mtDNA maintenance — MNGIE and mtDNA depletion syndromesMODULE:mitochondrial_dntp_supply Faithful replication of mitochondrial DNA (mtDNA), including in post-mitotic tissues, requires a balanced supply of the four deoxyribonucleoside... [more...][less]Faithful replication of mitochondrial DNA (mtDNA), including in post-mitotic tissues, requires a balanced supply of the four deoxyribonucleoside triphosphates (dNTPs) inside mitochondria. Because mitochondria cannot rely on the cell-cycle-regulated cytosolic de novo machinery, they use a dedicated salvage pathway plus a p53-inducible de novo input, and depend on cytosolic enzymes that keep nucleoside pools balanced. The mitochondrial deoxyribonucleoside kinases phosphorylate imported deoxyribonucleosides to dNMPs: thymidine kinase 2 (TK2) handles the pyrimidines (thymidine, deoxycytidine, deoxyuridine) and deoxyguanosine kinase (DGUOK) the purines (deoxyguanosine, deoxyadenosine). The p53-inducible ribonucleotide reductase small subunit RRM2B (p53R2), with RRM1, provides de novo deoxyribonucleoside diphosphates (dNDPs) by reducing NDPs — the main dNTP source for quiescent cells and mtDNA. Cytosolic thymidine phosphorylase (TYMP) governs systemic thymidine/deoxyuridine levels; its loss floods the dNTP pool with thymidine-derived nucleotides and destabilises mtDNA. Together these enzymes maintain the mitochondrial dNTP balance; imbalance (excess or deficiency) causes mtDNA depletion/deletions. Inherited defects are the classic mtDNA-maintenance disorders: TYMP -> MNGIE; TK2 -> myopathic mtDNA depletion; DGUOK -> hepatocerebral mtDNA depletion; RRM2B -> encephalomyopathic mtDNA depletion and dominant progressive external ophthalmoplegia. |
Metabolic Pathway | DRAFT | 0 | deoxyribonucleotide biosynthetic process |
5 | 4 | 4 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/mitochondrial_dntp_supply.yaml | ||
Mitochondrial degradosome in Drosophila melanogasterMODULE:dmel_mitochondrial_degradosomeCONCRETE The mitochondrial degradosome degrades mitochondrial RNA in the matrix. It is formed by the ATP-dependent RNA helicase Suv3, which unwinds... [more...][less]The mitochondrial degradosome degrades mitochondrial RNA in the matrix. It is formed by the ATP-dependent RNA helicase Suv3, which unwinds structured RNA, and the exoribonuclease PNPase, which degrades RNA 3' to 5' by phosphorolysis. The complex turns over mRNAs and removes non-coding and antisense transcripts produced by the bidirectional transcription of the mitochondrial genome. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | mitochondrial degradosome |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_mitochondrial_degradosome.yaml | |
Mitochondrial di-/tricarboxylate and glutamate carriers (SLC25A1 citrate, SLC25A10 dicarboxylate, SLC25A21 oxodicarboxylate, SLC25A22 glutamate)MODULE:mitochondrial_dicarboxylate_tricarboxylate_carriers The tricarboxylic-acid (TCA) cycle both consumes and generates carbon skeletons that must move between the mitochondrial matrix and the cytosol for... [more...][less]The tricarboxylic-acid (TCA) cycle both consumes and generates carbon skeletons that must move between the mitochondrial matrix and the cytosol for anabolism (lipogenesis, gluconeogenesis) and amino-acid metabolism. A set of SLC25 mitochondrial carriers exchanges these di- and tricarboxylate intermediates and related amino acids across the impermeable inner membrane. This module groups four such carriers. The citrate carrier SLC25A1 (CIC/CTP) exports matrix citrate in exchange for cytosolic malate, feeding cytosolic citrate lysis into acetyl-CoA (and NADPH) for fatty-acid and cholesterol synthesis. The dicarboxylate carrier SLC25A10 (DIC) exchanges malate or succinate for inorganic phosphate, supplying dicarboxylates for gluconeogenesis and lipogenesis and linking to sulfur metabolism. The oxodicarboxylate carrier SLC25A21 (ODC) transports the C5-C7 2-oxodicarboxylates 2-oxoadipate and 2-oxoglutarate, serving the mitochondrial steps of lysine and tryptophan degradation. The glutamate carrier SLC25A22 (GC1) imports L-glutamate in symport with a proton, feeding glutamate catabolism and ammonia handling (and, in neurons, glutamate metabolism). Loss-of-function causes distinct metabolic diseases: SLC25A1 — combined D-2- and L-2-hydroxyglutaric aciduria and a congenital myasthenic syndrome; SLC25A22 — early infantile epileptic encephalopathy with migrating partial seizures; and SLC25A21 has been linked to a 2-oxoadipate/2-oxoglutarate-dehydrogenase-related phenotype. |
Metabolic Pathway | DRAFT | 0 | mitochondrial citrate transmembrane transport malate transmembrane transport mitochondrial alpha-ketoglutarate transmembrane transport L-glutamate transmembrane transport |
2 | 4 | 1 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/mitochondrial_dicarboxylate_tricarboxylate_carriers.yaml | ||
Mitochondrial fatty acid beta-oxidation spiral (cross-species)MODULE:fatty_acid_beta_oxidation The core four-step spiral of mitochondrial fatty acid beta-oxidation, by which saturated fatty acyl-CoA esters are degraded two carbons at a time,... [more...][less]The core four-step spiral of mitochondrial fatty acid beta-oxidation, by which saturated fatty acyl-CoA esters are degraded two carbons at a time, releasing one acetyl-CoA and a chain-shortened acyl-CoA per turn that re-enters the cycle. The four obligate reactions are (1) FAD-dependent alpha,beta-dehydrogenation of acyl-CoA to (2E)-enoyl-CoA by an acyl-CoA dehydrogenase; (2) hydration of the trans double bond to (3S)-3-hydroxyacyl-CoA by an enoyl-CoA hydratase; (3) NAD+-dependent oxidation to 3-ketoacyl-CoA by a 3-hydroxyacyl-CoA dehydrogenase; and (4) thiolytic cleavage by a 3-ketoacyl-CoA thiolase to yield acetyl-CoA plus an acyl-CoA shortened by two carbons. Each step is carried out by a family of chain-length-specific isozymes: as the acyl chain shortens through successive turns of the spiral, the enzyme that acts changes. The long-chain steps 2-4 are performed by the membrane-bound mitochondrial trifunctional protein (MTP, an alpha2-beta2 heterotetramer whose alpha subunit carries the hydratase and dehydrogenase activities and whose beta subunit carries the thiolase), whereas the medium- and short-chain steps are carried out by separate soluble matrix enzymes. This module is built cross-species: each catalytic role is grounded with both the human enzyme(s) and the Drosophila melanogaster ortholog(s), so the conserved enzymatic logic and the species-specific gene complement can be compared directly. The chain-length axis is modelled as a variant set at each step; "use MF specific for chain length" where such a molecular-function term exists, with a fall-back to the general activity where it does not. This module covers the SATURATED spiral. Degradation of UNSATURATED fatty acids additionally requires an auxiliary-enzyme cassette - a delta(3),delta(2)-enoyl-CoA isomerase (fly mitochondrial CG4592/CG4594/CG4598 vs peroxisomal Dci), a delta(3,5),delta(2,4)-dienoyl-CoA isomerase (fly Ech1), and a 2,4-dienoyl-CoA reductase (DECR1, for which no clean Drosophila ortholog is currently assignable) - which are curated in the project but not modelled as variant sets here; see the Fatty Acid beta-Oxidation project page (unsaturated cassette section) for details. |
Metabolic Pathway | DRAFT | 0 | fatty acid beta-oxidation |
15 | 10 | 4 | 4 | 10 | 4 | 21/21 | 0 | ✗ | modules/fatty_acid_beta_oxidation.yaml | ||
Mitochondrial fission and fusionMODULE:mitochondrial_dynamicsCONCRETE In animals and fungi, mitochondrial shape is set by a balance between fission and fusion carried out by three classes of dynamin-family GTPases.... [more...][less]In animals and fungi, mitochondrial shape is set by a balance between fission and fusion carried out by three classes of dynamin-family GTPases. Fission of the outer membrane is driven by a dynamin-related protein (DNM1L/Drp1 in mammals, Dnm1 in budding yeast, DRP-1 in nematodes) that is recruited from the cytosol to constriction sites on the outer membrane. There it assembles into helices and uses GTP hydrolysis to constrict and sever the organelle. The same dynamin also divides peroxisomes. Recruitment depends on outer-membrane receptors whose identity differs between lineages: the tail-anchored adaptor MFF in animals, and Fis1 with the adaptors Mdv1 and Caf4 in budding yeast. In nematodes, the two MFF paralogs promote fission but are not essential for recruiting DRP-1. Fusion happens in two membrane-specific steps. Mitofusins (MFN1/MFN2, Fzo1, FZO-1) tether and fuse outer membranes. OPA1 and its orthologs (Mgm1 in yeast, EAT-3 in nematodes) fuse inner membranes; human L-OPA1 does this together with cardiolipin on the opposing membrane. When fusion is lost, unopposed fission fragments the mitochondrial network, and this fragmentation needs the fission dynamin. When fission is lost, the network becomes hyperconnected. The balance between the two is used in stress responses and in segregating damaged mitochondria for mitophagy. |
Biological Process | DRAFT | Opisthokonta |
5 | mitochondrion organization |
4 | 4 | 3 | 0 | 0 | 1 | 10/10 | 0 | ✗ | modules/mitochondrial_dynamics.yaml | |
Mitochondrial glutamyl-tRNA(Gln) amidotransferase (GatCAB) in Drosophila melanogasterMODULE:dmel_glutamyl_trna_amidotransferaseCONCRETE In mitochondria of animals there is no glutaminyl-tRNA synthetase. Instead, mitochondrial tRNA-Gln is first mischarged with glutamate by the... [more...][less]In mitochondria of animals there is no glutaminyl-tRNA synthetase. Instead, mitochondrial tRNA-Gln is first mischarged with glutamate by the non-discriminating mitochondrial glutamyl-tRNA synthetase, and the heterotrimeric GatCAB amidotransferase converts the bound glutamate to glutamine. GatA is a glutaminase that releases ammonia from glutamine, GatB phosphorylates the glutamate and transfers the ammonia to form Gln-tRNA(Gln), and GatC is a small subunit that stabilizes the complex. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | glutamyl-tRNA(Gln) amidotransferase complex |
4 | 4 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_glutamyl_trna_amidotransferase.yaml | |
Mitochondrial iron-sulfur cluster assembly (core ISC machinery)MODULE:mitochondrial_iron_sulfur_cluster_assemblyCONCRETE Mitochondria build [2Fe-2S] clusters with the iron-sulfur cluster (ISC) machinery, the one function retained by every mitochondrion-related... [more...][less]Mitochondria build [2Fe-2S] clusters with the iron-sulfur cluster (ISC) machinery, the one function retained by every mitochondrion-related organelle, including mitosomes and hydrogenosomes that have lost respiration. This module is the eukaryote-wide core of that machinery, written so that it can be evaluated in any genome: the NFS1-ISD11 cysteine desulfurase that mobilizes sulfur; the ISCU scaffold on which the cluster is built, with frataxin as its allosteric activator; and the HSCB-mtHsp70 chaperone pair that releases the cluster to the GLRX5 carrier for delivery. |
Biological Process | DRAFT | Eukaryota |
7 | [2Fe-2S] cluster assembly |
4 | 7 | 3 | 0 | 0 | 2 | 7/7 | 0 | ✗ | modules/mitochondrial_iron_sulfur_cluster_assembly.yaml | |
Mitochondrial nucleotide and glycine carriers (SLC25A24 ATP-Mg/Pi, SLC25A36 pyrimidine nucleotide, SLC25A38 glycine)MODULE:mitochondrial_nucleotide_glycine_carriers Mitochondria must import nucleotides and amino-acid precursors that are needed inside the matrix for mtDNA/RNA synthesis and for biosynthetic... [more...][less]Mitochondria must import nucleotides and amino-acid precursors that are needed inside the matrix for mtDNA/RNA synthesis and for biosynthetic pathways confined to the organelle. This module groups three SLC25 inner-membrane carriers that supply such precursors. SLC25A24 (APC1/SCaMC-1) is a Ca2+-regulated ATP-Mg/phosphate carrier that exchanges cytosolic Mg-ATP (or ADP) for matrix inorganic phosphate, adjusting the total matrix adenine-nucleotide pool in response to cytosolic calcium via its N-terminal EF-hand domain. SLC25A36 (PNC1) is the pyrimidine nucleotide carrier that transports pyrimidine (and, less well, purine) nucleotides across the inner membrane, maintaining the mitochondrial nucleotide pool for replication and transcription. SLC25A38 is the glycine carrier that imports glycine into the matrix, providing the substrate for the first, committed step of heme biosynthesis (ALA synthase: glycine + succinyl-CoA -> 5-aminolevulinate) in erythroid cells, as well as for mitochondrial glycine/one-carbon metabolism. Loss-of-function causes precursor-specific disease: SLC25A24 — Fontaine progeroid syndrome (Gorlin-Chaudhry-Moss); SLC25A38 — autosomal-recessive congenital sideroblastic anemia. |
Metabolic Pathway | DRAFT | 0 | mitochondrial ATP transmembrane transport pyrimidine nucleotide import into mitochondrion glycine import into mitochondrion |
2 | 3 | 1 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/mitochondrial_nucleotide_glycine_carriers.yaml | ||
Mitochondrial protein import machineryMODULE:mitochondrial_protein_importCONCRETE Nearly all mitochondrial proteins are made in the cytosol and imported. This module is the eukaryote-wide core of that machinery, written so that... [more...][less]Nearly all mitochondrial proteins are made in the cytosol and imported. This module is the eukaryote-wide core of that machinery, written so that it can be evaluated in any genome: the Tom40 outer-membrane pore through which most precursors enter; the Sam50 beta-barrel insertase; the TIM23 presequence translocase with its Hsp70-based import motor; the TIM22 carrier insertase; the intermembrane-space disulfide relay; and the mitochondrial processing peptidase that removes presequences. Optional parts are components missing from some eukaryotic lineages: receptors that PAINT places only in opisthokonts, and Mia40, which kinetoplastids lack. |
Biological Process | DRAFT | Eukaryota Opisthokonta |
12 | mitochondrial protein import pathway |
10 | 16 | 9 | 0 | 0 | 6 | 16/16 | 0 | ✗ | modules/mitochondrial_protein_import.yaml | |
Mitochondrial protein import machinery in Drosophila melanogasterMODULE:dmel_mitochondrial_protein_importCONCRETE Most mitochondrial proteins are made on cytosolic ribosomes and imported post-translationally. Nearly all enter through the TOM complex of the... [more...][less]Most mitochondrial proteins are made on cytosolic ribosomes and imported post-translationally. Nearly all enter through the TOM complex of the outer membrane, whose channel is formed by Tom40. Beta-barrel outer membrane proteins are then handed by the small TIM chaperones of the intermembrane space to the SAM complex for insertion. Carrier-type inner membrane proteins are inserted by the TIM22 complex, and presequence-bearing precursors are translocated by the TIM23 complex, driven into the matrix by the presequence translocase-associated motor (PAM) built around mitochondrial Hsp70 (Hsc70-5). Matrix presequences are removed by the mitochondrial processing peptidase, and some intermembrane space-sorted precursors are further cleaved by the inner membrane peptidase. Cysteine-rich intermembrane space proteins are imported and oxidatively folded by the Mia40-Alr disulfide relay. Drosophila has testis-specific paralogs of several subunits (for example tomboy40, tomboy20 and several Tim17 and Tim50 paralogs). |
Biological Process | DRAFT | Drosophila melanogaster |
0 | mitochondrial protein import pathway |
21 | 32 | 12 | 3 | 8 | 7 | 0/47 | 0 | ✗ | modules/dmel_mitochondrial_protein_import.yaml | |
Mitochondrial respiratory Complex I core (NADH:ubiquinone oxidoreductase) — catalytic N and Q modules and membrane-arm core; NDUFV1/NDUFV2/NDUFS1-3/NDUFS6-8/NDUFA9, MT-ND1/MT-ND5/MT-ND6MODULE:mitochondrial_complex_i_core Respiratory Complex I (NADH:ubiquinone oxidoreductase) is the largest enzyme of the electron transport chain and its main entry point: it oxidises... [more...][less]Respiratory Complex I (NADH:ubiquinone oxidoreductase) is the largest enzyme of the electron transport chain and its main entry point: it oxidises NADH, passes the electrons through a chain of flavin and iron-sulfur cofactors to reduce ubiquinone, and uses the energy released to pump four protons across the inner membrane. This module covers the catalytic core of the L-shaped peripheral (matrix) arm — the seven conserved "core" nuclear subunits plus the closely associated flavoprotein subunits — together with representative mtDNA-encoded core subunits of the membrane arm, organised into three functional modules. The N-module (NADH-oxidising) holds the flavin site: NDUFV1 (51 kDa) binds FMN and the NADH substrate, NDUFV2 (24 kDa) carries the first [2Fe-2S] cluster (N1a), and NDUFS1 (75 kDa) provides further Fe-S clusters, forming the flavoprotein (FP) subcomplex with the accessory NDUFS6. The Q-module (ubiquinone-reducing) forms the wire to the quinone site: NDUFS2 (49 kDa) and NDUFS3 (30 kDa) are cofactor-less core subunits shaping the ubiquinone cavity, NDUFS7 (PSST) coordinates the terminal [4Fe-4S] cluster N2 that donates electrons to ubiquinone, NDUFS8 (TYKY) carries the N6a/N6b [4Fe-4S] clusters of the electron-transfer wire, and the accessory NDUFA9 (SDR-fold, structural NADPH) stabilises the Q-module/membrane-arm junction; NDUFS4 is an accessory subunit required for assembly and stability of the whole peripheral arm. The P-module (membrane arm, proton-pumping) is represented by three of its seven mtDNA-encoded core subunits: MT-ND1 lines the quinone-channel exit and begins the E-channel, MT-ND6 forms part of the E-channel, and MT-ND5 is the distal antiporter-like subunit; each contributes to proton translocation within the assembled complex. Inherited defects in these core subunits are among the commonest causes of mitochondrial complex I deficiency — typically Leigh syndrome, leukoencephalopathy, fatal infantile lactic acidosis or encephalocardiomyopathy. |
Protein Complex | DRAFT | 0 | mitochondrial electron transport, NADH to ubiquinone mitochondrial respiratory chain complex I assembly |
5 | 13 | 4 | 0 | 0 | 3 | 13/13 | 0 | ✗ | modules/mitochondrial_complex_i_core.yaml | ||
Mitochondrial respiratory Complex II (succinate dehydrogenase) + assembly factors; SDHA/SDHB/SDHC/SDHD + SDHAF1/SDHAF2MODULE:mitochondrial_complex_ii Respiratory Complex II (succinate dehydrogenase, SDH) is the only enzyme shared between the tricarboxylic acid (TCA) cycle and the mitochondrial... [more...][less]Respiratory Complex II (succinate dehydrogenase, SDH) is the only enzyme shared between the tricarboxylic acid (TCA) cycle and the mitochondrial electron transport chain. It oxidises succinate to fumarate in the matrix and feeds the released electrons into the ubiquinone pool, without pumping protons. The holoenzyme is a heterotetramer anchored in the inner membrane: the flavoprotein subunit SDHA carries a covalently bound FAD and the succinate-oxidising active site; the iron-sulfur subunit SDHB relays the electrons through three Fe-S clusters ([2Fe-2S], [4Fe-4S], [3Fe-4S]); and the two integral-membrane subunits SDHC and SDHD form the membrane anchor, bind a single heme b and provide the ubiquinone-reduction site. Two dedicated matrix assembly factors build the soluble catalytic head before it docks onto the membrane anchor: SDHAF2 (SDH5) promotes the covalent attachment of FAD to SDHA (flavinylation), and SDHAF1 — a LYR-motif protein acting with the HSC20/HSPA9 Fe-S co-chaperone system — delivers and inserts the iron-sulfur clusters into SDHB. Germline defects in the SDH subunits and assembly factors cause hereditary paraganglioma-pheochromocytoma syndromes and, when biallelic, mitochondrial complex II deficiency (Leigh syndrome, leukoencephalopathy, cardiomyopathy). |
Protein Complex | DRAFT | 0 | mitochondrial electron transport, succinate to ubiquinone mitochondrial respiratory chain complex II assembly |
3 | 6 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/mitochondrial_complex_ii.yaml | ||
Mitochondrial respiratory Complex III (cytochrome bc1) — subunits and assembly; UQCRC1/UQCRC2/UQCRB/UQCRQ/UQCRH/UQCRFS1/CYC1 + BCS1L/LYRM7/TTC19/UQCC2/UQCC3MODULE:mitochondrial_complex_iii Respiratory Complex III (ubiquinol-cytochrome c oxidoreductase, the cytochrome bc1 complex) is the central proton-pumping enzyme of the... [more...][less]Respiratory Complex III (ubiquinol-cytochrome c oxidoreductase, the cytochrome bc1 complex) is the central proton-pumping enzyme of the mitochondrial electron transport chain: it oxidises ubiquinol and reduces cytochrome c through the protonmotive Q cycle, contributing to the transmembrane proton gradient that drives ATP synthesis. The functional complex is a homodimer, each protomer built from cytochrome b (mtDNA-encoded MT-CYB) and ten nuclear-encoded subunits. The three redox centres reside in cytochrome b (the two b-hemes and the Qo/Qi ubiquinone sites), the Rieske iron-sulfur protein UQCRFS1 (the [2Fe-2S] cluster), and cytochrome c1 (CYC1); the hinge protein UQCRH mediates the cytochrome c1-cytochrome c electron-transfer interface. The two large "core proteins" UQCRC1 and UQCRC2 (peptidase-M16-fold but non-catalytic) and the small subunits UQCRB and UQCRQ are structural, providing the scaffold and the ubiquinone-binding environment. Assembly is stepwise and requires dedicated factors: UQCC2 (with UQCC1) stabilises and promotes translation of MT-CYB to nucleate the complex; UQCC3 stabilises the cytochrome-b assembly intermediate and (via cardiolipin binding) supports supercomplex organisation; LYRM7 is a matrix chaperone that holds apo-UQCRFS1 before [2Fe-2S] insertion; BCS1L is the AAA-ATPase translocase that inserts the matured Rieske protein into the nearly complete complex; and TTC19 clears the UQCRFS1 N-terminal fragments generated during Rieske maturation. Inherited defects in the subunits or assembly factors cause mitochondrial complex III deficiency (a spectrum of encephalopathy, leukoencephalopathy, lactic acidosis, tubulopathy and — for BCS1L — GRACILE syndrome). |
Protein Complex | DRAFT | 0 | mitochondrial electron transport, ubiquinol to cytochrome c mitochondrial respiratory chain complex III assembly |
3 | 12 | 2 | 0 | 0 | 1 | 12/12 | 0 | ✗ | modules/mitochondrial_complex_iii.yaml | ||
Mitochondrial respiratory Complex IV (cytochrome c oxidase) — nuclear subunits and MT-CO1/CO2 assembly; COX5A/COX6A2/COX7B/COX8A + COX14/COX20MODULE:mitochondrial_complex_iv Respiratory Complex IV (cytochrome c oxidase, COX) is the terminal enzyme of the mitochondrial electron transport chain: it accepts electrons from... [more...][less]Respiratory Complex IV (cytochrome c oxidase, COX) is the terminal enzyme of the mitochondrial electron transport chain: it accepts electrons from reduced cytochrome c and uses them to reduce molecular oxygen to water, coupling this to proton pumping across the inner membrane. The three catalytic core subunits — MT-CO1 (the heme a/a3-CuB binuclear centre), MT-CO2 (the CuA centre) and MT-CO3 — are encoded by mitochondrial DNA; around ten nuclear-encoded structural subunits (COX4, COX5A, COX5B, COX6A/B/C, COX7A/B/C, COX8) surround and stabilise this core and modulate activity. Because the catalytic subunits are mtDNA-encoded and membrane-embedded, COX assembly is a highly ordered process guided by dedicated inner-membrane factors: COX14 (with COA3/MITRAC) couples MT-CO1 translation to its stepwise assembly, and COX20 chaperones the newly-made MT-CO2 through membrane insertion (with COX18) and copper (CuA) metallation by SCO1/SCO2, before the nuclear subunits are added. Inherited defects in the nuclear subunits or the assembly factors cause mitochondrial complex IV (cytochrome c oxidase) deficiency — a clinically heterogeneous group including Leigh syndrome, cardiomyopathy (COX6A2), X-linked linear skin defects with multiple congenital anomalies (COX7B) and encephalopathy/ataxia. |
Protein Complex | DRAFT | 0 | mitochondrial electron transport, cytochrome c to oxygen mitochondrial respiratory chain complex IV assembly |
3 | 7 | 2 | 0 | 0 | 1 | 7/7 | 0 | ✗ | modules/mitochondrial_complex_iv.yaml | ||
Mitochondrial respiratory Complex V (F1Fo ATP synthase) — subunits and F1 assembly; ATP5F1A/ATP5F1B/ATP5F1D/ATP5F1E/ATP5PO/ATP5MC3/ATP5MD + ATPAF2/TMEM70MODULE:mitochondrial_complex_v Complex V, the F1Fo ATP synthase, is the terminal enzyme of oxidative phosphorylation: it uses the proton-motive force generated by the electron... [more...][less]Complex V, the F1Fo ATP synthase, is the terminal enzyme of oxidative phosphorylation: it uses the proton-motive force generated by the electron transport chain (Complexes I-IV) to drive the synthesis of ATP from ADP and inorganic phosphate. It is a rotary molecular motor with two coupled sectors. The membrane-embedded Fo sector — the c-ring (ATP5MC1/2/3), the a-subunit (mtDNA-encoded MT-ATP6) and small membrane subunits including DAPIT (ATP5MD) and 6.8PL — conducts protons and rotates the central stalk; the matrix-facing F1 sector is the catalytic head, an alpha3-beta3 hexamer (ATP5F1A/ATP5F1B) whose three catalytic nucleotide sites are turned through their conformational cycle by the rotating central stalk (gamma/ATP5F1C, delta/ATP5F1D, epsilon/ATP5F1E). The peripheral (stator) stalk, anchored at the top by OSCP (ATP5PO), holds the F1 head stationary against the rotor so that rotation is converted into ATP synthesis rather than futile spinning. Assembly is factor-dependent: ATPAF2 (ATP12) is a matrix chaperone that binds the F1 alpha subunit to build the alpha3-beta3 catalytic core, and TMEM70 is an inner-membrane scaffold that promotes incorporation of subunit c into the Fo c-ring rotor. Neither factor is a subunit of the mature enzyme or carries its catalytic activity. Inherited defects in the subunits or assembly factors cause mitochondrial complex V (ATP synthase) deficiency — commonly a neonatal encephalopathy with 3-methylglutaconic aciduria, lactic acidosis and cardiomyopathy. |
Protein Complex | DRAFT | 0 | proton motive force-driven mitochondrial ATP synthesis mitochondrial proton-transporting ATP synthase complex assembly |
4 | 9 | 3 | 0 | 0 | 2 | 9/9 | 0 | ✗ | modules/mitochondrial_complex_v.yaml | ||
Mitochondrial ribosome in Drosophila melanogasterMODULE:dmel_mitochondrial_ribosomeCONCRETE The mitochondrial ribosome (mitoribosome) translates the small set of mitochondrial-DNA-encoded mRNAs, which in animals encode core subunits of the... [more...][less]The mitochondrial ribosome (mitoribosome) translates the small set of mitochondrial-DNA-encoded mRNAs, which in animals encode core subunits of the respiratory chain and ATP synthase. It consists of a small subunit built on the mitochondrially encoded 12S-type rRNA (mt:srRNA) and a large subunit built on the 16S-type rRNA (mt:lrRNA), together with nuclear-encoded mitochondrial ribosomal proteins. Animal mitoribosomes are protein-rich: they contain bacterial-type ribosomal proteins plus many mitochondria-specific proteins. In Drosophila, loss of the small-subunit protein tko (mRpS12) causes the technical knockout phenotype of bang sensitivity. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | mitochondrial ribosome |
3 | 2 | 2 | 0 | 0 | 0 | 0/81 | 0 | ✗ | modules/dmel_mitochondrial_ribosome.yaml | |
Mitochondrial sulfide oxidation in Drosophila melanogasterMODULE:dmel_sulfide_oxidationCONCRETE Hydrogen sulfide produced by cysteine catabolism and gut microbes is detoxified in the mitochondrial matrix. Sulfide:quinone oxidoreductase (Sqor)... [more...][less]Hydrogen sulfide produced by cysteine catabolism and gut microbes is detoxified in the mitochondrial matrix. Sulfide:quinone oxidoreductase (Sqor) oxidises sulfide to a protein-bound persulfide, passing the electrons to ubiquinone in the respiratory chain. The persulfide sulfur is then oxidised to sulfite by the persulfide dioxygenase ETHE1 (CG30022 in flies) or transferred to sulfite to form thiosulfate. Sulfite oxidase (shop) oxidises sulfite to sulfate, and the mitochondrial dicarboxylate carrier (Dic1) can export thiosulfate and sulfate in exchange for other anions. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | sulfide oxidation |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/dmel_sulfide_oxidation.yaml | |
Mitochondrial type II fatty acid synthesis in Drosophila melanogasterMODULE:dmel_mitochondrial_fatty_acid_synthesisCONCRETE Mitochondria carry their own type II fatty acid synthesis (mtFAS) system, in which separate enzymes act on acyl chains attached to the... [more...][less]Mitochondria carry their own type II fatty acid synthesis (mtFAS) system, in which separate enzymes act on acyl chains attached to the mitochondrial acyl carrier protein (ND-ACP). Malonyl groups are loaded onto ACP by the malonyl transacylase (beg), condensed by a beta-ketoacyl-ACP synthase (CG12170), reduced by a 3-ketoacyl-ACP reductase, dehydrated and then reduced by the enoyl-ACP reductase Mecr. The main product, octanoyl-ACP, is the precursor of lipoic acid; acylated ACP also binds and supports assembly of respiratory complex I and the iron-sulfur cluster assembly machinery. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | fatty acid biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 0/6 | 0 | ✗ | modules/dmel_mitochondrial_fatty_acid_synthesis.yaml | |
Mitochondrial unfolded protein responseMODULE:mitochondrial_uprCONCRETE The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nucleus signaling pathway that raises the expression of nuclear genes... [more...][less]The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nucleus signaling pathway that raises the expression of nuclear genes encoding mitochondrial chaperones and proteases when mitochondrial protein homeostasis is disturbed. Its executing transcription factor is a bZIP protein of the ATF4/ATF5 family that is partitioned between mitochondria and the nucleus: nematode ATFS-1 and its mammalian functional counterpart ATF5 both carry a mitochondrial targeting sequence, are kept in mitochondria in unstressed cells, and activate chaperone and protease genes when mitochondrial function fails; ATF5 rescues UPRmt signaling in atfs-1 mutant worms. The induced matrix chaperones, the HSP60 chaperonin and the mitochondrial HSP70, are both the classic reporters and the protective output of the response. How mitochondrial stress is relayed to the transcription factor differs between lineages. In Caenorhabditis elegans, where the pathway was defined, the key regulatory point is the import efficiency of ATFS-1: misfolded matrix proteins are degraded by the ClpP protease CLPP-1, the inner-membrane ABC transporter HAF-1 exports the resulting peptides and attenuates protein import under moderate stress, and ATFS-1 that escapes import reaches the nucleus. A nematode chromatin arm (DVE-1/UBL-5 together with the MET-2/LIN-65 H3K9 methylation machinery and the JMJD-3.1 H3K27 demethylase) acts alongside ATFS-1. In mammals, mitochondrial stress such as depolarization, import defects or iron deficiency activates the inner-membrane protease OMA1, which cleaves DELE1; the released DELE1 fragment activates the eIF2alpha kinase HRI (EIF2AK1) in the cytosol, and the resulting integrated stress response raises translation of ATF4 and ATF5. Mammalian CLPP is not required for the UPRmt, so the ClpP peptide signal is not a conserved part of the pathway. |
Signaling Pathway | DRAFT | Caenorhabditis elegans Homo sapiens Metazoa |
3 | mitochondrial unfolded protein response |
13 | 16 | 10 | 1 | 2 | 12 | 17/17 | 0 | ✗ | modules/mitochondrial_upr.yaml | |
Mitochondrion lifecycleMODULE:mitochondrion_lifecycleCONCRETE Mitochondria are never made de novo: they grow by importing nuclear-encoded proteins and lipids into pre-existing organelles, divide, fuse, carry... [more...][less]Mitochondria are never made de novo: they grow by importing nuclear-encoded proteins and lipids into pre-existing organelles, divide, fuse, carry out their metabolic functions, are kept in check by quality-control pathways, and are removed by selective autophagy. This umbrella module composes the modules for each of those stages by reference. Protein import and iron-sulfur cluster assembly are required in every eukaryote with a mitochondrion-related organelle, including anaerobic hydrogenosomes and mitosomes that have lost respiration; the other stages vary between lineages. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | mitochondrion organization mitochondrion |
14 | 0 | 13 | 0 | 0 | 0 | 0/0 | 0 | ✗ | modules/mitochondrion_lifecycle.yaml | |
MitophagyMODULE:mitophagyCONCRETE Mitophagy is the selective macroautophagy of mitochondria. In animals, damaged or unwanted mitochondria are marked on their outer membrane and... [more...][less]Mitophagy is the selective macroautophagy of mitochondria. In animals, damaged or unwanted mitochondria are marked on their outer membrane and captured by phagophores decorated with Atg8-family proteins (LC3 and GABARAP in mammals, LGG-1 in nematodes). Two kinds of mark are used. In the ubiquitin-dependent route, the kinase PINK1 accumulates on the outer membrane of depolarized or import-defective mitochondria and phosphorylates ubiquitin and the ubiquitin-like domain of the RBR E3 ligase Parkin at Ser65. Activated Parkin builds ubiquitin chains on outer-membrane proteins, and in mammals these chains are read by soluble ubiquitin-binding receptors such as optineurin and NDP52, which also bind LC3/GABARAP and recruit the autophagy initiation machinery. In the receptor-mediated route, integral outer-membrane proteins bind Atg8-family proteins directly through LC3-interacting regions. BNIP3 and NIX (BNIP3L) act in hypoxia-induced and developmental mitophagy, such as mitochondrial clearance in maturing reticulocytes, and FUNDC1 acts in hypoxia-induced mitophagy. These receptors are conserved in nematodes, where the BNIP3/NIX ortholog DCT-1 acts in stress-induced somatic mitophagy together with PINK-1 and the Parkin ortholog PDR-1, and the FUNDC1 ortholog FNDC-1 acts in hypoxia-reoxygenation mitophagy. Nematodes also have lineage-specific components. Paternal mitochondria and membranous organelles in the C. elegans embryo are cleared by the nematode-specific receptor ALLO-1 (allophagy), and in worm muscle the FIS1-family proteins FIS-1 and FIS-2 act at a late step to complete orderly disposal of fission-derived mitochondrial fragments. |
Biological Process | DRAFT | Eumetazoa |
5 | mitophagy |
10 | 11 | 5 | 1 | 4 | 5 | 18/18 | 0 | ✗ | modules/mitophagy.yaml | |
Mitotic and meiotic cohesin complexes in Drosophila melanogasterMODULE:dmel_cohesin_complexesCONCRETE Cohesin is a ring-shaped SMC complex that holds sister chromatids together from DNA replication until anaphase and also organizes interphase... [more...][less]Cohesin is a ring-shaped SMC complex that holds sister chromatids together from DNA replication until anaphase and also organizes interphase chromatin into loops. The ring is built from the SMC1-SMC3 heterodimer, whose ATPase heads are bridged by a kleisin subunit, which in turn binds a stromalin (SA) subunit. In mitotic cells the kleisin is Rad21, encoded in Drosophila by verthandi (vtd), and the SA subunit is SA1; separase cleavage of Rad21 opens the ring at anaphase. Drosophila meiosis uses meiosis-specific cohesion proteins: C(2)M, a kleisin-family protein required for synaptonemal complex formation, and Solo and Sunn, which are required for meiotic centromeric cohesion. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | cohesin complex |
6 | 4 | 2 | 1 | 3 | 0 | 0/7 | 0 | ✗ | modules/dmel_cohesin_complexes.yaml | |
Mitotic cell cycle progression (phase-transition control)MODULE:cell_cycle_progressionCONCRETE An umbrella module that composes the three irreversible, cyclin-CDK-gated phase transitions of the mitotic cell cycle into one cycle: (1) the G1/S... [more...][less]An umbrella module that composes the three irreversible, cyclin-CDK-gated phase transitions of the mitotic cell cycle into one cycle: (1) the G1/S transition (Start / restriction point), at which growth-coupled G1 cyclin-CDK releases the G1/S transcription program and SCF-dependent destruction of the CDK inhibitor commits the cell to S phase (MODULE:g1_s_transition); (2) the G2/M transition, at which the Wee1 / Cdc25 switch activates cyclin B-CDK1 and commits the cell to mitosis (MODULE:g2_m_transition); and (3) the metaphase/anaphase transition and mitotic exit, at which SAC-gated APC/C-Cdc20 destroys securin and the mitotic cyclins, separase cleaves cohesin, and a CDK-counteracting phosphatase resets the G1 state (MODULE:metaphase_anaphase_transition_and_mitotic_exit). The unifying logic is a single oscillator of cyclin-dependent kinase activity - rising from Start through mitotic entry and collapsing at mitotic exit - whose thresholds are made irreversible by positive-feedback proteolysis (SCF at G1/S, APC/C at M/A and exit) and by mutual antagonism between CDK and its inhibitors (CKIs, Wee1, PP2A-B55). Each part here is a compact summary node that names the phase-specific cyclin-CDK holoenzyme and the proteolytic switch; the detailed decompositions live in the three referenced modules. Representative members are drawn from human, Saccharomyces cerevisiae and Schizosaccharomyces pombe. Grounded in GO:0044772 (mitotic cell cycle phase transition). |
Biological Process | DRAFT | Eukaryota |
6 | mitotic cell cycle phase transition mitotic cell cycle |
4 | 3 | 3 | 0 | 0 | 5 | 16/16 | 0 | ✗ | modules/cell_cycle_progression.yaml | |
Mon1-Ccz1 Rab7 exchange factor complex in Drosophila melanogasterMODULE:dmel_mon1_ccz1_complexCONCRETE The Mon1-Ccz1 complex is the guanine nucleotide exchange factor for Rab7. Recruited to endosomes by Rab5 and phosphoinositides, it activates Rab7... [more...][less]The Mon1-Ccz1 complex is the guanine nucleotide exchange factor for Rab7. Recruited to endosomes by Rab5 and phosphoinositides, it activates Rab7 and thereby drives Rab5-to-Rab7 conversion during endosome maturation, and it also acts on autophagosomes. Active Rab7 recruits the HOPS tethering complex for fusion with lysosomes. In metazoans the complex contains a third subunit, RMC1, whose Drosophila ortholog is Bulli; it is needed for full activity of the complex in vivo. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Mon1-Ccz1 complex |
3 | 2 | 2 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_mon1_ccz1_complex.yaml | |
Mre11-Rad50-Nbs (MRN) complex in Drosophila melanogasterMODULE:dmel_mrn_complexCONCRETE The MRN complex senses DNA double-strand breaks. Rad50, an SMC-like ATPase with a long coiled-coil, tethers DNA ends; Mre11 is a nuclease with... [more...][less]The MRN complex senses DNA double-strand breaks. Rad50, an SMC-like ATPase with a long coiled-coil, tethers DNA ends; Mre11 is a nuclease with 3'-5' exonuclease and single-stranded endonuclease activities that starts resection of break ends; Nbs (Nibrin) mediates recruitment and activation of the ATM kinase. In Drosophila, mre11, rad50 and nbs are also required to prevent telomere fusions. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Mre11 complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_mrn_complex.yaml | |
Mucosal DUOX1-DUOXA1 hydrogen peroxide generator and epithelial signaling moduleMODULE:mucosal_duox1_lactoperoxidase_antimicrobial_systemCONCRETE Conserved vertebrate apical epithelial NADPH oxidase module in which the maturation factor DUOXA1 (maturation factor of dual oxidase 1) chaperones... [more...][less]Conserved vertebrate apical epithelial NADPH oxidase module in which the maturation factor DUOXA1 (maturation factor of dual oxidase 1) chaperones and assembles in a 1:1 heterodimeric complex with dual oxidase 1 (DUOX1) in the endoplasmic reticulum to target the holoenzyme to the apical plasma membrane of ciliated airway, urothelial, and squamous mucosal epithelia, where DUOX1 catalyzes Ca2+-activated, NADPH-dependent transmembrane electron transfer and extracellular hydrogen peroxide (H2O2) generation. Despite carrying an N-terminal extracellular peroxidase-homology domain (PHD), vertebrate DUOX1 lacks heme-binding histidines and does not possess intrinsic peroxidase activity. Instead, the extracellular H2O2 generated by the apical DUOX1-DUOXA1 complex feeds into two major downstream physiological pathways: (1) mucosal antimicrobial host defense, in which secreted lactoperoxidase (LPO) uses DUOX1-derived H2O2 to oxidize thiocyanate (SCN-) into hypothiocyanite (OSCN-) in the airway surface liquid, and (2) paracrine and autocrine epithelial redox signaling triggered by damage cues (extracellular ATP, Ca2+ influx, IL-33) that drive wound repair and mucin secretion. |
Biological Process | DRAFT | Homo sapiens Mammalia Mus musculus |
1 | NAD(P)H oxidase H2O2-forming activity hydrogen peroxide biosynthetic process innate immune response in mucosa wound healing |
3 | 2 | 2 | 0 | 0 | 1 | 2/4 | 0 | ✗ | modules/mucosal_duox1_lactoperoxidase_antimicrobial_system.yaml | |
Multiactivity mechanisms contributing to polar auxin transportMODULE:auxin_polar_transportCONCRETE Cell-to-cell auxin transport arises from the spatial arrangement and regulation of membrane uptake and export activities. This module represents... [more...][less]Cell-to-cell auxin transport arises from the spatial arrangement and regulation of membrane uptake and export activities. This module represents experimentally grounded land-plant transport combinations: complementary influx/efflux, pair-specific PIN–ABCB cooperation, and carrier activation by kinases or TWD1. Each named mechanism contains at least two substantive activities and native-context evidence; satisfying it identifies a supported mechanistic combination, not sufficiency to generate tissue polarity or a complete transport network. Carrier-mediated uptake is context-dependent because protonated IAA can also enter by diffusion. Native polarity and tissue flow are distinguished from cellular or heterologous export. Arabidopsis provides the characterized multiactivity mechanisms. Rice contributes only an optional sampled influx/efflux segment, and moss/liverwort PINs are exporter comparators; neither alone certifies an equivalent native mechanism. Nuclear signaling, biosynthesis, intracellular short-PIN/PILS compartmentation, general vesicle trafficking and bulk phloem transport are outside the modeled boundary. |
Biological Process | COMPLETE | Arabidopsis thaliana land plants Marchantia polymorpha Oryza sativa Japonica Group Physcomitrium patens |
0 | auxin polar transport |
30 | 20 | 21 | 2 | 8 | 7 | 17/17 | 0 | ✗ | modules/auxin_polar_transport.yaml | |
MurNAc 6-phosphate etherase route of muramic acid recyclingMODULE:murnac_6p_catabolic_recyclingCONCRETE A bacterial route that converts N-acetylmuramic acid (MurNAc) recovered from cell-wall turnover, or taken up from the environment, into... [more...][less]A bacterial route that converts N-acetylmuramic acid (MurNAc) recovered from cell-wall turnover, or taken up from the environment, into N-acetylglucosamine 6-phosphate (GlcNAc-6P). MurNAc 6-phosphate (MurNAc-6P) is formed either by a MurNAc-specific phosphotransferase-system (PTS) transporter that phosphorylates MurNAc during uptake, or by the anhydro-MurNAc kinase AnmK acting on 1,6-anhydro-MurNAc released from imported anhydromuropeptides. The etherase MurQ then removes the D-lactyl ether from MurNAc-6P, yielding GlcNAc-6P and D-lactate, and GlcNAc-6P joins the GlcNAc catabolic pathway. The RpiR-family repressor MurR keeps the murP-murQ genes off until MurNAc-6P binds it. This catabolic etherase route is the alternative to the Pseudomonas-type anabolic MupP-AmgK-MurU shortcut (MODULE:peptidoglycan_recycling). Anhydromuropeptide import and the NagZ and AmpD steps that free anhydro-MurNAc are modeled in that module; GlcNAc-6P deacetylation and further catabolism are outside the boundary. |
Metabolic Pathway | DRAFT | 0 | N-acetylmuramic acid catabolic process 1,6-anhydro-N-acetyl-beta-muramic acid catabolic process peptidoglycan turnover |
6 | 4 | 3 | 1 | 2 | 3 | 3/5 | 0 | ✗ | modules/murnac_6p_catabolic_recycling.yaml | ||
MutH-independent bacterial DNA mismatch repairMODULE:muth_independent_mismatch_repair A reusable four-stage bacterial module in which MutS recognizes a replication mismatch, the beta sliding clamp helps orient an endonuclease-bearing... [more...][less]A reusable four-stage bacterial module in which MutS recognizes a replication mismatch, the beta sliding clamp helps orient an endonuclease-bearing MutL that nicks DNA without MutH, and a helicase, single-stranded DNA-binding protein, and one or more directional exonucleases remove the error-containing tract before DNA polymerase and ligase restore the duplex. The module is explicitly distinct from the Dam/MutH-directed Escherichia coli route. Mismatch avoidance by polymerase proofreading, recombination control, and the other repair pathways that share UvrD, RecJ, polymerase, or ligase are outside the boundary. |
Biological Process | DRAFT | 0 | mismatch repair |
12 | 11 | 8 | 1 | 3 | 5 | 15/22 | 0 | ✗ | modules/muth_independent_mismatch_repair.yaml | ||
Mutator foci 22G-RNA amplification in Caenorhabditis elegansMODULE:c_elegans_mutator_22g_rna_amplificationCONCRETE In the Caenorhabditis elegans germline, silencing guided by primary small RNAs is weak, and is made effective by a second round of small RNA... [more...][less]In the Caenorhabditis elegans germline, silencing guided by primary small RNAs is weak, and is made effective by a second round of small RNA synthesis. A primary Argonaute such as RDE-1 recognizes a target transcript and recruits the NYN-domain endoribonuclease RDE-8, which cuts it. The ribonucleotidyltransferase RDE-3 (MUT-2) gives the 5' fragment a poly(UG) tail, and RNA-dependent RNA polymerases (RdRPs) then use the tailed RNA as a template to synthesize abundant 22-nucleotide, 5'-guanosine secondary siRNAs (22G-RNAs). Most of this amplification takes place in Mutator foci. These are perinuclear, phase-separated condensates that lie next to P granules at nuclear pores. The intrinsically disordered Q/N-rich protein MUT-16 is the scaffold of the foci. Distinct regions of MUT-16 recruit the RdRP RRF-1; MUT-15 (RDE-5), which in turn recruits RDE-8; the DEAD-box RNA helicase MUT-14, which acts redundantly with SMUT-1 to start amplification; RDE-3; and, through the adaptor RDE-2 (MUT-8), the 3'-5' exoribonuclease MUT-7. The 22G-RNAs made in this way are loaded into worm-specific Argonautes (WAGOs) that lack slicer residues, such as WAGO-1, and silence transposons, pseudogenes and other germline-repressed genes. A second germline RdRP, EGO-1, makes most of the 22G-RNAs bound by the catalytic Argonaute CSR-1, which target most germline-expressed genes and protect them from WAGO-mediated silencing instead of silencing them. The two RdRP systems are not fully separate: EGO-1 also contributes, partly redundantly with RRF-1, to WAGO-class 22G-RNAs. |
Biological Process | DRAFT | Caenorhabditis elegans |
0 | siRNA processing regulatory ncRNA-mediated post-transcriptional gene silencing |
9 | 11 | 6 | 1 | 2 | 10 | 11/11 | 0 | ✗ | modules/c_elegans_mutator_22g_rna_amplification.yaml | |
MuvB-containing transcription complexes in Drosophila melanogasterMODULE:dmel_muvb_complexesCONCRETE MuvB is a conserved core of five proteins (Mip130, Mip120, Mip40, Lin-52 and Caf1-55) that assembles with different partners to repress or activate... [more...][less]MuvB is a conserved core of five proteins (Mip130, Mip120, Mip40, Lin-52 and Caf1-55) that assembles with different partners to repress or activate cell-cycle and differentiation genes. With E2F2, Dp and the retinoblastoma-family proteins Rbf or Rbf2 it forms dREAM, which represses E2F target genes and developmentally regulated genes. With the Myb transcription factor it forms the Myb-MuvB complex (MMB), which activates G2/M genes and also controls site-specific chorion gene amplification. In spermatocytes a testis-specific relative, tMAC, which contains Aly, Comr, Tomb and Topi with Mip40 and Caf1-55, activates the meiotic and spermatid differentiation gene program. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | DRM complex |
7 | 5 | 2 | 1 | 4 | 1 | 1/14 | 0 | ✗ | modules/dmel_muvb_complexes.yaml | |
N-glycan LLO assembly I — cytoplasmic face (to Man5GlcNAc2-PP-dolichol); DPAGT1/ALG13/ALG14/ALG1/ALG2/ALG11MODULE:n_glycan_llo_assembly_cytoplasmic N-linked glycosylation begins with the stepwise assembly of the dolichol-linked oligosaccharide (LLO, or dolichol-PP-oligosaccharide) on the... [more...][less]N-linked glycosylation begins with the stepwise assembly of the dolichol-linked oligosaccharide (LLO, or dolichol-PP-oligosaccharide) on the cytoplasmic face of the endoplasmic-reticulum membrane. Using nucleotide-sugar donors from the cytosol, the pathway builds a Man5GlcNAc2 glycan on the polyprenol carrier dolichyl phosphate before the intermediate is flipped into the ER lumen. DPAGT1 (GlcNAc-1-phosphotransferase, the first and committed step, and the tunicamycin target) transfers GlcNAc-1-P from UDP-GlcNAc onto dolichyl phosphate to give GlcNAc-PP-dolichol; the bipartite UDP-GlcNAc transferase ALG13/ALG14 (ALG13 catalytic, ALG14 membrane-anchoring) adds the second GlcNAc to form the chitobiose core GlcNAc2-PP-dolichol; ALG1 (beta-1,4-mannosyltransferase) adds the first mannose; the bifunctional ALG2 (alpha-1,3 and alpha-1,6 mannosyltransferase) adds the second and third mannoses to give Man3GlcNAc2-PP-dolichol; and ALG11 (alpha-1,2-mannosyltransferase) adds the fourth and fifth mannoses to complete Man5GlcNAc2-PP-dolichol, the final cytoplasmic-face intermediate (subsequently flipped to the lumen by the RFT1 flippase, and extended by the lumenal ALG enzymes). All the mannose-addition steps in this segment use GDP-mannose. Inherited defects in each step cause a congenital disorder of glycosylation (CDG type I): DPAGT1-CDG (and a congenital myasthenic syndrome), ALG13-CDG (an X-linked developmental/epileptic encephalopathy), ALG14-CDG (congenital myasthenic syndrome), ALG1-CDG, ALG2-CDG (and CMS14) and ALG11-CDG. |
Metabolic Pathway | DRAFT | eukaryotes |
0 | dolichol-linked oligosaccharide biosynthetic process protein N-linked glycosylation |
6 | 6 | 5 | 0 | 0 | 4 | 18/18 | 0 | ✗ | modules/n_glycan_llo_assembly_cytoplasmic.yaml | |
N-glycan LLO assembly II — ER-lumenal face + glucosylation (to Glc3Man9GlcNAc2-PP-dolichol); RFT1/ALG3/ALG9/ALG12/ALG6/ALG8/ALG10MODULE:n_glycan_llo_assembly_lumenal After the Man5GlcNAc2-PP-dolichol intermediate is flipped from the cytoplasmic to the lumenal face of the endoplasmic-reticulum membrane (by the... [more...][less]After the Man5GlcNAc2-PP-dolichol intermediate is flipped from the cytoplasmic to the lumenal face of the endoplasmic-reticulum membrane (by the RFT1 flippase), the dolichol-linked oligosaccharide (LLO) is completed inside the ER lumen to the mature Glc3Man9GlcNAc2-PP-dolichol donor for protein N-linked glycosylation. Unlike the cytoplasmic-face steps, the lumenal glycosyltransferases use lipid-linked donors: dolichyl-phosphate-mannose (Dol-P-Man) for the mannose additions and dolichyl-phosphate-glucose (Dol-P-Glc) for the glucose additions. Four mannoses are added: ALG3 (alpha-1,3) adds the sixth mannose, ALG9 (alpha-1,2) adds the seventh and, later, the ninth mannose, and ALG12 (alpha-1,6) adds the eighth, giving Man9GlcNAc2-PP-dolichol. Three glucoses then cap the glycan: ALG6 (alpha-1,3) adds the first glucose, ALG8 (alpha-1,3) the second, and ALG10 (alpha-1,2) the third and terminal glucose, producing the mature Glc3Man9GlcNAc2-PP-dolichol. The terminal glucose is the recognition signal for efficient transfer of the glycan to nascent proteins by the oligosaccharyltransferase (and, after transfer, for glucosidase trimming and calnexin/calreticulin quality control). Inherited defects in each step cause a congenital disorder of glycosylation (CDG type I): ALG3-CDG (CDG-Id), ALG9-CDG (CDG-Il / Gillessen-Kaesbach-Nishimura syndrome), ALG12-CDG (CDG-Ig), ALG6-CDG (CDG-Ic, one of the commonest CDG-I subtypes) and ALG8-CDG (CDG-Ih). |
Metabolic Pathway | DRAFT | eukaryotes |
0 | dolichol-linked oligosaccharide biosynthetic process protein N-linked glycosylation |
9 | 8 | 8 | 0 | 0 | 7 | 19/19 | 0 | ✗ | modules/n_glycan_llo_assembly_lumenal.yaml | |
N-glycan trimming and processing in Drosophila melanogasterMODULE:dmel_n_glycan_processingCONCRETE After oligosaccharyltransferase transfers Glc3Man9GlcNAc2 to asparagine residues of nascent proteins, the N-glycan is trimmed in the endoplasmic... [more...][less]After oligosaccharyltransferase transfers Glc3Man9GlcNAc2 to asparagine residues of nascent proteins, the N-glycan is trimmed in the endoplasmic reticulum and then remodelled in the Golgi apparatus. In the ER, glucosidase I (Gcs1) removes the outer glucose and the glucosidase II heterodimer (Gcs2alpha catalytic and Gcs2beta regulatory subunits) removes the two inner glucoses; these steps also control entry into and exit from the calnexin-calreticulin folding cycle. Class I alpha-1,2-mannosidases trim mannoses in the ER and cis-Golgi. In the Golgi, GlcNAc transferase I (Mgat1) adds GlcNAc to the alpha-1,3 arm, which allows alpha-mannosidase II to remove two further mannoses. In insects most N-glycans are then converted to paucimannose glycans by the Golgi beta-N-acetylglucosaminidase Fused lobes (fdl), while a smaller fraction is extended to hybrid and complex glycans by GlcNAc transferase II, core fucosyltransferases, galactosyl-, GalNAc-, glucuronyl- and sialyltransferases. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | N-glycan processing |
14 | 16 | 13 | 0 | 0 | 9 | 1/17 | 0 | ✗ | modules/dmel_n_glycan_processing.yaml | |
N-terminal acetyltransferase complexes in Drosophila melanogasterMODULE:dmel_n_terminal_acetyltransferase_complexesCONCRETE N-terminal acetyltransferases (NATs) transfer an acetyl group from acetyl-CoA to the alpha-amino group of protein N termini, mostly... [more...][less]N-terminal acetyltransferases (NATs) transfer an acetyl group from acetyl-CoA to the alpha-amino group of protein N termini, mostly co-translationally at the ribosome. Each complex pairs a catalytic subunit with one or more auxiliary subunits that anchor it to the ribosome and shape substrate choice. NatA (catalytic Naa10, vnc in flies, with auxiliary Naa15-16) acetylates N termini exposed after removal of the initiator methionine; Naa50 (san) associates with NatA. NatB (Naa20 with Naa25, psidin) acetylates Met-Asp/Glu/Asn/Gln N termini. NatC (Naa30 with Naa35 and Naa38) acetylates Met followed by a hydrophobic residue. Drosophila has a testis-specific NatC catalytic paralog, Naa30B. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | NatA complex NatB complex NatC complex |
6 | 4 | 3 | 1 | 2 | 0 | 0/9 | 0 | ✗ | modules/dmel_n_terminal_acetyltransferase_complexes.yaml | |
NAD+ consumption — sirtuin deacylation, PARP/ARTD poly- and mono-ADP-ribosylation and CD38/BST1 NAD+ glycohydrolysis, with PARG and macrodomain reversal; SIRT1-7/PARP1-4/PARP6/PARP8-12/PARP14-16/TIPARP/TNKS/TNKS2/CD38/BST1/PARG/MACROD1/MACROD2/OARD1MODULE:nad_consumptionCONCRETE Besides serving as a hydride carrier in redox reactions, NAD+ is a substrate that is broken down by three classes of signalling enzymes. Each... [more...][less]Besides serving as a hydride carrier in redox reactions, NAD+ is a substrate that is broken down by three classes of signalling enzymes. Each cleaves the bond between nicotinamide and ribose, releases free nicotinamide and uses the ADP-ribose moiety. The sirtuins (SIRT1-7) are NAD+-dependent protein deacylases. They transfer an acetyl group, or another acyl group such as succinyl, malonyl, glutaryl, lipoyl or a long-chain fatty acyl, from a protein lysine to the ADP-ribose of NAD+, producing nicotinamide and 2''-O-acyl-ADP-ribose. SIRT1, SIRT6 and SIRT7 act in the nucleus, SIRT2 mainly in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in mitochondria. SIRT5 is chiefly a desuccinylase, demalonylase and deglutarylase, SIRT4 a lipoamidase, and SIRT4 and SIRT6 also mono-ADP-ribosylate proteins. The PARP (ARTD) family of ADP-ribosyltransferases transfers ADP-ribose from NAD+ to protein acceptor residues. PARP1, PARP2 and the tankyrases TNKS and TNKS2 build poly(ADP-ribose) chains; DNA-break-activated PARP1, with its cofactor HPF1, is the largest NAD+ consumer after genotoxic stress. Most other PARPs (PARP3, PARP4, PARP6, PARP8, PARP10-12, PARP14-16 and TIPARP/PARP7) attach a single ADP-ribose. The ectoenzymes CD38 and BST1 (CD157) are NAD+ glycohydrolases and ADP-ribosyl cyclases. They convert NAD+ mostly to ADP-ribose and partly to the calcium-mobilising messenger cyclic ADP-ribose, which they also hydrolyse. Protein ADP-ribosylation is reversed by PAR glycohydrolase (PARG), which cleaves PAR chains, and by the macrodomain hydrolases MACROD1, MACROD2 and OARD1 (TARG1), which remove the last ADP-ribose from glutamate and aspartate residues. The nicotinamide released by all of these reactions is recycled to NAD+ by the NAMPT salvage pathway. Because the consumers share a limited NAD+ pool, strong PARP1 or CD38 activity lowers NAD+ and with it sirtuin activity, coupling DNA damage, inflammation and ageing to metabolic signalling. |
Metabolic Pathway | DRAFT | Homo sapiens |
0 | NAD+ catabolic process |
16 | 31 | 3 | 5 | 12 | 2 | 5/28 | 0 | ✗ | modules/nad_consumption.yaml | |
NADP+ synthesis (NAD kinases NADK/NADK2) and nicotinamide riboside salvage (NMRK1/NMRK2)MODULE:nadp_synthesis_and_nr_salvage Two committed reactions that complete the cellular NAD(P) cofactor network beyond the core NAD+ biosynthesis hub. First, the nicotinamide riboside... [more...][less]Two committed reactions that complete the cellular NAD(P) cofactor network beyond the core NAD+ biosynthesis hub. First, the nicotinamide riboside (NR) salvage entry: nicotinamide riboside kinases NMRK1 (ubiquitous) and NMRK2 (muscle-enriched) phosphorylate the dietary/circulating NAD+ precursor nicotinamide riboside (and nicotinic acid riboside, and the reduced vitamers) with ATP to nicotinamide mononucleotide (NMN) / nicotinic acid mononucleotide (NaMN). NMN then enters the NMNAT step of the NAD+ biosynthesis hub (see MODULE:nad_biosynthesis_salvage), making NR the shortest two-step route to NAD+ and the basis for NR/NMN nutraceutical supplementation. Second, the NADP+ branch: NAD kinases phosphorylate the 2'-hydroxyl of the adenine ribose of NAD+ with ATP to give NADP+, the sole de novo source of the NADP(H) pool that drives reductive biosynthesis and antioxidant defence (glutathione and thioredoxin regeneration). Humans have two compartment-specific NAD kinases from distinct families: cytosolic NADK supplies the cytosolic/nuclear NADP(H) pool, and mitochondrial NADK2 supplies the matrix NADP(H) pool required for proline biosynthesis (feeding NADPH to ALDH18A1/P5CS), mitochondrial one-carbon metabolism and fatty-acid oxidation. NADK2 deficiency causes a severe metabolic encephalopathy (hyperlysinemia, 2,4-dienoyl-CoA reductase deficiency); NADK activity is itself redox- and growth-signal-regulated. |
Metabolic Pathway | DRAFT | 0 | NADP+ biosynthetic process NAD+ biosynthetic process via the salvage pathway |
4 | 3 | 3 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/nadp_synthesis_and_nr_salvage.yaml | ||
NADPH-driven glutathione/glutaredoxin and thioredoxin systems with peroxide and superoxide scavengingMODULE:glutathione_thioredoxin_redox_systemsCONCRETE Cells keep their thiols reduced and remove reactive oxygen species with two parallel NADPH-driven thiol-disulfide relays and a set of... [more...][less]Cells keep their thiols reduced and remove reactive oxygen species with two parallel NADPH-driven thiol-disulfide relays and a set of thiol-independent scavengers. In the glutathione/glutaredoxin system, the FAD enzyme glutathione reductase uses NADPH to reduce glutathione disulfide to glutathione, and glutathione in turn reduces dithiol glutaredoxins, which reduce protein disulfides and glutathione-protein mixed disulfides. In the thioredoxin system, thioredoxin reductase uses NADPH to reduce thioredoxin, which reduces protein disulfides, supplies electrons to biosynthetic reductases such as ribonucleotide reductase and PAPS reductase, and reduces the thiol peroxidases. Thioredoxin reductase is a low-molecular-weight flavoenzyme in fungi, plants and bacteria and a high-molecular-weight selenoprotein related to glutathione reductase in animals. Hydrogen peroxide and organic hydroperoxides are reduced by several families of thioredoxin-dependent thiol peroxidases (typical 2-Cys peroxiredoxins, glutathione-peroxidase-like peroxiredoxins, atypical 2-Cys and BCP-type peroxiredoxins). Superoxide dismutases convert superoxide to hydrogen peroxide (Cu/Zn enzyme in the cytosol and mitochondrial intermembrane space, Mn enzyme in the mitochondrial matrix), and haem catalases dismutate hydrogen peroxide to water and oxygen without thiol reductant. The two thiol systems overlap: in budding yeast at least one cytosolic thioredoxin or dithiol glutaredoxin is required for viability. |
Biological Process | DRAFT | eukaryotes |
0 | cell redox homeostasis cellular oxidant detoxification |
18 | 12 | 9 | 3 | 8 | 6 | 29/34 | 0 | ✗ | modules/glutathione_thioredoxin_redox_systems.yaml | |
NALCN sodium leak channel complex in Drosophila melanogasterMODULE:dmel_nalcn_channel_complexCONCRETE NALCN is a voltage-insensitive cation channel that carries a background sodium leak current and so sets the resting membrane potential and... [more...][less]NALCN is a voltage-insensitive cation channel that carries a background sodium leak current and so sets the resting membrane potential and excitability of neurons. Its pore-forming subunit, encoded in Drosophila by narrow abdomen (na), assembles with the large accessory proteins unc79 and unc80 and with Mid1, a protein related to yeast Mid1 and to the mammalian NALCN accessory factor NALF1 (FAM155A). In flies, na and its partners are needed for normal locomotor activity and circadian rhythmic behavior. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | sodium channel complex |
5 | 4 | 4 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/dmel_nalcn_channel_complex.yaml | |
NF-Y CCAAT-binding factor in Drosophila melanogasterMODULE:dmel_nf_y_complexCONCRETE NF-Y is a heterotrimeric transcription factor that binds the CCAAT box found in many eukaryotic promoters. Nf-YB and Nf-YC form a histone-fold... [more...][less]NF-Y is a heterotrimeric transcription factor that binds the CCAAT box found in many eukaryotic promoters. Nf-YB and Nf-YC form a histone-fold dimer that binds DNA nonspecifically and creates the surface for Nf-YA, which confers sequence-specific recognition of CCAAT. In Drosophila, NF-Y regulates genes in eye and neural development and in cell proliferation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | CCAAT-binding factor complex |
4 | 4 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_nf_y_complex.yaml | |
NR3C4 androgen receptor genomic signaling in characterized jawed vertebratesMODULE:androgen_receptor_signalingABSTRACT Full-length NR3C4 receptors couple androgen sensing to nuclear regulatory-DNA recognition and transcriptional responses in characterized jawed... [more...][less]Full-length NR3C4 receptors couple androgen sensing to nuclear regulatory-DNA recognition and transcriptional responses in characterized jawed vertebrates. Cytosolic HSP90 and context-dependent co-chaperones support receptor competence. Nuclear availability, cooperative receptor-DNA assembly and coregulator recruitment are distinct aspects of the genomic response, not a universally ordered import switch. Mammalian FKBP4/FKBP5, p23, NCOA1/NCOA2 and NCOR1 provide experimentally grounded optional implementations. Fish paralogs differ in localization, ligand response and native physiological requirement. Steroid synthesis/transport, non-NR3C4 androgen sensors, non-genomic monomer signaling and ligand-binding-domain-deficient cancer variants lie outside this module. |
Signaling Pathway | DRAFT | Gnathostomata Homo sapiens Mus musculus |
0 | androgen receptor signaling pathway |
12 | 10 | 5 | 2 | 6 | 12 | 15/15 | 0 | ✓ | modules/androgen_receptor_signaling.yaml | |
Nascent polypeptide-associated complex in Drosophila melanogasterMODULE:dmel_nascent_polypeptide_associated_complexCONCRETE The nascent polypeptide-associated complex (NAC) is a heterodimer of an alpha and a beta subunit that binds near the exit tunnel of translating... [more...][less]The nascent polypeptide-associated complex (NAC) is a heterodimer of an alpha and a beta subunit that binds near the exit tunnel of translating ribosomes and contacts emerging nascent chains. It acts as a ribosome-associated chaperone and sorting factor that shields nascent polypeptides and regulates their access to the signal recognition particle and to other targeting pathways. Drosophila has two alpha-subunit genes (Nacalpha and gNacalpha) and an expanded family of beta-subunit (BTF3-like) genes: bicaudal (bic), uncNacbeta and a cluster of betaNACtes genes, the latter expressed in the male germline. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | nascent polypeptide-associated complex |
8 | 9 | 2 | 2 | 5 | 0 | 0/9 | 0 | ✗ | modules/dmel_nascent_polypeptide_associated_complex.yaml | |
Necroptosis (RHIM-dependent RIPK3-MLKL lytic cell death) moduleMODULE:necroptosisCONCRETE A decomposition of the necroptotic process (GO:0070266): the caspase-8-restrained, RIPK3- and MLKL-dependent form of programmed necrosis. The... [more...][less]A decomposition of the necroptotic process (GO:0070266): the caspase-8-restrained, RIPK3- and MLKL-dependent form of programmed necrosis. The module follows GO's own partition of the process into a signaling phase (GO:0097527 necroptotic signaling pathway), the assembly of the RIPK1/RIPK3 RHIM platform that licenses the effector kinase (GO:1901026 ripoptosome assembly involved in necroptotic process; complex GO:0097342 ripoptosome), and an execution phase (GO:0097528) carried out by MLKL at the plasma membrane. Design intent: the committing chemistry is a single linear hand-off - an upstream RHIM-bearing sensor or adaptor nucleates a RHIM amyloid core with RIPK3, activated RIPK3 phosphorylates MLKL, and phosphorylated MLKL destabilizes the membrane - so the module is one ordered chain of parts rather than the redundant-suppressor topology used for ferroptosis. The branch point that makes necroptosis a distinct program sits upstream: three alternative initiators converge on the same RIPK3 core and are modelled as a variant set along the axis of which receptor supplies the RHIM (RIPK1 downstream of TNFR1 and other death receptors; TICAM1/TRIF downstream of TLR3 and endosomal TLR4; ZBP1 downstream of Z-form nucleic acid sensing). The caspase-8/FADD/cFLIP brake is modelled as an optional regulatory part that negatively regulates the chain, not as a core step: its proteolysis is what normally keeps the module off, and the same complex is the apoptotic alternative. |
Biological Process | DRAFT | Mammalia |
0 | necroptotic process |
9 | 12 | 5 | 1 | 3 | 5 | 8/8 | 0 | ✗ | modules/necroptosis.yaml | |
Neonatal Fc receptor (FCGRT/B2M) pH-dependent IgG and albumin salvage and transcytosis — endocytic uptake, V-ATPase acidification, FcRn acidic capture, EHD1/SNAP23 exocytic recycling vs. RAB7A/CTSD lysosomal catabolismMODULE:fcrn_igg_albumin_salvage_transcytosis Immunoglobulin G (IgG) antibodies, Fc-fusion biologics, and serum albumin (ALB) achieve their exceptionally long (~19-21 day) circulatory... [more...][less]Immunoglobulin G (IgG) antibodies, Fc-fusion biologics, and serum albumin (ALB) achieve their exceptionally long (~19-21 day) circulatory half-lives in humans through pH-dependent endosomal salvage mediated by the heterodimeric neonatal Fc receptor (FcRn), composed of the MHC class I-like alpha chain FCGRT (p51) and beta-2-microglobulin (B2M). Vascular endothelial cells, myeloid cells, and polarized barrier epithelia continuously internalize extracellular albumin and IgG from plasma into nascent endocytic vesicles via fluid-phase pinocytosis and clathrin/AP-2/DNM2-coated pits. At neutral extracellular pH (7.4), FcRn displays negligible affinity for IgG or albumin. Once V-ATPase (ATP6V1A) acidifies early sorting endosomes to pH ~6.0-5.5, protonation of surface histidine residues on the IgG CH2-CH3 interface and albumin domain III triggers high-affinity, non-cooperative 2:1:1 binding to endosomal FCGRT/B2M heterodimers. FcRn-bound cargo is sorted away from the degradative multivesicular body pathway into EHD1-dependent recycling tubules that dock and fuse with the plasma membrane via the target-SNARE SNAP23; exposure to neutral extracellular pH (7.4) immediately deprotonates the histidine switch and releases intact IgG and albumin back into circulation (or across polarized mucosal/placental barriers). Cargo that fails to engage FcRn (or is displaced by FcRn-blocking therapeutics such as efgartigimod or by FCGRT/B2M deficiency) remains in the endosomal lumen and progresses via ESCRT-I (TSG101) and RAB7A to lysosomes for proteolytic catabolism by cathepsin D (CTSD). |
Transport Step | DRAFT | 0 | cargo receptor activity endosomal lumen acidification endocytic recycling exocytosis endosome to lysosome transport |
8 | 12 | 7 | 0 | 0 | 7 | 14/14 | 0 | ✗ | Agent Based | modules/fcrn_igg_albumin_salvage_transcytosis.yaml | |
Netrin signaling pathway moduleMODULE:netrin_signalingABSTRACT Netrins are secreted laminin-related guidance cues. A netrin binds receptors of the DCC family (vertebrate DCC, Drosophila Frazzled) on a... [more...][less]Netrins are secreted laminin-related guidance cues. A netrin binds receptors of the DCC family (vertebrate DCC, Drosophila Frazzled) on a responding cell to mediate attraction, and receptors of the UNC5 family to mediate repulsion, steering migrating cells and axons toward or away from the netrin source. |
Signaling Pathway | DRAFT | Eumetazoa |
1 | netrin-activated signaling pathway |
5 | 3 | 2 | 1 | 2 | 1 | 3/11 | 0 | ✗ | modules/netrin_signaling.yaml | |
Neural crest gene regulatory network moduleMODULE:neural_crest_gene_regulatory_network The vertebrate neural crest gene regulatory network: the transcriptional program by which signals at the edge of the neural plate are converted,... [more...][less]The vertebrate neural crest gene regulatory network: the transcriptional program by which signals at the edge of the neural plate are converted, through a neural plate border layer and a crest specifier layer, into migratory multipotent crest cells, of which the cranial population forms skeletogenic ectomesenchyme. A parallel competence layer, shared with pluripotent blastula cells, keeps progenitors undifferentiated. Border specifiers (Gbx2, Msx1, AP-2alpha, Pax3, Zic1) are largely ancestral chordate genes already expressed at the amphioxus neural plate border; most crest specifiers were recruited at the base of vertebrates, mainly by changes in where they are expressed, and some cranial circuit components (Ets1) were added later in jawed vertebrates. Inducing signals (Wnt, BMP, FGF) are covered by the wnt_signaling, bmp_signaling and FGF modules and are treated here as upstream context. |
Developmental Process | DRAFT | Vertebrata |
0 | neural crest cell differentiation |
11 | 25 | 5 | 2 | 5 | 24 | 20/20 | 0 | ✓ | modules/neural_crest_gene_regulatory_network.yaml | |
Neural ectoderm anteroposterior specification moduleMODULE:neural_ectoderm_anteroposterior_specificationABSTRACT The developmental program that, during gastrulation, subdivides newly induced neural ectoderm along the anteroposterior axis into two parallel,... [more...][less]The developmental program that, during gastrulation, subdivides newly induced neural ectoderm along the anteroposterior axis into two parallel, lineage-committed brain progenitors: an OTX2-positive anterior neural ectoderm that generates the forebrain and midbrain, and a GBX2/HOX-positive posterior neural ectoderm that generates the hindbrain. The module begins where germ-layer specification ends - with SOX2-positive neural ectoderm established under combined BMP, TGF-beta and WNT inhibition - and is driven by a graded posteriorising input of FGF together with retinoic acid. That input is read out by a pair of mutually repressive homeodomain selectors, OTX2 and GBX2, whose shared border is the site at which the midbrain-hindbrain (isthmic) organizer forms; displacing the border displaces the organizer. The two territories are already committed rather than merely differently positioned: challenged with the opposite region's inducing signals they do not interconvert, and they carry diverging accessible-chromatin landscapes that foreshadow their regional identities. Downstream, the anterior territory resolves into FOXG1/SIX3 forebrain and EN1 midbrain progenitors, and the posterior territory into MAFB/HNF1B/HOXA3 rhombomere 5/6 hindbrain progenitors. Grounded in GO:0021999 (neural plate anterior/posterior regionalization). Upstream neural-versus-epidermal ectoderm allocation is supplied by modules/germ_layer_specification.yaml and modules/body_axis_specification.yaml; the signalling machinery is detailed in the fgfr_signaling, retinoic_acid_receptor_signaling, wnt_signaling, bmp_signaling and tgfb_smad_signaling modules; the cerebellar program that continues from the posterior territory's rhombomere 1 is in modules/cerebellum_development.yaml. |
Developmental Process | DRAFT | deuterostomes |
0 | neural plate anterior/posterior regionalization |
8 | 12 | 3 | 2 | 4 | 5 | 7/12 | 0 | ✓ | modules/neural_ectoderm_anteroposterior_specification.yaml | |
Neurexin-centred trans-synaptic adhesion complexesMODULE:neurexin_transsynaptic_adhesion Neurexins are presynaptic type I transmembrane proteins that act as a hub for trans-synaptic adhesion. Their extracellular LNS domains bind a set... [more...][less]Neurexins are presynaptic type I transmembrane proteins that act as a hub for trans-synaptic adhesion. Their extracellular LNS domains bind a set of structurally unrelated postsynaptic or secreted partners, forming protein bridges that span the synaptic cleft, hold the pre- and postsynaptic membranes together, and signal in both directions to organize synaptic properties. The best-established partners are the neuroligins, which are catalytically inactive esterase-fold transmembrane proteins; the leucine-rich-repeat LRRTM proteins; and a tripartite bridge in which secreted cerebellin hexamers link neurexin to the amino-terminal domain of delta-family ionotropic glutamate receptors (GluD1/GluD2). Which partner a neurexin engages is controlled in large part by alternative splicing, notably at neurexin splice site 4. OUT OF SCOPE: the intracellular scaffolds recruited by the neurexin and partner cytoplasmic tails (CASK, Mint, PSD-95, gephyrin), the synaptic vesicle release machinery, and the many other neurexin ligands (dystroglycan, neurexophilins, latrophilins, calsyntenins, GABA-A receptor, cerebellin-independent C1q-like proteins). Each of these can be added as further partner variants or as a separate module. |
Biological Process | DRAFT | Bilateria Vertebrata |
1 | synaptic membrane adhesion trans-synaptic signaling by trans-synaptic complex |
6 | 5 | 2 | 1 | 3 | 1 | 4/9 | 0 | ✗ | modules/neurexin_transsynaptic_adhesion.yaml | |
Neuromuscular junction acetylcholine receptor clustering — neural agrin, LRP4 coreceptor, MuSK kinase activation by DOK7, CRK/CRKL adaptors and rapsyn anchoring; AGRN/LRP4/MUSK/DOK7/CRK/CRKL/RAPSNMODULE:nmj_achr_clusteringCONCRETE At the vertebrate neuromuscular junction, nicotinic acetylcholine receptors (AChRs) are packed into the postsynaptic membrane of the skeletal... [more...][less]At the vertebrate neuromuscular junction, nicotinic acetylcholine receptors (AChRs) are packed into the postsynaptic membrane of the skeletal muscle fiber at about 10,000 per square micrometre, directly opposite the motor nerve terminal. They get there in two ways: subsynaptic nuclei transcribe the receptor genes at a higher rate, and receptors already in the membrane are clustered by tethering to a subsynaptic scaffold. The clustering signal starts with neural agrin, the z+ splice forms of AGRN that motor neurons secrete into the synaptic basal lamina. Agrin binds LRP4, a single-pass LDL-receptor-family protein on the muscle surface. LRP4 also binds the muscle-specific receptor tyrosine kinase MuSK. The arc-shaped LRP4 ectodomain holds agrin and MuSK together in a ternary complex, and this activates MuSK. Inside the cell, the adaptor DOK7 binds the phosphorylated NPXY juxtamembrane motif of MuSK through its PTB domain. Its PH-PTB region dimerises, which drives trans-autophosphorylation of the MuSK activation loop, so DOK7 acts as an intracellular activator of the kinase. MuSK then phosphorylates two tyrosines in the DOK7 C-terminal tail, and these recruit the adaptors CRK and CRKL, which relay the signal towards the actin cytoskeleton. Rapsyn (RAPSN), a 43 kDa peripheral membrane protein on the cytoplasmic face of the postsynaptic membrane, binds the AChR and links it to the MuSK-containing scaffold. Without rapsyn, receptors do not form clusters at all. Before innervation, MuSK, LRP4, rapsyn and AChRs already form aneural clusters in the central region of the muscle (prepatterning); nerve-derived agrin then sharpens and stabilises these clusters at the synapse. Loss-of-function variants in AGRN, LRP4, MUSK, DOK7 or RAPSN cause congenital myasthenic syndromes. Autoantibodies against MuSK or LRP4 cause forms of myasthenia gravis. |
Biological Process | DRAFT | Homo sapiens |
0 | skeletal muscle acetylcholine-gated channel clustering |
6 | 7 | 5 | 0 | 0 | 4 | 4/8 | 0 | ✗ | modules/nmj_achr_clustering.yaml | |
Neurotransmitter loading into synaptic vesiclesMODULE:synaptic_vesicle_neurotransmitter_loadingCONCRETE The vesicle-filling stage of the synaptic vesicle cycle. The vacuolar-type H+-ATPase on the synaptic vesicle membrane hydrolyses ATP to pump... [more...][less]The vesicle-filling stage of the synaptic vesicle cycle. The vacuolar-type H+-ATPase on the synaptic vesicle membrane hydrolyses ATP to pump protons into the lumen, generating a proton electrochemical gradient (a pH gradient plus a lumen-positive membrane potential). A vesicular neurotransmitter transporter then uses that gradient to concentrate transmitter into the vesicle against a steep concentration gradient. The transporter identity sets the transmitter phenotype of the terminal: VGLUT1/2/3 (SLC17A6/7/8) for glutamate, VGAT (SLC32A1) for GABA and glycine, VMAT2 (SLC18A2) for monoamines, and VAChT (SLC18A3) for acetylcholine. The module is modeled with human exemplars but the acidify -> load topology is conserved across metazoan chemical synapses. Grounded in GO:0098700 (neurotransmitter loading into synaptic vesicle) and GO:0097401 (synaptic vesicle lumen acidification). |
Biological Process | DRAFT | metazoa |
0 | neurotransmitter loading into synaptic vesicle |
7 | 4 | 2 | 1 | 4 | 1 | 5/9 | 0 | ✗ | modules/synaptic_vesicle_neurotransmitter_loading.yaml | |
Neurotrophin TRK receptor signaling pathway moduleMODULE:neurotrophin_trk_signaling Neurotrophins activate TRK receptor tyrosine kinases, engaging Ras-MAPK, PI3K-AKT, and PLC-gamma branches that regulate neuronal survival,... [more...][less]Neurotrophins activate TRK receptor tyrosine kinases, engaging Ras-MAPK, PI3K-AKT, and PLC-gamma branches that regulate neuronal survival, differentiation, and plasticity. |
Signaling Pathway | DRAFT | metazoa |
6 | neurotrophin TRK receptor signaling pathway |
4 | 8 | 3 | 0 | 0 | 2 | 2/6 | 0 | ✓ | modules/neurotrophin_trk_signaling.yaml | |
Neurotrophin signaling through Toll-family receptors moduleMODULE:neurotrophin_toll_signalingABSTRACT In Drosophila the secreted cystine-knot neurotrophins DNT1 (NT1, Spz2) and DNT2 (Spz5) act on neurons through the Toll-family receptors Toll-6 and... [more...][less]In Drosophila the secreted cystine-knot neurotrophins DNT1 (NT1, Spz2) and DNT2 (Spz5) act on neurons through the Toll-family receptors Toll-6 and Toll-7 rather than through Trk-family receptor tyrosine kinases. DNT binding to Toll-6 or Toll-7 regulates neuronal survival, motor axon targeting and structural synaptic plasticity; the kinase-less Trk-like receptor Kekkon-6 binds DNT2 and acts together with Toll-6 at synapses. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
2 | neurotrophin signaling pathway |
4 | 3 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/neurotrophin_toll_signaling.yaml | |
Nickel-dependent urease biogenesis and urea hydrolysisMODULE:urease_biogenesis_urea_hydrolysisCONCRETE Urease is a nickel metalloenzyme that hydrolyzes urea to ammonia and carbamate, which decomposes to a second ammonia and bicarbonate. Its catalytic... [more...][less]Urease is a nickel metalloenzyme that hydrolyzes urea to ammonia and carbamate, which decomposes to a second ammonia and bicarbonate. Its catalytic unit (the alpha chain or alpha region) is assembled first as an inactive apoprotein. The apoprotein is built from three chains (UreA gamma, UreB beta, UreC alpha) in most bacteria, from two chains in Helicobacter (a fused gamma-beta UreA plus a UreB alpha chain), and from a single chain in plants and fungi. The active site, two nickel ions bridged by a carbamylated lysine, is installed after assembly. That activation is carried out by conserved accessory proteins: UreD (UreH in Helicobacter) binds the apoprotein and, with UreF, recruits the SIMIBI-class GTPase UreG. In bacteria, the nickel metallochaperone UreE supplies nickel to UreG, and GTP hydrolysis by UreG releases nickel into the active site. Plants and fungi use UreD, UreF and UreG but have no UreE. The mature enzyme then hydrolyzes urea. The module does not include nickel uptake or homeostasis, urea transport, regulation of urease gene expression, or assimilation of the released ammonia. |
Biological Process | COMPLETE | 0 | urea catabolic process |
10 | 8 | 6 | 1 | 3 | 4 | 33/33 | 0 | ✗ | modules/urease_biogenesis_urea_hydrolysis.yaml | ||
Nicotine biosynthesis module (Nicotiana / Solanaceae)MODULE:nicotine_biosynthesis A plant-scoped, recursively decomposable decomposition of nicotine biosynthesis as it operates in Nicotiana (tobacco / wild tobacco). Nicotine is... [more...][less]A plant-scoped, recursively decomposable decomposition of nicotine biosynthesis as it operates in Nicotiana (tobacco / wild tobacco). Nicotine is an alkaloid built by condensing two separately made rings: a PYRIDINE ring supplied by the aspartate-derived NAD/quinolinate (pyridine nucleotide) branch, and a PYRROLIDINE ring (the N-methyl-Delta1-pyrrolinium cation) supplied by the polyamine/ornithine branch. The module separates these two upstream supply branches from the late "nicotine synthase" cascade that joins the rings, and from the vacuolar transport/metabolon step. This module is intentionally NOT a flat gene list (that lives in the per-gene NICAT reviews and the NICOTINE_BIOSYNTHESIS project). Its purpose is to capture the pathway-level structure that the individual gene reviews cannot: the two-branch convergence, the recently revised late steps, and the co-clustered transport component. The late steps are phrased to reflect the 2025-2026 revision of the pathway. In the classical model the N-methylpyrrolinium cation condensed with a nicotinic acid derivative directly. The new model ("complete biosynthesis of nicotine", Cell 2026, PMID:41928514; "nicotine biosynthesis completed by cryptic activating glucosylation", Nat Commun 2026, PMID:42151135) routes nicotinic acid through a hidden N-glucosylation/reduction/condensation/deglucosylation relay: a UDP-glucosyltransferase (UGT1/NaGT) glucosylates nicotinic acid to nicotinic acid N-glucoside, an A622/NaGR reductase and a BBL oxidase act on the activated glucoside during condensation with the pyrrolidine ring, and a beta-glucosidase (beta-GD1/NicGH) removes the sugar to release nicotine. A vacuolar-membrane MATE transporter (MATE1) co-clusters with A622 and beta-GD1 and is required for high heterologous production. This activating-glucosylation relay and the A622-MATE1-beta-GD1 metabolon are the parts of the pathway that GO biological-process and molecular-function terms flatten away. |
Metabolic Pathway | DRAFT | Nicotiana (wild and cultivated tobacco) |
0 | nicotine biosynthetic process |
21 | 14 | 14 | 3 | 6 | 11 | 13/13 | 1 | ✗ | modules/nicotine_biosynthesis.yaml | |
Nitric oxide-cGMP signaling pathway moduleMODULE:nitric_oxide_cgmp_signaling Nitric oxide activates soluble guanylate cyclase to raise cGMP, engaging PRKG and cyclic nucleotide phosphodiesterases that control vascular smooth... [more...][less]Nitric oxide activates soluble guanylate cyclase to raise cGMP, engaging PRKG and cyclic nucleotide phosphodiesterases that control vascular smooth muscle tone and other cGMP-dependent outputs. |
Signaling Pathway | DRAFT | metazoa |
3 | nitric oxide-cGMP-mediated signaling |
4 | 5 | 3 | 0 | 0 | 2 | 0/5 | 0 | ✓ | modules/nitric_oxide_cgmp_signaling.yaml | |
Nodal signaling pathway moduleMODULE:nodal_signaling Nodal/TGF-beta family ligands use EGF-CFC co-receptors and activin-class receptors to activate SMAD2/3 transcriptional programs for embryonic axis... [more...][less]Nodal/TGF-beta family ligands use EGF-CFC co-receptors and activin-class receptors to activate SMAD2/3 transcriptional programs for embryonic axis formation and cell-fate decisions. |
Signaling Pathway | DRAFT | metazoa |
2 | nodal signaling pathway |
5 | 7 | 4 | 0 | 0 | 3 | 4/7 | 0 | ✓ | modules/nodal_signaling.yaml | |
Notch signaling pathway in Drosophila melanogasterMODULE:dmel_notch_signalingCONCRETE Notch signaling is a juxtacrine pathway in which the transmembrane ligands Delta and Serrate on one cell bind the Notch receptor on a neighbouring... [more...][less]Notch signaling is a juxtacrine pathway in which the transmembrane ligands Delta and Serrate on one cell bind the Notch receptor on a neighbouring cell. Ligand binding, together with ligand endocytosis in the signal-sending cell, exposes Notch to cleavage by the ADAM10 metalloprotease Kuzbanian (S2 cleavage), after which the gamma-secretase complex (Presenilin, Nicastrin, Aph-1 and Pen-2) cleaves within the transmembrane domain (S3 cleavage) and releases the Notch intracellular domain. The intracellular domain enters the nucleus and forms a transcriptional activation complex with the CSL DNA-binding protein Suppressor of Hairless and the coactivator Mastermind, switching Su(H) target genes such as the Enhancer of split complex genes from repression to activation. The pathway controls lateral inhibition, boundary formation and binary cell-fate decisions throughout development. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | Notch signaling pathway |
7 | 8 | 6 | 0 | 0 | 4 | 12/12 | 0 | ✗ | modules/dmel_notch_signaling.yaml | |
NuRD nucleosome remodeling and deacetylase complex in Drosophila melanogasterMODULE:dmel_nurd_complexCONCRETE NuRD couples ATP-dependent nucleosome remodeling by the CHD-family ATPase Mi-2 with histone deacetylation by HDAC1 (Rpd3). The deacetylase core... [more...][less]NuRD couples ATP-dependent nucleosome remodeling by the CHD-family ATPase Mi-2 with histone deacetylation by HDAC1 (Rpd3). The deacetylase core also contains the MTA homolog MTA1-like and the histone-binding protein Caf1-55 (p55), and the complex further contains MBD-like, the GATAD2 homolog Simjang and CDK2AP1. NuRD represses transcription, contributes to Polycomb-dependent silencing of Hox genes, and in Drosophila Mi-2 also forms the dMec complex with the zinc-finger protein MEP-1. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | NuRD complex |
5 | 4 | 4 | 0 | 0 | 0 | 1/8 | 0 | ✗ | modules/dmel_nurd_complex.yaml | |
Nuclear DNA-directed RNA polymerases I, II and III in Drosophila melanogasterMODULE:dmel_nuclear_rna_polymerasesCONCRETE Eukaryotic nuclei contain three multisubunit DNA-directed RNA polymerases. RNA polymerase I transcribes the large ribosomal RNA precursor in the... [more...][less]Eukaryotic nuclei contain three multisubunit DNA-directed RNA polymerases. RNA polymerase I transcribes the large ribosomal RNA precursor in the nucleolus, RNA polymerase II transcribes mRNAs and most snRNAs and microRNA precursors, and RNA polymerase III transcribes tRNAs, 5S rRNA, U6 snRNA and other short structured RNAs. Each enzyme has two large catalytic subunits that form the active site, a set of subunits shared by all three enzymes (RPABC1, RPABC2, RPABC3, RPABC4 and RPABC5), subunits shared by Pol I and Pol III (RPAC1 and RPAC2), and enzyme-specific subunits. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | nuclear DNA-directed RNA polymerase complex |
4 | 3 | 3 | 0 | 0 | 0 | 0/31 | 0 | ✗ | modules/dmel_nuclear_rna_polymerases.yaml | |
Nuclear piRNA pathway complexes (RDC and PICTS) in Drosophila melanogasterMODULE:dmel_pirna_nuclear_complexesCONCRETE Two nuclear complexes act in the Drosophila germline piRNA pathway. The Rhino-Deadlock-Cutoff (RDC) complex binds dual-strand piRNA clusters, where... [more...][less]Two nuclear complexes act in the Drosophila germline piRNA pathway. The Rhino-Deadlock-Cutoff (RDC) complex binds dual-strand piRNA clusters, where the HP1 paralog Rhino recognises H3K9me3, and licenses non-canonical transcription of cluster precursors that are processed into piRNAs. The Panoramix-induced co-transcriptional silencing complex (PICTS, also called SFiNX), made of Panoramix, Nxf2, Nxt1 and dynein light chain Ctp, is recruited by piRNA-guided Piwi to nascent transposon transcripts and triggers H3K9 methylation and heterochromatin formation over the target. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | piRNA-mediated heterochromatin formation |
3 | 2 | 2 | 0 | 0 | 0 | 0/7 | 0 | ✗ | modules/dmel_pirna_nuclear_complexes.yaml | |
Nuclear pore complex and Ran-dependent karyopherin transportMODULE:nuclear_pore_transport_coreCONCRETE Proteins and RNAs cross the nuclear envelope through nuclear pore complexes, built from nucleoporins that form a scaffold of stacked rings and a... [more...][less]Proteins and RNAs cross the nuclear envelope through nuclear pore complexes, built from nucleoporins that form a scaffold of stacked rings and a central channel lined with FG repeats. Karyopherins of the importin-beta superfamily carry cargo through the channel, and the small GTPase Ran sets the direction: Ran-GTP, made in the nucleus by RCC1, releases import cargo and loads export cargo, while Ran-GDP is returned to the nucleus by NTF2. This module is the eukaryote-wide part of that system that can be grounded locally, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
6 | nucleocytoplasmic transport |
4 | 8 | 3 | 0 | 0 | 2 | 1/8 | 0 | ✗ | modules/nuclear_pore_transport_core.yaml | |
Nuclear pore complex in Drosophila melanogasterMODULE:dmel_nuclear_pore_complexCONCRETE The nuclear pore complex (NPC) is a large assembly of about 30 different nucleoporins, each present in multiple copies, that spans the nuclear... [more...][less]The nuclear pore complex (NPC) is a large assembly of about 30 different nucleoporins, each present in multiple copies, that spans the nuclear envelope and controls traffic between nucleus and cytoplasm. A symmetric core of stacked rings (two outer rings built from the Nup107-160 Y-complex, an inner ring, and a transmembrane ring) anchors a central channel filled with phenylalanine-glycine (FG) repeat nucleoporins that form the permeability barrier. Asymmetric cytoplasmic filaments and a nuclear basket attach to the core and act in mRNA export and in docking of transport receptors. Several Drosophila nucleoporins also act off the pore, for example in gene regulation and in mitosis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | nuclear pore |
8 | 8 | 7 | 0 | 0 | 0 | 1/31 | 0 | ✗ | modules/dmel_nuclear_pore_complex.yaml | |
Nucleokinesis (motor-driven nuclear translocation) moduleMODULE:nucleokinesisABSTRACT Nucleokinesis is the directed translocation of the nucleus within a cell that is migrating or changing shape, most prominently in migrating neurons... [more...][less]Nucleokinesis is the directed translocation of the nucleus within a cell that is migrating or changing shape, most prominently in migrating neurons and in the interkinetic nuclear migration of neuroepithelial and radial glial progenitors. In migrating neurons it follows a two-stroke cycle: the centrosome and Golgi first advance into a swelling of the leading process, and the nucleus then moves forward toward them in a saltatory step. The nucleus is coupled to cytoplasmic motors through its envelope, either by LINC complexes (inner-nuclear-membrane SUN proteins bound to outer-nuclear-membrane KASH nesprins, with nesprin-2 recruiting dynein and kinesin through the adaptor BICD2) or, in G2 radial glial progenitors, by nuclear-pore-anchored dynein adaptors (RANBP2-BICD2 and NUP133-CENPF-NDE1/NDEL1). Cytoplasmic dynein, with dynactin and the LIS1-NDEL1/NDE1 regulatory module, pulls the nucleus toward microtubule minus ends at the centrosome along a perinuclear microtubule cage stabilized by doublecortin. Non-muscle myosin II contraction at the rear of the soma assists forward nuclear movement, and in progenitors the kinesin-3 KIF1A drives the opposite, basally directed nuclear movement. CDK5/p35 phosphorylation of NDEL1 links the core machinery to migration signaling. The same dynein-driven program also operates outside the central nervous system: trunk neural crest cells use it to pull their nucleus through confined tissue spaces. Loss of LIS1 or DCX causes lissencephaly, reflecting the dependence of cortical neuronal migration on this machinery. |
Biological Process | DRAFT | Metazoa |
1 | nuclear migration nuclear migration along microtubule nucleokinesis in radial glia-guided cortical migration interkinetic nuclear migration |
10 | 11 | 6 | 1 | 3 | 4 | 18/18 | 0 | ✓ | modules/nucleokinesis.yaml | |
Nucleus and nuclear envelope lifecycleMODULE:nucleus_lifecycleCONCRETE The nucleus is bounded by a double-membrane envelope continuous with the endoplasmic reticulum and perforated by nuclear pore complexes. Pores are... [more...][less]The nucleus is bounded by a double-membrane envelope continuous with the endoplasmic reticulum and perforated by nuclear pore complexes. Pores are inserted into the intact envelope during interphase and, in cells with an open mitosis, the envelope and pores are disassembled at prophase and rebuilt around the daughter chromosomes, with ESCRT-III sealing the remaining holes. Throughout, the pores and the Ran system move proteins and RNAs between nucleus and cytoplasm. This umbrella module composes the modules for those stages by reference. The pore and Ran transport core is required in every eukaryote; the single-species descriptions are optional. |
Organelle Lifecycle | DRAFT | Eukaryota |
0 | nucleus organization nucleus |
5 | 0 | 4 | 0 | 0 | 2 | 0/0 | 0 | ✗ | modules/nucleus_lifecycle.yaml | |
Oligosaccharyltransferase (OST) complex - N-glycan transfer (STT3A/STT3B + accessory subunits)MODULE:oligosaccharyltransferase_complex The oligosaccharyltransferase (OST) complex is the endoplasmic-reticulum-membrane enzyme that performs the central, committed step of N-linked... [more...][less]The oligosaccharyltransferase (OST) complex is the endoplasmic-reticulum-membrane enzyme that performs the central, committed step of N-linked glycosylation: en-bloc transfer of the preassembled Glc3Man9GlcNAc2 glycan from dolichyl diphosphate (Dol-PP) onto the side-chain amide of asparagine residues within N-X-S/T sequons of nascent secretory and membrane proteins. Humans have two OST isoforms distinguished by their catalytic subunit. The STT3A complex (OST-A) is docked at the SEC61 translocon and glycosylates sequons co-translationally as the polypeptide enters the ER; its subunit OSTC (DC2) tethers it to the translocon. The STT3B complex (OST-B) acts post-translationally and translocon-independently, providing a proofreading second pass that glycosylates skipped, C-terminal and closely-spaced sequons; its thioredoxin-like oxidoreductase subunits MAGT1 and TUSC3 use a CXXC motif to transiently engage substrate cysteines, enabling glycosylation of cysteine-proximal sequons. Both isoforms share a set of non-catalytic scaffold subunits - ribophorin I (RPN1), ribophorin II (RPN2), OST48 (DDOST) and DAD1 - required for complex integrity and substrate presentation. Defects in individual subunits cause congenital disorders of glycosylation (STT3A-, STT3B-, DDOST-CDG), X-linked immunodeficiency with magnesium defect (MAGT1/XMEN) and autosomal-recessive intellectual disability (TUSC3). |
Metabolic Pathway | DRAFT | 0 | protein N-linked glycosylation protein co-translational transfer of dolichol-linked oligosaccharide protein post-translational transfer of dolichol-linked oligosaccharide |
4 | 8 | 3 | 0 | 0 | 3 | 9/9 | 0 | ✗ | modules/oligosaccharyltransferase_complex.yaml | ||
OpgH-associated periplasmic glucan synthesis and processingMODULE:osmoregulated_periplasmic_glucan_biosynthesisCONCRETE OpgH membrane glucosyltransferases support synthesis of beta-glucan backbones in characterized OpgGH-dependent systems. The required native... [more...][less]OpgH membrane glucosyltransferases support synthesis of beta-glucan backbones in characterized OpgGH-dependent systems. The required native chemical contribution of OpgG remains unresolved. Particular realizations additionally need OpgI or a compatible ACP-dependent membrane system. Periplasmic processing includes E. coli OpgD hydrolysis and Xanthomonas OpgD alpha-1,6 cyclization, which are distinct reactions within the same protein subfamily. Caulobacter OpgH provides a comparative homolog whose native product chemistry remains unresolved. |
Biological Process | COMPLETE | Pseudomonadota |
0 | osmoregulated periplasmic glucan biosynthetic process |
10 | 8 | 7 | 1 | 2 | 0 | 11/11 | 0 | ✓ | modules/osmoregulated_periplasmic_glucan_biosynthesis.yaml | |
Oxidative phosphorylation (OXPHOS) moduleMODULE:oxidative_phosphorylation A taxon-neutral decomposition of oxidative phosphorylation: the coupled process by which a respiratory electron transport chain (ETC) oxidizes... [more...][less]A taxon-neutral decomposition of oxidative phosphorylation: the coupled process by which a respiratory electron transport chain (ETC) oxidizes reduced cofactors and uses the released free energy to pump protons across a coupling membrane, and an F1Fo-ATP synthase uses the resulting proton-motive force to phosphorylate ADP. The module is deliberately phrased in terms of functional modules, protein complexes, and pathway segments rather than a fixed gene list, so it can represent the mitochondrial inner-membrane chain of eukaryotes and the plasma-membrane respiratory chains of aerobic bacteria. Design intent for complexes (the central modelling question): each respiratory complex is represented as a single PROTEIN_COMPLEX node whose emergent, complex-level catalytic activity is carried by ONE complex-level annoton (the redox half-reaction it performs), with its functionally important subunits exposed as `active_units` on the complex descriptor rather than as separate per-subunit annotons. This mirrors the GO `contributes_to` philosophy: an individual subunit contributes to but does not independently enable the complex activity. Large, internally modular complexes (Complex I; the F1Fo-ATP synthase) are additionally decomposed with `parts` into their functional sub-modules (the N/Q/proton-pumping arms of Complex I; the F1 catalytic head and Fo proton turbine of ATP synthase) — this recursive decomposition is the payoff of the module representation over a flat subunit list. Lineage- and chemistry-specific alternatives that bypass the proton-pumping complexes (type-II NADH dehydrogenase, the alternative oxidase, bacterial bd-type oxidases) are captured as `variant_sets` along explicit axes, so OXPHOS reads as one conserved energy-conservation plan with multiple implementations. Complex assembly/biogenesis is treated as a distinct process from chain operation and kept as an optional sub-module. |
Biological Process | DRAFT | aerobic (and facultative) bacteria mitochondriate eukaryotes |
0 | oxidative phosphorylation aerobic respiration generation of precursor metabolites and energy |
24 | 24 | 18 | 2 | 5 | 9 | 5/5 | 18 | ✗ | modules/oxphos.yaml | |
Oxidative protein folding in the ERMODULE:er_oxidative_protein_foldingCONCRETE Proteins entering the endoplasmic reticulum fold in its lumen with the help of the Hsp70 chaperone BiP and form disulfide bonds through a relay in... [more...][less]Proteins entering the endoplasmic reticulum fold in its lumen with the help of the Hsp70 chaperone BiP and form disulfide bonds through a relay in which protein disulfide isomerase oxidizes the substrate and is itself reoxidized by the flavoprotein Ero1, which passes the electrons to oxygen; animals also use peroxiredoxin-4, VKOR-family enzymes and GPX7/8. Glycoproteins are also monitored by the calnexin/calreticulin cycle. This module is the eukaryote-wide core of ER folding, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
6 | protein folding in endoplasmic reticulum |
5 | 5 | 4 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/er_oxidative_protein_folding.yaml | |
Oxygenic photosynthesis moduleMODULE:oxygenic_photosynthesis A taxon-neutral decomposition of oxygenic photosynthesis as a recursively decomposable module. The module separates the thylakoid light reactions... [more...][less]A taxon-neutral decomposition of oxygenic photosynthesis as a recursively decomposable module. The module separates the thylakoid light reactions (light harvesting, water oxidation at photosystem II, the cytochrome b6f complex, photosystem I, mobile electron carriers, ferredoxin-NADP+ reductase, and the ATP synthase) from carbon fixation by the Calvin-Benson-Bassham reductive pentose-phosphate cycle, and adds optional photoprotection/electron balancing, the inorganic carbon-concentrating mechanism, and chlorophyll supply. It is phrased as functions, complexes, and pathway segments rather than a fixed gene list so it can represent cyanobacterial, algal, and plant implementations. Anoxygenic photosynthesis (single reaction center, non-water electron donors) is explicitly out of scope. The C4 and CAM carbon-concentrating shuttles are siblings rather than parts: each includes the Calvin-Benson-Bassham module by reference in its own right, C4 operating between two cell types and CAM separating the two carboxylations in time (MODULE:c4_carbon_shuttle, MODULE:cam_carbon_shuttle). |
Biological Process | DRAFT | cyanobacteria eukaryotic algae land plants |
0 | oxygenic photosynthesis |
11 | 8 | 5 | 2 | 5 | 2 | 1/1 | 5 | ✓ | modules/photosynthesis.yaml | |
P granule assembly and asymmetric segregation in Caenorhabditis elegansMODULE:c_elegans_p_granule_assembly_segregationCONCRETE P granules are the germline ribonucleoprotein condensates of Caenorhabditis elegans. In adult germ cells they sit on the cytoplasmic face of... [more...][less]P granules are the germline ribonucleoprotein condensates of Caenorhabditis elegans. In adult germ cells they sit on the cytoplasmic face of nuclear pore clusters, where newly exported mRNAs pass through them. In oocytes and embryos they are cytoplasmic and are inherited by the germline founder cell. The condensate is built in layers. The PGL proteins PGL-1 and PGL-3 (with PGL-2 after embryogenesis) self-associate and bind RNA to form the liquid core. The Vasa-family DEAD-box helicases GLH-1 and GLH-4 (with GLH-2) gather at nuclear pores independently of the PGLs and are needed for the PGLs to reach the nuclear periphery. DEPS-1 is a perinuclear P granule protein that is needed for PGL-1 localization and GLH-1 accumulation, and that binds the Piwi protein PRG-1. In the zygote, the intrinsically disordered proteins MEG-3 and MEG-4 condense with mRNA on the surface of PGL droplets. This shell stabilizes the granules, recruits about 500 mRNAs, and makes the granules co-segregate with the germline. Segregation to the posterior blastomere uses two regulatory inputs. First, PAR polarity sets up an anterior-high gradient of the RNA-binding proteins MEX-5 and MEX-6. MEX-5 competes with PGL-3 and MEG-3 for RNA, so granules dissolve in the anterior and condense in the posterior. Second, the DYRK kinase MBK-2 phosphorylates MEG-1 and MEG-3 to promote granule disassembly, and the PP2A phosphatase with its PPTR-1/PPTR-2 B56 regulatory subunits reverses this to promote assembly. MEG-1 and MEG-2 scaffold a second germ plasm condensate. These germline P-bodies carry the DDX6 helicase CGH-1 and other decapping and deadenylation regulators, and they are needed to specify the germline founder cell. Loss of P granule components causes temperature-sensitive or complete sterility, and germ cells that lack P granules can switch to somatic fates. |
Organelle Lifecycle | DRAFT | Caenorhabditis elegans |
0 | P granule organization |
7 | 17 | 6 | 0 | 0 | 7 | 17/17 | 0 | ✗ | modules/c_elegans_p_granule_assembly_segregation.yaml | |
PAPS biosynthesis and Golgi import (sulfate activation) (PAPSS1/2 -> SLC35B2/3)MODULE:paps_sulfate_activation Sulfation of biomolecules requires an activated sulfonate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the universal substrate of every... [more...][less]Sulfation of biomolecules requires an activated sulfonate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS), the universal substrate of every cytosolic and Golgi-lumenal sulfotransferase (sulfation of glycosaminoglycans/proteoglycans, glycolipids, steroids and DHEA, thyroid hormone, catecholamines, tyrosine residues and xenobiotics). PAPS is made in two steps by a single bifunctional enzyme, PAPS synthase (PAPSS1, ubiquitous; PAPSS2, predominant in cartilage): an ATP sulfurylase (sulfate adenylyltransferase) domain condenses inorganic sulfate with ATP to adenosine 5'-phosphosulfate (APS) + pyrophosphate, and an APS kinase (adenylyl-sulfate kinase) domain phosphorylates APS with a second ATP to PAPS + ADP. The cytosolic PAPS pool feeds cytosolic sulfotransferases directly, and is imported into the Golgi lumen by the antiporters SLC35B2 (PAPST1) and SLC35B3 (PAPST2), which exchange cytosolic PAPS for lumenal PAP (adenosine 3',5'-bisphosphate, the spent product), supplying the Golgi sulfotransferases that sulfate secreted and membrane glycoconjugates. Defects illustrate the pathway's importance: biallelic PAPSS2 mutations cause spondyloepimetaphyseal dysplasia (Pakistani-type brachyolmia) and androgen excess through defective proteoglycan and DHEA sulfation. |
Metabolic Pathway | DRAFT | 0 | 3'-phosphoadenosine 5'-phosphosulfate biosynthetic process sulfate assimilation 3'-phospho-5'-adenylyl sulfate transmembrane transport |
3 | 3 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/paps_sulfate_activation.yaml | ||
PDGFR signaling pathway moduleMODULE:pdgfr_signaling Platelet-derived growth factor ligands activate PDGFR receptor tyrosine kinases, recruiting SH2 adaptors and lipid-kinase branches that control... [more...][less]Platelet-derived growth factor ligands activate PDGFR receptor tyrosine kinases, recruiting SH2 adaptors and lipid-kinase branches that control mesenchymal proliferation, migration, and survival. |
Signaling Pathway | DRAFT | metazoa |
10 | platelet-derived growth factor receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 4/5 | 0 | ✓ | modules/pdgfr_signaling.yaml | |
PMK-1 p38 MAPK intestinal innate immunity in Caenorhabditis elegansMODULE:c_elegans_pmk1_intestinal_immunityCONCRETE In the Caenorhabditis elegans intestine, a conserved p38 MAPK cassette is the main signaling route by which infection and other physiological... [more...][less]In the Caenorhabditis elegans intestine, a conserved p38 MAPK cassette is the main signaling route by which infection and other physiological stresses induce antibacterial defense genes. The TIR-domain protein TIR-1, the nematode ortholog of SARM1, oligomerizes into puncta in intestinal epithelial cells under pathogen or non-pathogen stress. Its NAD+ glycohydrolase activity, which oligomerization strongly potentiates, is required to activate the cascade. TIR-1 acts upstream of the ASK1-family MAP3K NSY-1, which activates the MKK3/6-family MAP2K SEK-1, which in turn phosphorylates and activates the p38 MAPK PMK-1. PMK-1 phosphorylates the CREB/ATF bZIP transcription factor ATF-7. Unphosphorylated ATF-7 represses PMK-1-regulated genes, and phosphorylation switches it to an activator. ATF-7 occupies regulatory regions of pathogen-induced genes in a PMK-1-dependent manner and controls most genes induced by Pseudomonas aeruginosa infection. These outputs include secreted proteins such as C-type lectin domain proteins, lysozymes, CUB-like proteins and ShK-toxin-domain peptides, most of which have not been shown to act against microbes. The ShKT gene sysm-1 (T24B8.5) is the standard transcriptional reporter of pathway activity, but its only demonstrated function is as a secreted intestinal signal that promotes DNA damage-induced germ cell apoptosis. The pathway acts cell-autonomously in the intestine, cooperates with the GATA factor ELT-2, and is required for resistance to Gram-negative and Gram-positive bacteria. The same TIR-1/NSY-1/SEK-1 module also has neuronal roles in AWC asymmetry and serotonin-dependent behavior, and PMK-1 has a second transcriptional target, SKN-1, in the oxidative stress response. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | antibacterial innate immune response p38MAPK cascade |
5 | 7 | 4 | 0 | 0 | 3 | 7/7 | 0 | ✗ | modules/c_elegans_pmk1_intestinal_immunity.yaml | |
PTW/PP1 phosphatase complexes in Drosophila melanogasterMODULE:dmel_ptw_pp1_complexesCONCRETE The PTW/PP1 complex is a nuclear phosphatase complex made of the PP1-targeting subunit PNUTS, the DNA-binding HMG-box protein Tox4, the WD40... [more...][less]The PTW/PP1 complex is a nuclear phosphatase complex made of the PP1-targeting subunit PNUTS, the DNA-binding HMG-box protein Tox4, the WD40 protein Wdr82 and a protein phosphatase 1 catalytic subunit. In other animals it binds chromatin, dephosphorylates RNA polymerase II and transcription elongation factors near the ends of genes and in promoter-proximal regions, and is needed for chromatin reorganization at mitotic exit. Drosophila has four PP1 catalytic subunits (Pp1-87B, Pp1alpha-96A, Pp1-13C and Flapwing, Flw), and FlyBase defines a PTW complex for each. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | PTW/PP1 phosphatase complex |
7 | 5 | 2 | 1 | 4 | 1 | 1/7 | 0 | ✗ | modules/dmel_ptw_pp1_complexes.yaml | |
PVR receptor tyrosine kinase signaling in Drosophila melanogasterMODULE:dmel_pvr_signalingCONCRETE PVR is the single Drosophila receptor tyrosine kinase related to vertebrate PDGF and VEGF receptors. It is activated by three secreted ligands,... [more...][less]PVR is the single Drosophila receptor tyrosine kinase related to vertebrate PDGF and VEGF receptors. It is activated by three secreted ligands, Pvf1, Pvf2 and Pvf3. PVR signaling guides the migration of border cells in the ovary and of other cells during development, and supports the survival, proliferation and migration of embryonic and larval hemocytes, and acts in dorsal closure and thorax closure. Downstream of the receptor, signaling runs through several branches: the Ras-Raf-MEK-ERK cascade, a Crk-Myoblast city-Ced-12 route to the Rac GTPase that drives actin-based migration, a PI3K-Akt-TOR branch that supports growth and survival, and JNK and p38 kinase cascades. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | platelet-derived growth factor receptor signaling pathway vascular endothelial growth factor receptor signaling pathway |
8 | 33 | 7 | 0 | 0 | 6 | 11/33 | 0 | ✗ | modules/dmel_pvr_signaling.yaml | |
Pan-metazoan Hedgehog/Smoothened signaling pathway moduleMODULE:hedgehog_signalingCONCRETE A taxon-neutral decomposition of Hedgehog (Hh) signaling, the metazoan cell-cell communication system in which a dually lipidated Hedgehog ligand... [more...][less]A taxon-neutral decomposition of Hedgehog (Hh) signaling, the metazoan cell-cell communication system in which a dually lipidated Hedgehog ligand released by a signal-sending cell controls the activator/repressor balance of Ci/GLI zinc-finger transcription factors in a receiving cell. The module is written around the segments that are shared from cnidarians and insects to vertebrates: autocatalytic cholesterol-coupled processing and N-terminal palmitoylation of the ligand; reception by the twelve-pass Patched receptor and its Ig/fibronectin-domain co-receptors; relief of Patched-mediated restriction of sterol access to the class-F receptor Smoothened; kinase-driven proteolytic processing of Ci/GLI into a transcriptional repressor when the pathway is off; and Smoothened-dependent conversion of Ci/GLI into an activator through Suppressor of fused, Fused-family kinases, and a kinesin-4 scaffold. Where lineages differ they are modeled as variants on an explicit axis rather than as separate pathways: the vertebrate implementation runs the activation step in the primary cilium with GPR161, intraflagellar transport, and KIF7, while the Drosophila implementation runs the equivalent step on a cytoplasmic Hedgehog signaling complex nucleated by the Costal-2 kinesin at the plasma membrane. Sonic hedgehog (SHH) is the vertebrate exemplar ligand, but it is one of three vertebrate paralogs of the single ancestral Hedgehog ligand and is used here only as a representative member. |
Signaling Pathway | DRAFT | Drosophila melanogaster metazoa vertebrates |
4 | smoothened signaling pathway pattern specification process |
11 | 27 | 6 | 2 | 4 | 16 | 22/38 | 0 | ✗ | modules/hedgehog_signaling.yaml | |
Pantoate-derived coenzyme A biosynthesisMODULE:coenzyme_a_biosynthesis Synthesis of coenzyme A (CoA) from pantoate and beta-alanine. The pantoate branch transfers a hydroxymethyl group to 3-methyl-2-oxobutanoate,... [more...][less]Synthesis of coenzyme A (CoA) from pantoate and beta-alanine. The pantoate branch transfers a hydroxymethyl group to 3-methyl-2-oxobutanoate, reduces 2-dehydropantoate to (R)-pantoate, and reaches 4'-phosphopantothenate by one of two reaction-order variants. Bacteria and eukaryotes generally use PanC to form pantothenate and then one of three unrelated pantothenate kinase families. Most archaea instead phosphorylate pantoate with PoK before PPS condenses 4-phosphopantoate with beta-alanine, so free pantothenate is not an intermediate. Four subsequent reactions add and decarboxylate cysteine, adenylylate 4'-phosphopantetheine, and phosphorylate dephospho-CoA. CoaB and CoaC may be separate or fused, and the final CoaD and CoaE activities may be separate or fused in CoA synthase. The phosphopantothenoylcysteine decarboxylase may be a homo-oligomeric flavoprotein or, in budding yeast, a heterotrimer in which two paralogous subunit types each contribute an essential catalytic residue. Beta-alanine is supplied by lineage-specific routes and is modeled as an optional supply part with two characterized enzymatic variants: PanD-dependent decarboxylation of L-aspartate in bacteria, and the polyamine-oxidation route of Saccharomyces-type yeasts, in which a flavin polyamine oxidase cleaves spermine to spermidine and 3-aminopropanal and cytosolic aldehyde dehydrogenases oxidize 3-aminopropanal to beta-alanine. Pyrimidine degradation and uptake are further sources that are not modeled here. CoA salvage, phosphopantetheine release from acyl carrier proteins, and downstream CoA-dependent metabolism are outside the module boundary. |
Metabolic Pathway | DRAFT | 7 | pantothenate biosynthetic process coenzyme A biosynthetic process |
29 | 19 | 14 | 6 | 14 | 10 | 34/46 | 0 | ✓ | modules/coenzyme_a_biosynthesis.yaml | ||
ParABS-type DNA segregation (chromosomes and type I plasmids)MODULE:parabs_dna_segregationABSTRACT Reusable module for the bacterial ParABS DNA-segregation machine, which moves newly replicated copies of a replicon into the two daughter-cell... [more...][less]Reusable module for the bacterial ParABS DNA-segregation machine, which moves newly replicated copies of a replicon into the two daughter-cell halves. A centromere-like DNA site (parS on chromosomes; sopC, parS or O_B on plasmids) is bound by a ParB-type protein that, in the characterized systems, loads as a CTP-dependent sliding clamp and spreads to form a partition complex. A deviant Walker-type ParA ATPase binds the nucleoid non-specifically as an ATP-bound dimer, and the partition complex stimulates its ATP hydrolysis, releasing it from DNA; the resulting ParA gradient positions and separates the partition complexes. The same two roles are filled by chromosome-encoded ParA/ParB (Soj/Spo0J) at origin-proximal parS sites and by type I plasmid partition proteins such as SopA/SopB of F, ParA/ParB of P1 and IncC/KorB of RK2. |
Biological Process | DRAFT | bacteria |
0 | chromosome segregation plasmid partitioning |
7 | 6 | 2 | 2 | 4 | 1 | 9/14 | 0 | ✗ | modules/parabs_dna_segregation.yaml | |
Parathyroid hormone receptor signaling — PTH acting through PTH1R, dual Gs/adenylyl cyclase and Gq/PLC coupling, NHERF/ezrin scaffold control of coupling, and GRK2/beta-arrestin desensitizationMODULE:pth_receptor_signalingCONCRETE Parathyroid hormone (PTH), secreted by the parathyroid glands when blood calcium falls, acts on kidney and bone through the parathyroid hormone 1... [more...][less]Parathyroid hormone (PTH), secreted by the parathyroid glands when blood calcium falls, acts on kidney and bone through the parathyroid hormone 1 receptor (PTH1R), a class B G protein-coupled receptor that is also activated by PTH-related protein. A single PTH1R couples to two G protein routes: the stimulatory G alpha s (GNAS), which activates adenylyl cyclase, cAMP production and protein kinase A, and is the main route; and G alpha q/11, which activates phospholipase C beta, producing inositol trisphosphate (calcium release) and diacylglycerol (protein kinase C). The balance between the two is set by scaffold proteins at the receptor's carboxy-terminal tail. The PDZ-domain scaffolds NHERF1 and NHERF2 bind the PTH1R carboxy terminus; NHERF2 simultaneously binds phospholipase C beta 1, biasing PTH1R toward phospholipase C signalling and inhibiting adenylyl cyclase through Gi/o, and NHERF1 likewise enables PTH-stimulated calcium signalling. Ezrin, an actin-membrane linker, binds both PTH1R and NHERF1 and supports apical PTH1R localization and signalling in renal proximal tubule cells. Signalling is terminated when GRK2 phosphorylates the agonist-occupied receptor and beta-arrestins (ARRB1, ARRB2) bind it, uncoupling it from G proteins and driving its dynamin-dependent endocytosis. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cellular response to parathyroid hormone stimulus |
9 | 7 | 6 | 1 | 2 | 7 | 1/9 | 0 | ✗ | modules/pth_receptor_signaling.yaml | |
Pentose phosphate pathwayMODULE:pentose_phosphate_pathwayCONCRETE A reusable central-carbon module for the pentose phosphate pathway, covering the oxidative conversion of glucose 6-phosphate to ribulose... [more...][less]A reusable central-carbon module for the pentose phosphate pathway, covering the oxidative conversion of glucose 6-phosphate to ribulose 5-phosphate, the non-oxidative interconversion of pentose phosphates with fructose 6-phosphate and glyceraldehyde 3-phosphate, and the activation of ribose 5-phosphate to 5-phospho-alpha-D-ribose 1-diphosphate (PRPP). The oxidative branch generates NADPH through glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, with 6-phosphogluconolactonase hydrolyzing the intermediate lactone; its first step is irreversible and rate-limiting. The reversible non-oxidative branch uses ribose-5-phosphate isomerase, ribulose-phosphate 3-epimerase, transketolase, and transaldolase to balance ribose 5-phosphate, xylulose 5-phosphate, sedoheptulose 7-phosphate, erythrose 4-phosphate, fructose 6-phosphate, and glyceraldehyde 3-phosphate according to the demand for NADPH, nucleotide precursors and glycolytic intermediates. Ribose 5-phosphate leaves the pathway mainly through ribose-phosphate diphosphokinase, whose product PRPP feeds nucleotide, histidine and tryptophan biosynthesis. In eukaryotes the pathway is cytosolic. Yeast and bacterial proteins are used as concrete exemplars. |
Metabolic Pathway | DRAFT | 2 | pentose-phosphate shunt |
12 | 9 | 11 | 0 | 0 | 10 | 34/36 | 0 | ✓ | modules/pentose_phosphate_pathway.yaml | ||
Pentose phosphate pathway — non-oxidative branch + PRPP synthesis; transaldolase/RPIA deficiency, PRPS1 disordersMODULE:pentose_phosphate_nonoxidative_branch The non-oxidative branch of the pentose phosphate pathway is a set of reversible sugar-phosphate rearrangements that interconvert the five-carbon... [more...][less]The non-oxidative branch of the pentose phosphate pathway is a set of reversible sugar-phosphate rearrangements that interconvert the five-carbon sugar ribulose-5-phosphate (from the oxidative branch) with ribose-5-phosphate for nucleotide synthesis and with the glycolytic intermediates fructose-6-phosphate and glyceraldehyde-3-phosphate — allowing cells to balance their demand for NADPH versus ribose-5-phosphate. Ribose-5-phosphate isomerase (RPIA) interconverts ribulose-5-phosphate and ribose-5-phosphate; ribulose-5-phosphate 3-epimerase (RPE) interconverts ribulose-5-phosphate and xylulose-5-phosphate; transketolase (TKT, thiamine-diphosphate-dependent) transfers two-carbon units, converting xylulose-5-phosphate + ribose-5-phosphate to sedoheptulose-7-phosphate + glyceraldehyde-3-phosphate (and, in a second reaction, xylulose-5-phosphate + erythrose-4-phosphate to fructose-6-phosphate + glyceraldehyde-3-phosphate); and transaldolase (TALDO1) transfers a three-carbon unit, converting sedoheptulose-7-phosphate + glyceraldehyde-3-phosphate to erythrose-4-phosphate + fructose-6-phosphate. Finally, phosphoribosyl pyrophosphate synthetase (PRPS1) uses ribose-5-phosphate + ATP to make 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) + AMP — the activated precursor that commits pentose carbon to de novo and salvage synthesis of purine, pyrimidine and pyridine (NAD) nucleotides. Inherited defects: transaldolase (TALDO1) deficiency causes liver disease and hemolytic anemia; ribose-5-phosphate isomerase (RPIA) deficiency is an extremely rare progressive leukoencephalopathy; and PRPS1 loss-of-function causes Arts syndrome / CMTX5 / DFN2 while gain-of-function (superactivity) causes purine overproduction with gout. |
Metabolic Pathway | DRAFT | 0 | pentose-phosphate shunt, non-oxidative branch |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/pentose_phosphate_nonoxidative_branch.yaml | ||
Pentose phosphate pathway — oxidative branch (NADPH generation); G6PD deficiency / favismMODULE:pentose_phosphate_oxidative_branch The oxidative branch of the pentose phosphate pathway is the cytosolic route that diverts glucose-6-phosphate away from glycolysis to generate... [more...][less]The oxidative branch of the pentose phosphate pathway is the cytosolic route that diverts glucose-6-phosphate away from glycolysis to generate NADPH and pentose sugars. In three irreversible steps it converts glucose-6-phosphate to ribulose-5-phosphate, producing two molecules of NADPH and one CO2: glucose-6-phosphate dehydrogenase (G6PD) oxidises glucose-6-phosphate to 6-phosphogluconolactone (reducing NADP+ to NADPH) as the committed, rate-limiting step; 6-phosphogluconolactonase (PGLS) hydrolyses the labile lactone to 6-phosphogluconate; and 6-phosphogluconate dehydrogenase (PGD) oxidatively decarboxylates 6-phosphogluconate to ribulose-5-phosphate + CO2 (reducing a second NADP+). The NADPH produced is the cell's principal reducing power for reductive biosynthesis (fatty acids, cholesterol, nucleotides) and, critically in erythrocytes, for regenerating reduced glutathione to defend against oxidative stress; the ribulose-5-phosphate feeds the non-oxidative branch (and thence ribose-5-phosphate for nucleotide synthesis). Inherited G6PD deficiency is the most common human enzyme defect (~400 million people), X-linked, causing acute oxidant-triggered hemolytic anemia (favism, drug/infection-induced), neonatal jaundice, and — in severe class-I variants — chronic nonspherocytic hemolytic anemia. |
Metabolic Pathway | DRAFT | 0 | pentose-phosphate shunt, oxidative branch |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/pentose_phosphate_oxidative_branch.yaml | ||
Peptidoglycan precursor biosynthesis and lipid II exportMODULE:peptidoglycan_precursor_biosynthesisCONCRETE A reusable bacterial pathway that converts UDP-N-acetylglucosamine to UDP-MurNAc-pentapeptide, transfers that nucleotide precursor to the... [more...][less]A reusable bacterial pathway that converts UDP-N-acetylglucosamine to UDP-MurNAc-pentapeptide, transfers that nucleotide precursor to the undecaprenyl carrier to form lipid I, glycosylates lipid I to form lipid II, and translocates lipid II across the cytoplasmic membrane. D-Ala-D-Ala synthesis is modeled as a convergent input to MurF, and alternative MurE branches represent meso-diaminopimelate- and L-lysine-containing stem peptides. The module ends at lipid II export and does not include glycan polymerization, peptide cross-linking, carrier recycling, or cell-wall remodeling. |
Metabolic Pathway | DRAFT | 0 | peptidoglycan biosynthetic process |
13 | 11 | 10 | 1 | 2 | 9 | 19/22 | 0 | ✓ | modules/peptidoglycan_precursor_biosynthesis.yaml | ||
Peroxisomal fatty-acid beta-oxidationMODULE:peroxisomal_beta_oxidation Peroxisomal beta-oxidation chain-shortens acyl-CoAs two carbons per turn inside the peroxisomal matrix. In fungi such as budding yeast and in... [more...][less]Peroxisomal beta-oxidation chain-shortens acyl-CoAs two carbons per turn inside the peroxisomal matrix. In fungi such as budding yeast and in plants it is the only fatty-acid beta-oxidation system of the cell, whereas in animals it handles the substrates mitochondria cannot: very-long-chain fatty acids, 2-methyl-branched fatty acids (pristanic acid), the C27 bile-acid intermediates and dicarboxylic acids. Long-chain substrates enter as acyl-CoA through an ABC-D half-transporter dimer, which in yeast hydrolyses the thioester during transport so that the fatty acid is re-activated on the matrix side by an acyl-CoA synthetase; medium-chain fatty acids enter independently and are activated inside. In humans the two peroxisomal ABC-D half-transporters divide the substrates between them: ABCD1 (ALDP) takes straight-chain very-long-chain acyl-CoA, and ABCD3 (PMP70) takes the branched-chain, C27 bile-acid and dicarboxylic acyl-CoAs. Each turn uses four reactions with peroxisome-specific enzymes: an FAD acyl-CoA oxidase that passes electrons directly to O2 (making H2O2, degraded by catalase); hydration and NAD+-dependent dehydrogenation by multifunctional proteins (the D-specific, (3R)-hydroxyacyl-CoA-forming multifunctional enzyme type 2 in fungi and as the main animal enzyme, plus an L-specific bifunctional protein in animals); and thiolytic cleavage by peroxisomal 3-ketoacyl-CoA thiolases. Because the peroxisomal membrane is impermeable to NAD(H), NADP(H) and acetyl-CoA, the pathway also depends on matrix redox shuttles (a peroxisomal malate dehydrogenase reoxidising NADH) and on carnitine or glyoxylate-cycle routes that export the acetyl units. Unsaturated fatty acids additionally need auxiliary enzymes: a delta3-delta2-enoyl-CoA isomerase and an NADPH-dependent 2,4-dienoyl-CoA reductase, whose NADPH is regenerated inside the peroxisome by NADP-dependent isocitrate dehydrogenase. In humans, single-enzyme defects (ACOX1, HSD17B4, EHHADH, SCP2, ABCD1) and peroxisome biogenesis disorders cause accumulation of very-long-chain and branched fatty acids and bile-acid intermediates with severe neurological disease. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | fatty acid beta-oxidation fatty acid beta-oxidation using acyl-CoA oxidase |
12 | 11 | 11 | 0 | 0 | 9 | 18/20 | 0 | ✗ | modules/peroxisomal_beta_oxidation.yaml | |
Peroxisomal protein import machineryMODULE:peroxisomal_protein_importCONCRETE Peroxisomal proteins are made in the cytosol and imported post-translationally, membrane proteins by the Pex19/Pex3 route and folded matrix... [more...][less]Peroxisomal proteins are made in the cytosol and imported post-translationally, membrane proteins by the Pex19/Pex3 route and folded matrix proteins by a receptor cycle: the PTS1 receptor Pex5 carries cargo to the Pex14/Pex13 docking machinery, releases it into the matrix, and is then monoubiquitinated by the Pex2/Pex10/Pex12 RING peroxins and extracted for reuse by the Pex1/Pex6 AAA ATPase. This module is the eukaryote-wide core of that machinery, written so that it can be evaluated in any genome; lineage-specific peroxins are optional parts. |
Biological Process | DRAFT | Eukaryota human and metazoan cells where RRBP1 is retained Mammalia metazoan lineages and some fungi |
13 | protein import into peroxisome matrix protein import into peroxisome membrane |
13 | 15 | 11 | 1 | 1 | 5 | 13/13 | 1 | ✗ | modules/peroxisomal_protein_import.yaml | |
Peroxisome lifecycleMODULE:peroxisome_lifecycleCONCRETE Peroxisomes grow by importing membrane and matrix proteins, divide, carry out lineage- and tissue-specific metabolism, and are removed by... [more...][less]Peroxisomes grow by importing membrane and matrix proteins, divide, carry out lineage- and tissue-specific metabolism, and are removed by pexophagy. This umbrella module composes the modules for those stages by reference. Protein import is required in every eukaryote with peroxisomes or peroxisome-derived organelles; division, metabolism and turnover vary between lineages or are not yet written as eukaryote-wide rules. |
Organelle Lifecycle | DRAFT | Eukaryota metazoan lineages |
4 | peroxisome organization peroxisome |
9 | 4 | 6 | 1 | 2 | 3 | 5/5 | 1 | ✓ | modules/peroxisome-lifecycle.yaml | |
Phagocytic engulfmentMODULE:phagocytic_engulfment Phagocytic engulfment is the receptor-driven internalization of a large particle (a microbe, an opsonized target, or an apoptotic cell) into a... [more...][less]Phagocytic engulfment is the receptor-driven internalization of a large particle (a microbe, an opsonized target, or an apoptotic cell) into a plasma-membrane-derived vacuole, the nascent phagosome. A cell-surface receptor recognizes the particle, either directly (beta-glucan, phosphatidylserine) or through a bound opsonin or bridging ligand (IgG, iC3b, GAS6). Receptor engagement then activates Rho-family GTPases, Rac and Cdc42 for Fc-gamma and apoptotic-cell receptors and RhoA for complement receptor 3. The GTPases drive Arp2/3-dependent actin polymerization that extends pseudopods around the particle. Class I PI3K activity and dynamin are then needed to complete pseudopod extension and close the phagocytic cup. The Rac-to-actin core is shared by animal phagocytes and phagotrophic amoebae. In Dictyostelium, Rac GTPases, the SCAR/WAVE nucleation-promoting factor and the Arp2/3 complex build the phagocytic cup, and PI(3,4,5)P3 forms at the site of engulfment. The receptors differ between lineages. Amoebae recognize bacteria with receptors such as the GPCR fAR1 and the adhesion protein SibA. Animals use the CED-1/Draper/MEGF10 receptor family and its CED-6/GULP adaptor, and the CRK/DOCK180/ELMO Rac GEF (CED-2/CED-5/CED-12 in C. elegans). Vertebrates add opsonin receptors for IgG and complement and lectin receptors such as Dectin-1. |
Biological Process | DRAFT | Bilateria Dictyostelium discoideum Eukaryota Vertebrata |
7 | phagocytosis, engulfment |
12 | 23 | 4 | 2 | 7 | 3 | 18/45 | 0 | ✗ | modules/phagocytic_engulfment.yaml | |
PhagocytosisMODULE:phagocytosisABSTRACT Phagocytosis is how eukaryotic cells take in large particles: microbes, dead or dying cells, aged red cells and debris. A receptor on the phagocyte... [more...][less]Phagocytosis is how eukaryotic cells take in large particles: microbes, dead or dying cells, aged red cells and debris. A receptor on the phagocyte recognises the particle, Rho-family GTPases drive actin to wrap the membrane around it, and the sealed phagosome then matures by fusing with endosomes and lysosomes into an acidic, degradative phagolysosome. There the cargo is digested and its products are returned to the cytosol. Protists use this route to feed; animal phagocytes use it for defence and for clearing cells. In animals, the digested cargo can also switch on programmes in the phagocyte itself, such as proliferation, priming, differentiation or an anti-inflammatory response, that depend on what was eaten. |
Biological Process | DRAFT | Eukaryota |
0 | phagocytosis |
9 | 0 | 4 | 1 | 4 | 3 | 0/0 | 0 | ✗ | modules/phagocytosis.yaml | |
Phagolysosomal cargo degradationMODULE:phagolysosomal_cargo_degradationABSTRACT Once a phagosome has matured into a phagolysosome, acid hydrolases digest the engulfed particle and transporters in the phagolysosomal membrane... [more...][less]Once a phagosome has matured into a phagolysosome, acid hydrolases digest the engulfed particle and transporters in the phagolysosomal membrane return the products to the cytosol. DNase II finishes digesting the DNA of engulfed cells; cathepsins digest proteins; in amoebae that eat bacteria, lysozymes break down the bacterial cell wall. Amino acids, nucleosides, heme and cholesterol are then exported by dedicated transporters. Digestion is how phagotrophic protists feed and how animal phagocytes dispose of dead cells and microbes. Loss of a hydrolase or an exporter leaves undigested cargo, and undigested DNA in particular can trigger innate immune signalling. |
Biological Process | DRAFT | Eukaryota |
1 | digestion of phagocytosed material in the phagolysosome |
10 | 7 | 5 | 1 | 4 | 1 | 4/16 | 0 | ✗ | modules/phagolysosomal_cargo_degradation.yaml | |
Phagophore assembly site (PAS)MODULE:phagophore_assembly_siteCONCRETE The phagophore assembly site (PAS, historically the pre-autophagosomal structure) is the single perivacuolar punctum in budding yeast at which the... [more...][less]The phagophore assembly site (PAS, historically the pre-autophagosomal structure) is the single perivacuolar punctum in budding yeast at which the autophagy machinery is concentrated and from which the phagophore emerges. It is not a membrane-bounded organelle: the PAS is a liquid-like condensate of Atg proteins, nucleated by phase separation of the Atg1 kinase complex on an Atg17-Atg31-Atg29 scaffold (starvation-induced bulk autophagy) or on an Atg11-cargo scaffold (selective autophagy and the Cvt pathway), and tethered to the vacuolar membrane by Vac8. Membrane is present at the PAS but is a component of it rather than its boundary: a small number of Atg9 vesicles cluster at the site and are incorporated into the outer autophagosomal membrane, and the downstream machinery - the class III PI3K complex I, the Atg2-Atg18 lipid transfer bridge, and the Atg8 conjugation system - is recruited onto the condensate in a defined hierarchy. The site is dismantled from within: Atg1, activated by lipidated Atg8 on the growing phagophore, phosphorylates Atg13 and triggers dissociation and rapid turnover of Atg1 complex subunits at the PAS. This module models the PAS as a cellular component with a nucleation step, a composition, a positioning mechanism, and a turnover step. |
Cellular Component | DRAFT | Saccharomyces cerevisiae |
0 | phagophore assembly site autophagosome assembly |
9 | 12 | 6 | 1 | 2 | 6 | 3/18 | 0 | ✗ | modules/phagophore_assembly_site.yaml | |
Phagophore-organelle membrane contact siteMODULE:phagophore_organelle_contact_siteCONCRETE A phagophore-organelle membrane contact site is the zone of apposition through which a growing phagophore (isolation membrane) is physically held... [more...][less]A phagophore-organelle membrane contact site is the zone of apposition through which a growing phagophore (isolation membrane) is physically held against a donor or anchor organelle while the autophagosome is built. Canonically this is the phagophore-endoplasmic reticulum membrane contact site: a bridging assembly in which an ATG2-family rod spans the ~10-20 nm gap between the ER and the phagophore rim, an Atg18/WIPI4-family beta-propeller clamps the ATG2 tip onto phosphatidylinositol 3-phosphate (PI3P) on the phagophore, and lipid scramblases work on both sides - VMP1 and TMEM41B in the donor ER membrane, and the ATG9 trimer at the phagophore rim - so that glycerophospholipids delivered by ATG2 into one leaflet are equilibrated across the bilayer. The site is nucleated by the Atg1/ULK1 kinase complex together with class III PI3K-derived PI3P, operates as a lipid conduit that drives phagophore expansion, and is taken apart when contacts are dissolved and the phagophore is sealed. Related contact sites use the same bridging logic with a different partner organelle: PI3P-rich endosomes can serve as an alternative ATG2 lipid donor, and in budding yeast Vac8 anchors the phagophore assembly site to the vacuole, giving a positional rather than lipid-donating attachment. This module models the site as a cellular component with an assembly step, a composition, a lipid flux function, and a disassembly step. |
Cellular Component | DRAFT | eukaryotes Saccharomyces cerevisiae |
3 | organelle membrane contact site phagophore assembly site autophagosome assembly |
11 | 17 | 7 | 1 | 3 | 7 | 14/25 | 0 | ✗ | modules/phagophore_organelle_contact_site.yaml | |
Phagosome maturationMODULE:phagosome_maturationABSTRACT Phagosome maturation turns the nascent phagosome, which has no microbicidal or degradative activity, into a phagolysosome. It does so through an... [more...][less]Phagosome maturation turns the nascent phagosome, which has no microbicidal or degradative activity, into a phagolysosome. It does so through an ordered series of fusion and fission events with endocytic and lysosomal compartments. The sealed phagosome first recruits active Rab5, and the class III PI3K VPS34 makes PI(3)P on its membrane. PIKfyve converts part of this PI(3)P to PI(3,5)P2. The Mon1-Ccz1 complex, a Rab5 effector and Rab7 GEF, then hands the vacuole over to Rab7. Rab7 and the HOPS tethering complex drive fusion with late endosomes and lysosomes, and the V-ATPase delivered by these fusions acidifies the lumen. This core machinery is shared by eukaryotes and works the same way in amoebae that eat bacteria, in nematode and fly cells that clear apoptotic corpses, and in mammalian macrophages. Animals add lineage-specific parts: the Rab7 effector RILP and LAMP membrane proteins. In vertebrate professional phagocytes, the NOX2 NADPH oxidase also assembles on the phagosomal membrane and produces superoxide into the lumen. |
Organelle Lifecycle | DRAFT | Eukaryota Vertebrata |
14 | phagosome maturation |
6 | 11 | 5 | 0 | 0 | 3 | 19/52 | 0 | ✗ | modules/phagosome_maturation.yaml | |
PhnWX 2-aminoethylphosphonate degradationMODULE:2_aminoethylphosphonate_degradation A reusable two-reaction bacterial pathway that degrades 2-aminoethylphosphonate through phosphonoacetaldehyde. PhnW first transfers the amino group... [more...][less]A reusable two-reaction bacterial pathway that degrades 2-aminoethylphosphonate through phosphonoacetaldehyde. PhnW first transfers the amino group to pyruvate, producing L-alanine and phosphonoacetaldehyde. PhnX then hydrolytically cleaves the carbon-phosphorus bond, yielding acetaldehyde and inorganic phosphate. Transport of 2-aminoethylphosphonate and downstream acetaldehyde metabolism are outside the module boundary. |
Metabolic Pathway | COMPLETE | Bacteria with a PhnWX degradation route |
0 | organic phosphonate catabolic process |
3 | 2 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/2_aminoethylphosphonate_degradation.yaml | |
Phosphocreatine shuttle / creatine kinase system (human)MODULE:phosphocreatine_shuttle The creatine kinase (CK) / phosphocreatine energy-buffer system, which uses the creatine produced by creatine biosynthesis (see... [more...][less]The creatine kinase (CK) / phosphocreatine energy-buffer system, which uses the creatine produced by creatine biosynthesis (see MODULE:creatine_biosynthesis) as a spatial and temporal buffer of ATP. This module covers creatine *utilization*, not its synthesis. A single reversible reaction, creatine kinase activity (ATP + creatine <=> ADP + phosphocreatine, GO:0004111), is run in two cellular locations by compartment-specific isozymes to form a shuttle: mitochondrial CK isozymes (CKMT1A/B ubiquitous, CKMT2 sarcomeric) sit in the mitochondrial intermembrane space and use ATP exported from oxidative phosphorylation to phosphorylate creatine, producing phosphocreatine; phosphocreatine, being small and diffusible, moves through the cytosol to sites of high ATP turnover, where cytosolic CK isozymes (CKB brain-type, CKM muscle-type; assembled as CK-BB, CK-MB, and CK-MM dimers) regenerate ATP from phosphocreatine and ADP exactly where it is consumed. The net effect is to shuttle high-energy phosphate from mitochondria to ATPases and to buffer the cytosolic ATP/ADP ratio in tissues with high, fluctuating energy demand (skeletal and cardiac muscle, brain, photoreceptors, spermatozoa). The same enzymes also support a thermogenic "futile creatine cycle" (GO:0140651) in some adipocytes, in which phosphocreatine is hydrolysed back to creatine (releasing heat) rather than donating phosphate to ADP. The catalytic species are oligomers, and the participants here are modelled as protein complexes mirroring Reactome: the mitochondrial limb as alternative homo-octamers and the cytosolic limb as the CK-MM, CK-BB, and CK-MB dimers (the heterodimer being a genuine two-gene-product catalytic unit). This module is distinct from, and downstream of, creatine biosynthesis: it consumes creatine, it does not make it. |
Metabolic Pathway | DRAFT | 0 | phosphocreatine biosynthetic process |
8 | 5 | 2 | 2 | 5 | 2 | 4/4 | 0 | ✗ | modules/phosphocreatine_shuttle.yaml | ||
Phosphoinositide biosynthesis (PI -> PI3P/PI4P -> PI(3,5)P2/PI(4,5)P2 kinase network)MODULE:phosphoinositide_biosynthesisCONCRETE Phosphatidylinositol (PI) is phosphorylated on the inositol ring by a conserved set of lipid kinases to give the phosphoinositides that mark... [more...][less]Phosphatidylinositol (PI) is phosphorylated on the inositol ring by a conserved set of lipid kinases to give the phosphoinositides that mark eukaryotic membranes and recruit effector proteins. A class III phosphatidylinositol 3-kinase (Vps34), held on membranes by its regulatory protein-kinase subunit, makes PI 3-phosphate (PI3P) on endosomes and autophagic membranes. Phosphatidylinositol 4-kinases make PI 4-phosphate (PI4P) in distinct places: the type III-beta enzyme (Pik1/PI4KB) on the trans-Golgi, the type III-alpha enzyme (Stt4/PI4KA), recruited by an Efr3-Ypp1 scaffold, at the plasma membrane, and a type II enzyme on plasma and vacuolar/endosomal membranes. Two kinds of PIP kinase add a 5-phosphate: the type I PI4P 5-kinase (Mss4/PIP5K1) converts plasma-membrane PI4P to PI(4,5)P2, the precursor of inositol-trisphosphate signalling and a regulator of the cortical actin cytoskeleton, and the FYVE-domain PI3P 5-kinase (Fab1/PIKfyve), acting in a complex with Vac14 and the Fig4 phosphatase, converts PI3P to PI(3,5)P2 on the vacuole/late endosome, where it controls vacuole size and membrane homeostasis. Because each kinase acts in its own compartment, the network produces membrane-specific lipid identities rather than a linear pathway; lipid phosphatases (Sac1, synaptojanins, Fig4) reverse these steps and are outside this module. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | phosphatidylinositol phosphate biosynthetic process phosphatidylinositol-3-phosphate biosynthetic process 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate biosynthetic process 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate biosynthetic process |
8 | 6 | 4 | 1 | 3 | 2 | 14/17 | 0 | ✗ | modules/phosphoinositide_biosynthesis.yaml | |
Phosphorylase kinase complex (activates glycogenolysis) — GSD IXMODULE:phosphorylase_kinase_complex Phosphorylase kinase (PhK) is the large (~1.3 MDa) hexadecameric (alpha-beta-gamma-delta)4 holoenzyme that switches on glycogen breakdown by... [more...][less]Phosphorylase kinase (PhK) is the large (~1.3 MDa) hexadecameric (alpha-beta-gamma-delta)4 holoenzyme that switches on glycogen breakdown by phosphorylating glycogen phosphorylase on Ser14, converting the low-activity phosphorylase b to the active phosphorylase a. It is the key node coupling hormonal and neural/contractile signals to glycogenolysis: the catalytic gamma subunit (muscle PHKG1 / liver-testis PHKG2) is a Ca2+/calmodulin-regulated Ser/Thr protein kinase held in an autoinhibited state by the large regulatory alpha (muscle PHKA1 / liver PHKA2) and beta (PHKB) subunits; phosphorylation of the alpha and beta subunits by cAMP-dependent protein kinase (PKA, downstream of adrenaline/glucagon) and Ca2+ binding to the delta subunit (calmodulin, which reports muscle contraction) relieve this inhibition and activate the complex. The activated PhK then phosphorylates glycogen phosphorylase, triggering the phosphorolysis step of glycogenolysis. Inherited defects cause glycogen storage disease type IX (one of the most common glycogenoses), with tissue-specific subtypes reflecting the subunit isoforms: PHKA2 -> GSD IXa (X-linked liver, most common); PHKB -> GSD IXb (liver + muscle); PHKG2 -> GSD IXc (liver, more severe, cirrhosis risk); PHKA1 -> GSD IXd (X-linked muscle, exercise intolerance). |
Protein Complex | DRAFT | 0 | phosphorylase kinase activity |
2 | 3 | 1 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/phosphorylase_kinase_complex.yaml | ||
Phosphorylated L-serine biosynthesisMODULE:phosphorylated_serine_biosynthesis A reusable three-reaction pathway that converts the glycolytic intermediate 3-phospho-D-glycerate to L-serine through 3-phosphooxypyruvate and... [more...][less]A reusable three-reaction pathway that converts the glycolytic intermediate 3-phospho-D-glycerate to L-serine through 3-phosphooxypyruvate and O-phospho-L-serine. NAD+-dependent D-3-phosphoglycerate dehydrogenase catalyses the first, committed oxidation; a pyridoxal 5'-phosphate-dependent phosphoserine aminotransferase transfers the amino group of L-glutamate to 3-phosphooxypyruvate; and a Mg2+-dependent HAD-family phosphoserine phosphatase releases free L-serine. The module represents the conserved SerA, SerC and SerB reaction roles independently of genomic arrangement and of which paralog carries them: budding yeast, for example, has two phosphoglycerate dehydrogenase paralogs. L-serine made this way is also the main precursor of glycine and of folate one-carbon units, but those conversions, and the alternative glyoxylate and threonine routes to glycine and serine, are separate modules. Additional activities of individual enzymes, including 2-oxoglutarate reduction to D-2-hydroxyglutarate by some SerA proteins and vitamin B6 precursor transamination by some SerC proteins, are outside this pathway boundary. |
Metabolic Pathway | DRAFT | 0 | L-serine biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 11/13 | 0 | ✓ | modules/phosphorylated_serine_biosynthesis.yaml | ||
Photoperiodic (long-day) flowering via the CONSTANS-FLOWERING LOCUS T pathway (Arabidopsis)MODULE:photoperiodic_flowering_co_ftCONCRETE The external-coincidence mechanism by which Arabidopsis measures day length and converts long days into flowering. In leaf phloem companion cells... [more...][less]The external-coincidence mechanism by which Arabidopsis measures day length and converts long days into flowering. In leaf phloem companion cells the morning-phased Dof repressors (CYCLING DOF FACTORs, represented by CDF1) bind the CONSTANS (CO) and FLOWERING LOCUS T (FT) promoters and repress them, partly by recruiting TOPLESS. In long-day afternoons the clock-phased FKF1 and GIGANTEA (GI) proteins coincide with light; blue-light activation of the FKF1 LOV domain promotes FKF1-GI complex formation on the CO promoter and SCF(FKF1)-dependent degradation of the CDFs, relieving CO repression. CO protein is unstable in the dark because the COP1-SPA E3 ubiquitin ligase targets it for proteasomal degradation; in the light, photoactivated CRY2 (blue) and phyA (far-red) inhibit COP1-SPA and FKF1 binds and stabilizes CO, so CO protein accumulates only when CO mRNA expression overlaps with light at the end of a long day. CO, in an NF-Y-like trimer with NF-YB/NF-YC, binds CORE (CCACA) elements and activates FT transcription in companion cells. FT protein (florigen) moves through the phloem to the shoot apical meristem, where 14-3-3 proteins bridge it to the phosphorylated bZIP transcription factor FD; this florigen activation complex activates floral integrator and floral meristem identity genes such as SOC1 and AP1, committing the meristem to flowering. The circadian oscillator that phases GI, FKF1, CDF and CO expression, phytochrome-mediated photomorphogenesis, FT transport machinery and the vernalization/autonomous pathways are outside this module. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | long-day photoperiodism, flowering |
6 | 13 | 5 | 0 | 0 | 4 | 12/12 | 0 | ✗ | modules/photoperiodic_flowering_co_ft.yaml | |
Photorespiratory C2 cycle (2-phosphoglycolate to 3-phosphoglycerate) in land plantsMODULE:photorespiration_c2_cycleABSTRACT The photorespiratory C2 cycle salvages 2-phosphoglycolate, the two-carbon product of the oxygenase reaction of ribulose-1,5-bisphosphate... [more...][less]The photorespiratory C2 cycle salvages 2-phosphoglycolate, the two-carbon product of the oxygenase reaction of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), and returns three of every four carbons to the Calvin-Benson cycle as 3-phosphoglycerate. The pathway runs through three organelles. In the chloroplast, 2-phosphoglycolate phosphatase dephosphorylates 2-phosphoglycolate to glycolate, which the inner-envelope glycolate/glycerate translocator exports. In the peroxisome, glycolate oxidase oxidizes glycolate to glyoxylate with O2, generating H2O2 that catalase removes, and glyoxylate is transaminated to glycine, mainly by glutamate:glyoxylate aminotransferase. In the mitochondrion, the glycine decarboxylase (glycine cleavage) complex converts one glycine to CO2, NH3 and 5,10-methylenetetrahydrofolate, and serine hydroxymethyltransferase uses the one-carbon unit and a second glycine to make serine. Back in the peroxisome, serine:glyoxylate aminotransferase converts serine to hydroxypyruvate while aminating a second glyoxylate, and hydroxypyruvate reductase reduces hydroxypyruvate to glycerate; a cytosolic hydroxypyruvate reductase provides a bypass. In the chloroplast, D-glycerate 3-kinase phosphorylates glycerate to 3-phosphoglycerate. The NH3 released in the mitochondrion is refixed in the chloroplast by plastidic glutamine synthetase and ferredoxin-dependent glutamate synthase, which return the glutamate used by the glyoxylate transamination. Loss of most core steps makes plants unable to grow in normal air but viable at elevated CO2. The Rubisco oxygenase reaction itself, the Calvin-Benson cycle, the transporters for the other intermediates (largely unidentified), supply of NADH to the peroxisome, alternative glycolate routes in algae and cyanobacteria, and C4 or CAM carbon-concentrating mechanisms are outside this module's boundary. |
Metabolic Pathway | DRAFT | land plants |
0 | photorespiration |
17 | 12 | 14 | 1 | 2 | 14 | 14/14 | 0 | ✗ | modules/photorespiration_c2_cycle.yaml | |
Phytochrome control of photomorphogenesis (phyA/phyB - PIF - COP1/SPA - HY5)MODULE:phytochrome_photomorphogenesisCONCRETE Red and far-red light control seedling de-etiolation and growth in Arabidopsis thaliana through the phytochrome photoreceptors. In darkness two... [more...][less]Red and far-red light control seedling de-etiolation and growth in Arabidopsis thaliana through the phytochrome photoreceptors. In darkness two repressor systems keep seedlings etiolated: the PIF bHLH transcription factors (PIF1, PIF3, PIF4 and relatives) promote skotomorphogenic growth and repress chlorophyll biosynthesis and germination, and the nuclear CUL4-DDB1-COP1-SPA E3 ubiquitin ligase targets photomorphogenesis-promoting transcription factors such as HY5 for proteasomal degradation. Light converts phytochromes to the active Pfr form, phyB mainly under red light and phyA under far-red light. Pfr phytochromes enter the nucleus and form photobodies, where they act on both repressor systems. (1) They bind PIFs through APB and APA motifs. This triggers rapid PIF phosphorylation, with SPA1 kinase activity contributing in a phyB-PIF1-SPA1 complex, followed by ubiquitination and proteasomal degradation; PIF1 is turned over through the CUL4-COP1-SPA ligase. (2) They bind SPA proteins and disrupt the COP1-SPA interaction, which inactivates the ligase. HY5 then accumulates and, with the loss of PIF activity, drives photomorphogenic gene expression: hypocotyl growth inhibition, cotyledon expansion and greening. In darkness PIF1 also enhances COP1 E3 activity, so the two repressor systems act synergistically. Blue-light cryptochromes (CRY1) inhibit the same COP1-SPA node and are included only as a converging input. UVR8, PIF-independent phyB outputs, thermomorphogenesis (PIF4-temperature), photoperiodic flowering (COP1-SPA-CO) and hormone crosstalk are outside the module boundary. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | red or far-red light signaling pathway photomorphogenesis |
6 | 11 | 5 | 0 | 0 | 6 | 9/9 | 0 | ✗ | modules/phytochrome_photomorphogenesis.yaml | |
Pins-Inscuteable (Raps-Insc) complex in Drosophila melanogasterMODULE:dmel_raps_insc_complexCONCRETE Partner of Inscuteable (Pins, also called Raps) and Inscuteable (Insc) form a complex at the apical cortex of dividing neuroblasts. Insc binds the... [more...][less]Partner of Inscuteable (Pins, also called Raps) and Inscuteable (Insc) form a complex at the apical cortex of dividing neuroblasts. Insc binds the Par complex through Bazooka and recruits Pins, which with the G protein alpha subunit Galphai binds Mud (NuMA) and orients the mitotic spindle along the apical-basal axis. This coupling of cell polarity to spindle orientation ensures that basal cell-fate determinants segregate into the smaller ganglion mother cell during asymmetric neuroblast division. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | raps-insc complex |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✗ | modules/dmel_raps_insc_complex.yaml | |
Plant NLR resistosome activation and signallingMODULE:plant_nlr_resistosome_signalingABSTRACT Effector-triggered immunity by plant NB-LRR receptors. Direct or indirect recognition of a pathogen effector switches the NB-ARC domain from ADP-... [more...][less]Effector-triggered immunity by plant NB-LRR receptors. Direct or indirect recognition of a pathogen effector switches the NB-ARC domain from ADP- to ATP-bound and drives oligomerisation into a resistosome. The N-terminal signalling domain then determines the output chemistry: coiled-coil (CC) domains assemble a funnel that acts as a calcium-permeable cation channel, whereas TIR domains assemble paired active sites with NAD+-cleaving activity whose nucleotide products are received by EDS1-family heterodimers, which in turn recruit helper RNLs that are themselves calcium channels. Both branches converge on Ca2+ influx and the hypersensitive response. |
Signaling Pathway | DRAFT | flowering plants |
0 | nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway plant-type hypersensitive response |
10 | 11 | 3 | 3 | 6 | 2 | 2/10 | 0 | ✗ | modules/plant_nlr_resistosome_signaling.yaml | |
Plant cellulose biosynthesis moduleMODULE:plant_cellulose_biosynthesis A taxon-neutral decomposition of plant cellulose biosynthesis as a recursively decomposable module. Cellulose is synthesized at the plasma membrane... [more...][less]A taxon-neutral decomposition of plant cellulose biosynthesis as a recursively decomposable module. Cellulose is synthesized at the plasma membrane by the cellulose synthase complex (CSC, the "rosette"), which polymerizes UDP-glucose into (1->4)-beta-D-glucan chains that coalesce into crystalline microfibrils in the apoplast. The module separates (1) UDP-glucose substrate supply, (2) glucan polymerization by the CSC with distinct primary- and secondary-cell-wall CESA isoform sets, (3) guidance of CSC trajectory by the cortical microtubule cytoskeleton, (4) accessory enzymes/proteins required for productive synthesis (KORRIGAN endoglucanase, COBRA), and (5) microfibril assembly and organization. It is phrased as functions, complexes, and pathway segments rather than a fixed gene list so it can represent angiosperm, grass, and (with substitution) algal implementations. Concrete UniProt members are Arabidopsis exemplars, not species-restricting claims. Cellulose synthase-like (CSL) backbones of hemicelluloses, lignin biosynthesis, and the bacterial BcsA-type machinery are out of scope. As a bioenergy module, the polymerization step and its CESA isoform composition are the principal determinants of biomass recalcitrance and the main engineering targets for improved lignocellulosic saccharification. |
Metabolic Pathway | DRAFT | charophyte / eukaryotic algae (with isoform substitution) land plants |
0 | plant-type cell wall cellulose biosynthetic process cellulose biosynthetic process |
12 | 9 | 7 | 2 | 4 | 4 | 0/9 | 3 | ✗ | modules/cellulose_biosynthesis.yaml | |
Plant chitin perception by LysM receptor complexesMODULE:chitin_perceptionABSTRACT Flowering plants detect chitin oligosaccharides released from fungal cell walls at the plasma membrane with lysin-motif (LysM) pattern recognition... [more...][less]Flowering plants detect chitin oligosaccharides released from fungal cell walls at the plasma membrane with lysin-motif (LysM) pattern recognition receptors. Perception needs two activities that different plant lineages divide differently between receptor proteins: high-affinity binding of long-chain chitin oligomers, and an active intracellular serine/threonine kinase. In rice, the kinase-less LysM receptor-like protein CEBiP is the chitin-binding subunit; two CEBiP ectodomains sandwich one chitin octamer, and ligand-induced association with the LysM receptor kinase OsCERK1 supplies the kinase, while OsCERK1 itself is not the chitin binder. In Arabidopsis, the LysM receptor kinase LYK5, whose intracellular domain is a catalytically inactive pseudokinase, is the high-affinity chitin binder, and it recruits CERK1, which both binds chitin with low affinity and is the active kinase. The LYK5 paralog LYK4, also a pseudokinase, binds chitin only weakly and acts as a LYK5-associated co-receptor or scaffold that enhances signalling; lyk4 lyk5 double mutants lose chitin responses. In both configurations the activated CERK1 kinase phosphorylates receptor-like cytoplasmic kinases (RLCKs) of the PBL27/OsRLCK185 type, which phosphorylate MAP kinase kinase kinases (MAPKKK5 in Arabidopsis; OsMAPKKKepsilon and OsMAPKKK18 in rice) that activate the MKK4/MKK5 to MPK3/MPK6 relay, driving defence gene expression and callose deposition. In Arabidopsis, RLCK VII-4 kinases such as PBL19 also phosphorylate MAPKKK5 and may carry most of this step, so the genetic weight of PBL27 is disputed. A parallel branch through BIK1 activates the plasma membrane NADPH oxidase RBOHD, which produces the apoplastic burst of reactive oxygen species. The two branches separate genetically: loss of MAPKKK5 or PBL27 does not reduce the ROS burst. |
Signaling Pathway | DRAFT | Arabidopsis thaliana Magnoliopsida (flowering plants) Oryza sativa subsp. japonica |
0 | detection of molecule of fungal origin cell surface pattern recognition receptor signaling pathway |
17 | 15 | 14 | 1 | 2 | 8 | 14/14 | 0 | ✓ | modules/chitin_perception.yaml | |
Plant lignin (monolignol) biosynthesis moduleMODULE:plant_lignin_monolignol_biosynthesis A taxon-neutral decomposition of plant lignin biosynthesis as a recursively decomposable module. Lignin is a phenolic heteropolymer deposited in... [more...][less]A taxon-neutral decomposition of plant lignin biosynthesis as a recursively decomposable module. Lignin is a phenolic heteropolymer deposited in secondary cell walls that provides mechanical support and water conduction but is the principal determinant of lignocellulosic biomass recalcitrance. The module separates (1) the general phenylpropanoid entry (PAL -> C4H -> 4CL) that converts L-phenylalanine into p-coumaroyl-CoA, (2) the monolignol-specific "metabolic grid" (HCT, C3'H, CCoAOMT, CCR, F5H, COMT, CAD) that reduces and differentially hydroxylates/methylates hydroxycinnamoyl intermediates into the three canonical monolignols (p-coumaryl, coniferyl, and sinapyl alcohol), (3) export of monolignols across the plasma membrane into the apoplast, and (4) oxidative radical coupling of monolignols by cell-wall laccases and class III peroxidases into the growing lignin polymer, whose p-hydroxyphenyl (H), guaiacyl (G), and syringyl (S) unit composition is set by which monolignols are supplied. It is phrased as functions and pathway segments rather than a fixed gene list so it can represent angiosperm, gymnosperm, and grass implementations (gymnosperms make almost no S lignin because they lack F5H/CYP84A activity; grasses additionally incorporate ferulate/coumarate esters, out of scope here). Concrete UniProt members are Arabidopsis exemplars, not species-restricting claims. As a bioenergy module, monolignol supply flux and the S/G ratio are the dominant engineering levers for reducing recalcitrance and improving saccharification and pulping. |
Metabolic Pathway | DRAFT | grasses (with additional wall-bound hydroxycinnamate esters) land plants (angiosperms and gymnosperms) |
1 | lignin biosynthetic process phenylpropanoid biosynthetic process |
20 | 16 | 16 | 1 | 3 | 5 | 1/14 | 3 | ✗ | modules/lignin_monolignol_biosynthesis.yaml | |
Plant miRNA biogenesis and AGO1 RISC loadingMODULE:plant_mirna_biogenesisCONCRETE In Arabidopsis thaliana, microRNAs (miRNAs) are transcribed by RNA polymerase II as capped and polyadenylated primary transcripts (pri-miRNAs) that... [more...][less]In Arabidopsis thaliana, microRNAs (miRNAs) are transcribed by RNA polymerase II as capped and polyadenylated primary transcripts (pri-miRNAs) that fold into imperfect stem-loop hairpins. Unlike animals, which split processing between nuclear Drosha and cytoplasmic Dicer, plants carry out both cleavage steps in the nucleus with a single RNase III enzyme, DICER-LIKE1 (DCL1). DCL1 works in a microprocessor with the double-stranded RNA-binding protein HYPONASTIC LEAVES1 (HYL1, also called DRB1) and the C2H2 zinc-finger protein SERRATE (SE). The three proteins meet in nuclear dicing bodies (D-bodies) and nucleoplasm. DCL1 alone can cut miRNA precursors, but most of its products are then misplaced. HYL1 and SE raise the rate of DCL1 cleavage and position the cuts, so that the correct 21-nt miRNA/miRNA* duplex is released. The small-RNA methyltransferase HUA ENHANCER1 (HEN1) then adds a 2'-O-methyl group to the 3'-terminal ribose of each strand of the duplex. This methyl mark protects the miRNA from 3' uridylation, trimming and degradation. The guide strand is then loaded into ARGONAUTE1 (AGO1), the main plant miRNA effector. AGO1 cleaves complementary target mRNAs through its PIWI-domain slicer activity and can also repress their translation. The miRNA-AGO1 complex is the output of this module. |
Biological Process | DRAFT | Arabidopsis thaliana |
0 | miRNA processing miRNA-mediated post-transcriptional gene silencing |
4 | 8 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/plant_mirna_biogenesis.yaml | |
Plant seed triacylglycerol (oil) biosynthesis moduleMODULE:plant_seed_triacylglycerol_biosynthesis A taxon-neutral decomposition of plant seed storage-oil (triacylglycerol, TAG) assembly as a recursively decomposable module. In developing... [more...][less]A taxon-neutral decomposition of plant seed storage-oil (triacylglycerol, TAG) assembly as a recursively decomposable module. In developing oilseeds, acyl groups (produced by plastidial fatty acid synthesis and activated as acyl-CoA) are assembled onto a glycerol backbone at the endoplasmic reticulum by the glycerol-phosphate (Kennedy) pathway and packaged into cytosolic oil bodies (lipid droplets) stabilized by oleosins. The module separates (1) acylation of glycerol-3-phosphate to lysophosphatidic acid (GPAT), (2) acylation of LPA to phosphatidic acid (LPAAT), (3) dephosphorylation of PA to diacylglycerol (PAP), (4) the final acyl transfer to DAG forming TAG by two alternative routes - acyl-CoA-dependent (DGAT1/DGAT2) and acyl-CoA-independent (PDAT, using phospholipid acyl donors) - and (5) oil-body biogenesis and oleosin stabilization. It is phrased as functions and pathway segments rather than a fixed gene list so it can represent Arabidopsis and crop oilseeds (soybean, rapeseed/canola, oil palm, camelina); concrete UniProt members are Arabidopsis exemplars, not species-restricting claims. Plastidial de novo fatty acid synthesis, acyl-chain desaturation/modification, and TAG catabolism (lipolysis/beta-oxidation) are upstream/downstream and out of scope. As a bioenergy module, total TAG flux (DGAT/PDAT capacity), the acyl-CoA pool, and oil-body number/size (oleosin dosage) are the principal engineering levers for raising seed-oil yield for biodiesel and oleochemical feedstocks. |
Metabolic Pathway | DRAFT | oilseed angiosperms (Arabidopsis and crop oilseeds) |
2 | triglyceride biosynthetic process seed oilbody biogenesis |
8 | 6 | 5 | 1 | 2 | 4 | 1/9 | 0 | ✗ | modules/seed_triacylglycerol_biosynthesis.yaml | |
Plant vacuole lifecycleMODULE:plant_vacuole_lifecycleCONCRETE The plant lytic vacuole, the largest compartment of most plant cells, is an acidic, hydrolase-filled organelle that also stores ions and... [more...][less]The plant lytic vacuole, the largest compartment of most plant cells, is an acidic, hydrolase-filled organelle that also stores ions and metabolites and generates turgor. It grows from prevacuolar compartments and multivesicular bodies that fuse with the tonoplast, receives its hydrolases through sorting receptors, keeps its lumen acidic with the V-ATPase and the vacuolar pyrophosphatase, and in some cells is reorganized or dismantled, as in seed protein storage vacuoles and programmed cell death. This umbrella module composes the modules for those stages by reference. Intralumenal vesicle formation, hydrolase sorting, fusion with the tonoplast, acidification and tonoplast transport are required in the green lineage. |
Organelle Lifecycle | DRAFT | Viridiplantae |
0 | vacuole organization plant-type vacuole |
6 | 0 | 5 | 0 | 0 | 4 | 0/0 | 0 | ✗ | modules/plant_vacuole_lifecycle.yaml | |
Plant xylan (glucuronoxylan) biosynthesis moduleMODULE:plant_xylan_biosynthesis A taxon-neutral decomposition of plant heteroxylan biosynthesis as a recursively decomposable module. Xylan is the dominant hemicellulose of the... [more...][less]A taxon-neutral decomposition of plant heteroxylan biosynthesis as a recursively decomposable module. Xylan is the dominant hemicellulose of the secondary cell wall: a (1->4)-beta-D-xylan backbone decorated with (alpha-1,2)-linked (4-O-methyl)glucuronic acid and O-acetyl groups in eudicots (glucuronoxylan, GX) and additionally with alpha-arabinofuranosyl and feruloyl-arabinose substitutions in grasses (glucuronoarabinoxylan, GAX). Xylan coats and tethers cellulose microfibrils and is covalently and non-covalently associated with lignin in the lignin-carbohydrate complex, so it is a major contributor to biomass recalcitrance and a key acetyl-group source that inhibits downstream fermentation. The module separates (1) Golgi backbone elongation by the IRX9/IRX10/IRX14 xylan synthase machinery, (2) synthesis of the reducing-end oligosaccharide sequence that may prime/terminate the chain in eudicots, (3) alpha-glucuronosyl sidechain addition (GUX), (4) 4-O-methylation of the glucuronic acid (GXM), and (5) O-acetylation (ESK1/TBL29 with RWA acetyl-CoA supply). It is phrased as functions, complexes, and pathway segments rather than a fixed gene list so it can represent eudicot GX and grass GAX implementations; concrete UniProt members are Arabidopsis exemplars, not species-restricting claims. As a bioenergy module, xylan substitution pattern (acetylation, methyl-GlcA) and quantity are principal engineering targets for reducing recalcitrance and acetate-driven fermentation inhibition. |
Metabolic Pathway | DRAFT | eudicots (glucuronoxylan, GX) grasses / commelinid monocots (glucuronoarabinoxylan, GAX) |
0 | xylan biosynthetic process glucuronoxylan biosynthetic process |
10 | 10 | 7 | 1 | 2 | 5 | 6/17 | 0 | ✗ | modules/xylan_biosynthesis.yaml | |
Plasmalogen biosynthesis (oxygen-dependent alkyl-ether desaturation route and anaerobic diacyl-lipid reduction route)MODULE:plasmalogen_biosynthesisABSTRACT Formation of plasmalogens: glycerolipids that carry a 1-(1Z-alkenyl) (vinyl) ether at sn-1, usually with an acyl chain at sn-2 and a phospho or... [more...][less]Formation of plasmalogens: glycerolipids that carry a 1-(1Z-alkenyl) (vinyl) ether at sn-1, usually with an acyl chain at sn-2 and a phospho or glyco head group at sn-3. The class is defined by the vinyl-ether bond alone, so it spans hundreds of molecular species that differ in head group, sn-1 alkenyl chain and sn-2 acyl chain. The vinyl ether is made by two routes that share no enzymes and no intermediates. In animals and other eukaryotes the oxygen- dependent route builds an ether lipid from scratch. Peroxisomal GNPAT acylates dihydroxyacetone phosphate, and AGPS exchanges that acyl chain for a fatty alcohol supplied by FAR1, forming the ether bond. PexRAP then reduces the 1-alkyl-DHAP, and ER enzymes acylate, dephosphorylate and add the ethanolamine head group (SELENOI) to give plasmanyl-PE. Finally the PEDS1 (TMEM189) desaturase introduces the vinyl-ether double bond with O2 and cytochrome b5. PEDS1 and its myxobacterial ortholog CarF belong to one PANTHER subfamily, and the eukaryotic pathway is thought to have come from myxobacteria by horizontal gene transfer. In obligate and facultative anaerobic bacteria the vinyl ether is made without an alkyl-ether intermediate and without oxygen. A plasmalogen synthase of the benzoyl-CoA reductase / 2-hydroxyacyl-CoA dehydratase family reduces the sn-1 acyl ester of a complete diacyl phospholipid directly to the alk-1'-enyl ether. This enzyme is either one polypeptide (PlsA) or two (PlsA with PlsR). Because the bacterial enzyme acts on whichever diacyl lipids the cell makes, it gives plasmenyl PE, PG and other head groups. Outside the module are the supply of diacyl phospholipids and of CDP-ethanolamine, plasmenylcholine formation and acyl-chain remodelling (for example EC 2.3.1.25 lysoplasmalogen acyltransferases), and plasmalogen turnover. |
Metabolic Pathway | DRAFT | 0 | plasmalogen biosynthetic process |
5 | 3 | 0 | 2 | 4 | 0 | 1/6 | 0 | ✗ | modules/plasmalogen_biosynthesis.yaml | ||
Plastid division by the FtsZ and ARC5 ringsMODULE:plastid_divisionCONCRETE Plastids divide by binary fission with a machinery built from both of their ancestries. Inside, the bacterium-derived tubulin-like GTPases FtsZ1... [more...][less]Plastids divide by binary fission with a machinery built from both of their ancestries. Inside, the bacterium-derived tubulin-like GTPases FtsZ1 and FtsZ2 form the Z ring in the stroma, anchored to the inner envelope; outside, the host-derived dynamin-related GTPase ARC5 assembles on the cytosolic face and constricts the outer envelope. The Min system, inherited from bacteria, keeps the ring at the midpoint. This module is the green-lineage core of plastid division. |
Biological Process | DRAFT | Viridiplantae |
7 | plastid fission chloroplast fission |
6 | 6 | 5 | 0 | 0 | 5 | 0/7 | 0 | ✗ | modules/plastid_division.yaml | |
Plastid lifecycleMODULE:plastid_lifecycleCONCRETE Plastids are never made from scratch: they grow by importing nucleus-encoded proteins through the TOC-TIC translocons and multiply by binary... [more...][less]Plastids are never made from scratch: they grow by importing nucleus-encoded proteins through the TOC-TIC translocons and multiply by binary fission, and each cell inherits them from its parent. In green tissue they differentiate into chloroplasts that carry out photosynthesis and much of the cell's lipid, amino acid and cofactor synthesis; they can also become amyloplasts, chromoplasts or etioplasts, and are removed by chloroplast autophagy and other degradation routes. This umbrella module composes the modules for those stages by reference. Protein import and division are required in the green lineage; the photosynthesis modules are optional. The umbrella is written for land plants. |
Organelle Lifecycle | DRAFT | land plants |
0 | plastid organization plastid |
7 | 0 | 6 | 0 | 0 | 2 | 0/0 | 0 | ✗ | modules/plastid_lifecycle.yaml | |
Plastid protein import through the TOC-TIC transloconsMODULE:plastid_protein_importCONCRETE Almost all plastid proteins are made in the cytosol with an N-terminal transit peptide and enter the organelle through two translocons in series.... [more...][less]Almost all plastid proteins are made in the cytosol with an N-terminal transit peptide and enter the organelle through two translocons in series. At the outer envelope, the GTPase receptors Toc34 and Toc159 recognise the transit peptide and pass the preprotein to the Toc75 beta-barrel channel; at the inner envelope Tic236 tethers the TOC complex to the TIC complex, whose Tic20 channel and Tic110 receive it, and a stromal ATP-driven motor of the Hsp100 ClpC and the stromal Hsp70 (cpHsc70), with Hsp90C, draws it into the stroma, where the transit peptide is removed. This module is the land-plant core of that pathway, written so that it can be evaluated in a plant genome. |
Biological Process | DRAFT | land plants |
21 | protein targeting to chloroplast protein import into chloroplast stroma |
18 | 20 | 17 | 0 | 0 | 17 | 0/32 | 0 | ✗ | modules/plastid_protein_import.yaml | |
Podovirus short-tail assembly, receptor-triggered nozzle remodeling, and internal core protein DNA-ejectosome channel formationMODULE:phage_podovirus_short_tail_ejectionCONCRETE A coordinated morphogenetic and host-entry module characteristic of T7-like podoviruses (Autographiviridae and related short-tailed Caudoviricetes)... [more...][less]A coordinated morphogenetic and host-entry module characteristic of T7-like podoviruses (Autographiviridae and related short-tailed Caudoviricetes) that solves the topological challenge of translocating a double-stranded DNA genome across the Gram-negative outer membrane, peptidoglycan cell wall, periplasm, and inner membrane using a non-contractile tail shorter than the cell envelope thickness. During procapsid assembly, a cylindrical internal core stack of gp14, gp15, and the lytic transglycosylase gp16 is assembled coaxially atop the dodecameric portal ring (gp8) inside the capsid. Following DNA packaging, the dodecameric gatekeeper adaptor (gp11), hexameric tail nozzle (gp12), tail assembly protein (gp7.3), and six trimeric tail fibers (gp17) assemble onto the portal vertex. Upon irreversible lipopolysaccharide receptor engagement and tail fiber reorientation, conformational opening of the gp12 nozzle gates the sequential ejection of gp14 (forming the outer membrane pore), gp16 (locally hydrolyzing periplasmic peptidoglycan via its N-terminal lytic transglycosylase domain and spanning the inner membrane), and gp15 (forming a hexameric periplasmic tunnel with gp16) to construct a continuous trans-envelope DNA-ejectosome conduit into the host cytoplasm. |
Biological Process | COMPLETE | Caudoviricetes Escherichia phage T7 |
0 | viral tail assembly adhesion receptor-mediated virion attachment to host cell symbiont entry into host cell via disruption of host cell wall peptidoglycan symbiont genome ejection through host cell envelope, short tail mechanism |
4 | 8 | 3 | 0 | 0 | 3 | 8/8 | 0 | ✗ | modules/phage_podovirus_short_tail_ejection.yaml | |
Polycomb group repressive complexes in Drosophila melanogasterMODULE:dmel_polycomb_group_complexesCONCRETE Polycomb group (PcG) proteins maintain the repressed state of developmental regulators such as the Hox genes through cell divisions. They act... [more...][less]Polycomb group (PcG) proteins maintain the repressed state of developmental regulators such as the Hox genes through cell divisions. They act through several distinct complexes recruited to Polycomb response elements (PREs). PRC2 trimethylates histone H3 lysine 27 through the E(z) methyltransferase. PRC1 binds H3K27me3 through the Polycomb chromodomain and compacts chromatin. dRAF and the variant PRC1-like complexes monoubiquitylate histone H2A lysine 118 through the Sce (dRing) E3 ligase. PhoRC, built around the sequence-specific DNA-binding protein Pho (or its paralog Phol) and Sfmbt, helps target PcG complexes to PREs. PR-DUB, formed by Calypso and Asx, removes H2A ubiquitin. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | PcG protein complex |
16 | 17 | 6 | 4 | 9 | 0 | 2/31 | 0 | ✗ | modules/dmel_polycomb_group_complexes.yaml | |
Polyol pathway in Drosophila melanogasterMODULE:dmel_polyol_pathwayCONCRETE The polyol pathway converts glucose to fructose in two steps. An NADPH-dependent aldose reductase of the aldo-keto reductase 1B family reduces... [more...][less]The polyol pathway converts glucose to fructose in two steps. An NADPH-dependent aldose reductase of the aldo-keto reductase 1B family reduces glucose to sorbitol, and an NAD+-dependent sorbitol dehydrogenase oxidises sorbitol to fructose. Drosophila has two aldose reductase genes in the FlyBase group (Ar1 and Ar2) and two sorbitol dehydrogenase genes (Sord1 and Sord2). |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | fructose biosynthetic process |
3 | 4 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/dmel_polyol_pathway.yaml | |
Prefoldin complex in Drosophila melanogasterMODULE:dmel_prefoldinCONCRETE Prefoldin is a heterohexameric co-chaperone shaped like a jellyfish, with six coiled-coil tentacles that bind nascent or unfolded polypeptides,... [more...][less]Prefoldin is a heterohexameric co-chaperone shaped like a jellyfish, with six coiled-coil tentacles that bind nascent or unfolded polypeptides, notably actin and tubulin, and pass them to the CCT chaperonin. It is built from two alpha-class subunits (Pfdn3, encoded by mgr, and Pfdn5) and four beta-class subunits (Pfdn1, Pfdn2, Pfdn4 and Pfdn6). In Drosophila, mgr is needed for normal tubulin levels and spindle formation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | prefoldin complex |
3 | 7 | 2 | 0 | 0 | 0 | 0/6 | 0 | ✗ | modules/dmel_prefoldin.yaml | |
Primary cilium life cycle moduleMODULE:primary_cilium_life_cycleCONCRETE The primary cilium is a microtubule-based sensory organelle templated by the mother centriole. Its life cycle runs from licensing of the mother... [more...][less]The primary cilium is a microtubule-based sensory organelle templated by the mother centriole. Its life cycle runs from licensing of the mother centriole as a basal body, through ciliary vesicle formation, transition zone assembly and IFT-driven axoneme extension, to maintenance of a distinct ciliary membrane, control of cilium length, and disassembly when the cell re-enters the cell cycle. This module captures the ordered stages and the protein roles that carry out each stage, using human proteins as concrete members. |
Organelle Lifecycle | DRAFT | Homo sapiens |
0 | cilium organization non-motile cilium |
9 | 33 | 8 | 0 | 0 | 25 | 60/60 | 0 | ✗ | modules/primary_cilium_life_cycle.yaml | |
Primordial germ cell specification moduleMODULE:primordial_germ_cell_specification The early-metazoan program that sets aside the primordial germ cells (PGCs) - the lineage that will form the gametes - from the soma. Two... [more...][less]The early-metazoan program that sets aside the primordial germ cells (PGCs) - the lineage that will form the gametes - from the soma. Two evolutionarily alternative strategies achieve this and are modelled as a variant set along the "specification mode" axis: (1) preformation, in which maternally inherited germ plasm (a specialised cytoplasm rich in germline determinants such as Vasa/DDX4, Nanos, and Piwi-clade proteins) autonomously specifies PGCs in flies, worms, fish, and frogs; and (2) induction, in which BMP signalling from extraembryonic tissue instructs competent epiblast cells to become PGCs via the PRDM1/PRDM14/TFAP2C tripartite network, as in mouse and (inferred) human. Both routes converge on a conserved germline ground state: transcriptional quiescence of the somatic program, retention of pluripotency potential, and protection of the genome by piRNA-guided transposon silencing. Grounded in GO:0007281 (germ cell development) with the germ plasm component GO:0060293. See modules/bmp_signaling.yaml for the inductive signal. |
Developmental Process | DRAFT | metazoa |
1 | germ cell development |
5 | 5 | 2 | 1 | 2 | 2 | 3/7 | 0 | ✗ | modules/primordial_germ_cell_specification.yaml | |
Prokaryotic molybdenum cofactor biosynthesis from GTP to Mo-molybdopterin and optional dinucleotide variantsMODULE:molybdenum_cofactor_biosynthesisCONCRETE A reusable prokaryotic module for molybdenum cofactor biosynthesis constructs the pyranopterin dithiolene ligand from GTP, loads it with... [more...][less]A reusable prokaryotic module for molybdenum cofactor biosynthesis constructs the pyranopterin dithiolene ligand from GTP, loads it with molybdenum, and may append a nucleotide to produce a client-class-specific cofactor variant. MoaA first performs radical-SAM cyclization of GTP and MoaC rearranges the cyclic intermediate to cyclic pyranopterin monophosphate (cPMP). Molybdopterin synthase then inserts two sulfurs: MoeB activates the small MoaD sulfur carrier, and the MoaD-MoaE synthase converts cPMP to molybdopterin (MPT). Across prokaryotic realizations, MPT is adenylylated by a separate bacterial MogA or by a catalytically competent prokaryotic MoaB lineage, and MoeA then inserts molybdate to form Mo-MPT. Some realizations stop at Mo-MPT, whereas others use MobA to make MGD or MocA to make MCD. The module excludes upstream sulfur supply, molybdate transport, terminal cofactor sulfuration, cofactor insertion into client apoenzymes, mature molybdoenzyme reactions, pathway regulation, eukaryotic MOCS/CNX/GPHN fusion organization, and human disease. |
Metabolic Pathway | COMPLETE | 5 | Mo-molybdopterin cofactor biosynthetic process |
15 | 10 | 10 | 2 | 4 | 6 | 15/15 | 0 | ✓ | modules/molybdenum_cofactor_biosynthesis.yaml | ||
Proline-P5C biosynthesis and catabolismMODULE:proline_metabolismCONCRETE Eukaryotic proline metabolism interconverts L-glutamate, L-ornithine, delta-1-pyrroline-5-carboxylate (P5C) and L-proline. In the biosynthetic arm,... [more...][less]Eukaryotic proline metabolism interconverts L-glutamate, L-ornithine, delta-1-pyrroline-5-carboxylate (P5C) and L-proline. In the biosynthetic arm, L-glutamate is phosphorylated to L-glutamyl 5-phosphate and reduced with NADPH to L-glutamate 5-semialdehyde, which cyclizes spontaneously to P5C; P5C reductase then forms L-proline. The two glutamate-activating reactions are catalyzed either by two separate enzymes, a glutamate 5-kinase and a gamma-glutamyl-phosphate reductase (as in fungi), or by the kinase and reductase domains of a single bifunctional P5C synthase (as in animals and plants). Ornithine aminotransferase can feed the same semialdehyde/P5C pool from L-ornithine. In the catabolic arm, a FAD-dependent proline dehydrogenase associated with the mitochondrial respiratory chain oxidizes L-proline back to P5C, and a mitochondrial NAD-dependent P5C dehydrogenase oxidizes the semialdehyde to L-glutamate, so that proline can serve as a carbon and nitrogen source. Biosynthesis and degradation are separated by compartment and by regulation (feedback control of glutamate 5-kinase, proline-induced expression of the catabolic enzymes). |
Metabolic Pathway | DRAFT | Eukaryota |
0 | L-proline biosynthetic process L-proline catabolic process |
12 | 8 | 9 | 1 | 2 | 7 | 18/18 | 0 | ✗ | modules/proline_metabolism.yaml | |
Propionyl-CoA catabolism (propionate to succinyl-CoA via the methylmalonyl-CoA pathway)MODULE:propionyl_coa_catabolism The mitochondrial pathway that converts propionyl-CoA to succinyl-CoA, the anaplerotic route by which propionate carbon enters the TCA cycle.... [more...][less]The mitochondrial pathway that converts propionyl-CoA to succinyl-CoA, the anaplerotic route by which propionate carbon enters the TCA cycle. Propionyl-CoA arises from the catabolism of the branched-chain amino acids isoleucine and valine, of methionine and threonine, of odd-chain fatty acids, and of the cholesterol side chain (and from gut-microbial propionate). Three enzymatic steps: (1) the biotin-dependent propionyl-CoA carboxylase (PCC), an alpha6-beta6 dodecamer of PCCA (biotin-carboxylase / biotin-carboxyl-carrier alpha subunit) and PCCB (carboxyltransferase beta subunit), carboxylates propionyl-CoA to (2S)-methylmalonyl-CoA (D-methylmalonyl-CoA) using bicarbonate and ATP; (2) methylmalonyl-CoA epimerase (MCEE) racemises this to (2R)-methylmalonyl-CoA (L-methylmalonyl-CoA); and (3) the adenosylcobalamin (AdoCbl / vitamin B12)- dependent methylmalonyl-CoA mutase (MMUT) performs the carbon-skeleton rearrangement of L-methylmalonyl-CoA to succinyl-CoA. The mutase step depends on a dedicated cobalamin cofactor-supply system: MMAB (cblB) is the ATP:cob(I)alamin adenosyltransferase that synthesises AdoCbl, and MMAA (cblA) is a mitochondrial G3E-family GTPase that gates AdoCbl loading onto MMUT and protects/reactivates the holo-mutase. Inherited defects map cleanly onto the steps: PCCA/PCCB → propionic acidemia; MCEE → (usually mild) methylmalonic aciduria; MMUT → methylmalonic aciduria (mut type); MMAB → cblB and MMAA → cblA methylmalonic aciduria (both often vitamin-B12-responsive because they act on cofactor supply). |
Metabolic Pathway | DRAFT | 0 | propionyl-CoA catabolic process |
5 | 6 | 4 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/propionyl_coa_catabolism.yaml | ||
Prostanoid biosynthesis — cyclooxygenase conversion of arachidonate to PGH2 and its isomerisation or reduction to PGE2, PGD2, PGI2, TXA2 and PGF2alpha; PTGS1/PTGS2/PTGES/PTGES2/PTGES3/HPGDS/PTGDS/PTGIS/TBXAS1/AKR1C3/AKR1B1/PRXL2B/CBR1MODULE:prostanoid_biosynthesisCONCRETE Prostanoids (the prostaglandins, prostacyclin and the thromboxanes) are oxygenated derivatives of arachidonate that act locally through... [more...][less]Prostanoids (the prostaglandins, prostacyclin and the thromboxanes) are oxygenated derivatives of arachidonate that act locally through G-protein-coupled prostanoid receptors in inflammation, pain and fever, vascular tone, platelet function, immunity and reproduction. Their synthesis is a two-stage reaction chain. In the first, committed stage, prostaglandin G/H synthase (cyclooxygenase, COX), a bifunctional haem enzyme on the lumenal face of the endoplasmic reticulum and nuclear envelope, adds two molecules of O2 to free arachidonate to form the hydroperoxy endoperoxide prostaglandin G2 (PGG2) at its cyclooxygenase site, and reduces PGG2 to the hydroxy endoperoxide prostaglandin H2 (PGH2) at its peroxidase site. Two isoforms carry out this stage: COX-1 (PTGS1), expressed constitutively in most tissues and in platelets, and COX-2 (PTGS2), induced by cytokines, growth factors and lipopolysaccharide and responsible for most prostanoid production in inflammation. Both are the targets of non-steroidal anti-inflammatory drugs. In the second stage, PGH2 is converted by cell-type-specific terminal enzymes into the individual prostanoids. Prostaglandin E2 (PGE2) is formed by isomerisation by the glutathione-dependent, inducible microsomal PGE synthase-1 (PTGES), by microsomal PGE synthase-2 (PTGES2) and by the cytosolic PGE synthase p23 (PTGES3). PGD2 is formed by the glutathione-dependent haematopoietic PGD synthase (HPGDS) of mast cells and other immune cells, and by the secreted lipocalin-type PGD synthase (PTGDS) of the brain, male genital tract and heart. Prostacyclin (PGI2) and thromboxane A2 (TXA2) are formed by two atypical cytochrome P450 isomerases of the endoplasmic reticulum, prostacyclin synthase (PTGIS, CYP8A1) in endothelium and thromboxane synthase (TBXAS1, CYP5A1) in platelets, which need no external electron donor or O2. PGF2alpha is formed by reduction rather than isomerisation: aldo-keto reductases AKR1C3 and AKR1B1 reduce PGH2 with NADPH, the thioredoxin-like prostamide/PGF synthase PRXL2B reduces PGH2 with reduced thioredoxin, and carbonyl reductase CBR1 reduces PGE2 at C-9. AKR1C3 also reduces PGD2 at C-11, giving the stereoisomer 11-epi-PGF2alpha (9alpha,11beta-PGF2). Which prostanoids a cell makes depends on its complement of terminal enzymes and on their coupling to COX-1 or COX-2. |
Metabolic Pathway | DRAFT | Homo sapiens |
0 | prostanoid biosynthetic process |
20 | 14 | 2 | 5 | 17 | 3 | 1/13 | 0 | ✗ | modules/prostanoid_biosynthesis.yaml | |
Protein O-glycosylation in Drosophila melanogasterMODULE:dmel_protein_o_glycosylationCONCRETE O-glycosylation attaches sugars to the hydroxyl groups of serine, threonine or hydroxylysine. Flies use several independent O-glycosylation... [more...][less]O-glycosylation attaches sugars to the hydroxyl groups of serine, threonine or hydroxylysine. Flies use several independent O-glycosylation pathways, each started by a dedicated transferase. Mucin-type O-GalNAc glycans are initiated by a family of polypeptide GalNAc transferases (Pgant) and extended by core 1 galactosyltransferase (C1GalTA) and glucuronyltransferase. EGF repeats of Notch and other receptors carry O-fucose added by Ofut1 and elongated by the GlcNAc transferase Fringe, and O-glucose added by Rumi and extended with xylose by Shams and Xxylt. Thrombospondin repeats are O-fucosylated by Ofut2. O-mannose glycans are added in the ER by the Rotated abdomen-Twisted (POMT1-POMT2) complex and, on cadherins, by the TMTC transferases. Nuclear and cytosolic proteins are modified by single O-GlcNAc residues by Super sex combs (OGT) and the modification is removed by O-GlcNAcase, while EGF repeats receive extracellular O-GlcNAc from Eogt. Collagen hydroxylysines are galactosylated after hydroxylation by Plod. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | protein O-linked glycosylation |
23 | 28 | 20 | 1 | 2 | 7 | 2/29 | 0 | ✗ | modules/dmel_protein_o_glycosylation.yaml | |
Protein kinase C signaling — chaperone-assisted maturation, PDPK1 and mTORC2 priming, isoform-class activation by DAG/Ca2+ or the PAR scaffold, RACK1/PICK1 anchoring and PHLPP termination; PRKCA/B/G/D/E/H/Q/Z/I, PDPK1, HSP90AA1/CDC37, PARD3/PARD6, RACK1, PICK1, PHLPP1/2MODULE:protein_kinase_c_signalingCONCRETE The protein kinase C (PKC) family comprises nine human AGC-group serine/threonine kinases, divided into three classes by the second messengers that... [more...][less]The protein kinase C (PKC) family comprises nine human AGC-group serine/threonine kinases, divided into three classes by the second messengers that activate them. All have an N-terminal autoinhibitory pseudosubstrate and a C-terminal kinase domain. Conventional PKCs (PRKCA, PRKCB, PRKCG) have a tandem diacylglycerol (DAG)-binding C1 domain and a calcium-binding C2 domain and need both DAG and Ca2+; novel PKCs (PRKCD, PRKCE, PRKCH, PRKCQ) have a C1 domain with higher DAG affinity and a C2 domain that does not bind calcium, so they need DAG alone; atypical PKCs (PRKCZ, PRKCI) have a single C1 domain that does not bind DAG and are controlled instead by protein-protein interactions, chiefly through the PB1 domain with PAR6 and with PAR3 in the PAR polarity complex. Newly synthesised conventional and novel PKCs are held by the HSP90-CDC37 kinase chaperone while they are processed by three ordered phosphorylations. PDPK1 (PDK1) phosphorylates the activation loop, and then the turn motif and hydrophobic motif in the C-terminal tail are phosphorylated in a step that requires mTORC2. The resulting mature, stable enzyme sits in the cytosol with its pseudosubstrate in the active site. When phospholipase C generates DAG and IP3-released calcium, conventional PKCs are recruited to the plasma membrane by the C2 domain and engage DAG through C1; novel PKCs go to DAG-containing membranes directly. Membrane binding releases the pseudosubstrate, and the active kinase is positioned at particular sites by anchoring proteins, including RACK1, which binds activated PKC, and the PDZ-BAR protein PICK1. The open, active conformation is also sensitive to phosphatases. PHLPP1 and PHLPP2 dephosphorylate the hydrophobic motif, which moves PKC to the detergent-insoluble fraction for degradation and so sets the cellular level of signalling-competent PKC. Atypical PKCs are phosphorylated by PDPK1 in an agonist-dependent manner and, within the PAR3-PAR6-aPKC complex, regulate cell polarity. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | protein kinase C signaling |
12 | 17 | 8 | 1 | 3 | 11 | 7/23 | 0 | ✗ | modules/protein_kinase_c_signaling.yaml | |
Protein phosphatase 2A holoenzymes in Drosophila melanogasterMODULE:dmel_pp2a_holoenzymesCONCRETE Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase formed by a core dimer of a scaffold (A) subunit and a catalytic (C) subunit,... [more...][less]Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase formed by a core dimer of a scaffold (A) subunit and a catalytic (C) subunit, joined by one of several regulatory B subunits that select substrates and subcellular location. In Drosophila the catalytic subunit is Microtubule star (Mts) and the scaffold is Pp2A-29B. The B55-family subunit Twins (Tws) directs PP2A to mitotic substrates and regulates mitotic exit, while the B56 subunits Widerborst (Wdb) and Well rounded (Wrd) act in planar cell polarity, Hedgehog and Wingless signaling, insulin signaling and synapse development. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | protein phosphatase type 2A complex |
6 | 4 | 2 | 1 | 3 | 1 | 5/5 | 0 | ✗ | modules/dmel_pp2a_holoenzymes.yaml | |
Protein prenylation and CAAX processing (FTase/GGTase-I/RabGGTase -> RCE1 -> ICMT)MODULE:protein_prenylation_caax_processing Prenylation is a lipid post-translational modification that irreversibly attaches a farnesyl (C15) or geranylgeranyl (C20) isoprenoid — supplied as... [more...][less]Prenylation is a lipid post-translational modification that irreversibly attaches a farnesyl (C15) or geranylgeranyl (C20) isoprenoid — supplied as FPP/GGPP from the mevalonate pathway — to C-terminal cysteines of ~300 human proteins (Ras, Rho, Rac, Rab and other small GTPases, nuclear lamins, kinases), anchoring them to membranes and enabling signalling and vesicular trafficking. Three heterodimeric prenyltransferases do the attachment. Farnesyltransferase (FTase = the shared alpha subunit FNTA + the beta subunit FNTB) and geranylgeranyltransferase type I (GGTase-I = FNTA + PGGT1B) recognise a C-terminal CAAX motif directly and prenylate its cysteine — FTase when X is Met/Ser/Gln/Ala, GGTase-I when X is Leu/Phe. Rab geranylgeranyltransferase (GGTase-II / RabGGTase = RABGGTA + RABGGTB) instead double-geranylgeranylates the C-terminal CC/CXC cysteines of Rab GTPases, which must first be presented by the Rab escort protein REP1/REP2 (CHM/CHML). For the CAAX (FTase/GGTase-I) substrates, two further ER-membrane maturation steps follow: the glutamate-type intramembrane protease RCE1 removes the -AAX tripeptide, exposing the prenylcysteine as the new C-terminus, and the SAM-dependent methyltransferase ICMT carboxymethylates that prenylcysteine, maximising hydrophobicity and membrane affinity. The pathway is a major anticancer target (Ras farnesylation; FTIs) and underlies Hutchinson-Gilford progeria (lamin A prenylation). RabGGTase/REP defects cause choroideremia (via CHM), and RCE1/ICMT are Ras-pathway drug targets. |
Metabolic Pathway | DRAFT | 0 | protein geranylgeranylation CAAX-box protein processing |
6 | 5 | 5 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/protein_prenylation_caax_processing.yaml | ||
Protoporphyrin-dependent heme B biosynthesis through alternative entry and oxidation routesMODULE:heme_biosynthesisCONCRETE A reusable cross-taxon model of protoporphyrin-dependent heme B biosynthesis. C5 glutamyl-tRNA and C4/Shemin reactions can independently supply... [more...][less]A reusable cross-taxon model of protoporphyrin-dependent heme B biosynthesis. C5 glutamyl-tRNA and C4/Shemin reactions can independently supply 5-aminolevulinate (ALA); many organisms encode one route, while some encode both. A shared tetrapyrrole trunk then feeds independently selected oxygen-dependent or oxygen-independent coproporphyrinogen oxidases and HemJ-, HemG-, or HemY/PPOX-family protoporphyrinogen oxidases. All realizations converge at protoporphyrin IX, which a species-neutral ferrochelatase reaction converts to heme B. This protoporphyrin-dependent (PPD, "classical") route is one of three known routes to heme B; the coproporphyrin-dependent (CPD) route of Firmicutes and Actinobacteria and the siroheme-dependent alternative heme biosynthesis (AHB) route of sulfate-reducing bacteria and archaea share the ALA-to- uroporphyrinogen III core but are outside this module. |
Metabolic Pathway | DRAFT | 13 | heme B biosynthetic process |
18 | 13 | 10 | 3 | 7 | 8 | 36/51 | 0 | ✓ | modules/heme_biosynthesis.yaml | ||
Proximal B cell receptor signalingMODULE:b_cell_receptor_signalingCONCRETE Antigen-engaged B-cell receptors use CD79 signaling tails, SYK and BLNK to organize tyrosine phosphorylation. Class IA PI3K supplies PIP3 for BTK... [more...][less]Antigen-engaged B-cell receptors use CD79 signaling tails, SYK and BLNK to organize tyrosine phosphorylation. Class IA PI3K supplies PIP3 for BTK recruitment, and BTK promotes PLCG2-dependent IP3 and DAG production. CD19, BCAP and LYN modulate this network according to receptor and cellular context. |
Signaling Pathway | DRAFT | Gallus gallus Homo sapiens Mus musculus |
0 | B cell receptor signaling pathway |
22 | 20 | 21 | 0 | 0 | 12 | 22/22 | 0 | ✓ | modules/b_cell_receptor_signaling.yaml | |
Pseudomonad GacS/GacA lifestyle-control phosphorelayMODULE:pseudomonad_gac_lifestyle_phosphorelayCONCRETE The pseudomonad Gac two-component system, a global lifestyle switch between motile/acute and sessile/community behaviour. The membrane hybrid... [more...][less]The pseudomonad Gac two-component system, a global lifestyle switch between motile/acute and sessile/community behaviour. The membrane hybrid sensor kinase GacS autophosphorylates and relays phosphate through its own receiver and HPt modules to the conserved receiver aspartate of the LuxR-type response regulator GacA, which then acts as a DNA-binding transcriptional regulator of surface-associated behaviours including adhesin expression and biofilm development. A second membrane hybrid sensor kinase, RetS, acts on the same relay as an opposing input rather than as an independent pathway. The module covers sensing, His->Asp phosphotransfer, and the transcriptional output; the individual downstream regulons (type VI secretion, exopolysaccharide synthesis, c-di-GMP effectors) are separate modules. |
Signaling Pathway | DRAFT | Pseudomonas |
0 | phosphorelay signal transduction system |
6 | 4 | 5 | 0 | 0 | 3 | 3/3 | 0 | ✗ | modules/pseudomonad_gac_lifestyle_phosphorelay.yaml | |
Pseudomonad lanthanide-switch PQQ alcohol oxidationMODULE:pseudomonad_lanthanide_switch_pqq_alcohol_oxidationCONCRETE A reusable pseudomonad module coupling PedS2/PedR2 two-component signaling to metal-conditioned periplasmic alcohol oxidation. In the absence of... [more...][less]A reusable pseudomonad module coupling PedS2/PedR2 two-component signaling to metal-conditioned periplasmic alcohol oxidation. In the absence of usable lanthanides, phosphorylated PedR2 favors expression of the calcium-dependent PQQ alcohol dehydrogenase PedE. Lanthanide availability shifts the system toward the lanthanide-dependent paralog PedH. Both enzymes oxidize diverse alcohols in the periplasm and pass electrons to cytochrome c. PQQ biosynthesis, downstream aldehyde metabolism, and lanthanide uptake are adjacent systems and are outside this module. The enzymes carry the cytochrome-c alcohol dehydrogenase assignment, but their specific physiological cytochrome c partner in KT2440 remains inferred. |
Biological Process | COMPLETE | Pseudomonas |
0 | phosphorelay signal transduction system alcohol metabolic process |
7 | 4 | 4 | 1 | 2 | 3 | 4/4 | 0 | ✓ | modules/pseudomonad_lanthanide_switch_pqq_alcohol_oxidation.yaml | |
Pseudomonadaceae CbrA/CbrB carbon catabolite control via Crc/HfqMODULE:pseudomonad_cbr_crc_catabolite_controlCONCRETE The CbrA/CbrB two-component system of the Pseudomonadaceae and the post-transcriptional machinery it controls, which together set carbon catabolite... [more...][less]The CbrA/CbrB two-component system of the Pseudomonadaceae and the post-transcriptional machinery it controls, which together set carbon catabolite repression and balance carbon against nitrogen utilization. The membrane sensor histidine kinase CbrA phosphorylates the conserved receiver aspartate of CbrB, and CbrB acts as a sigma-54-dependent enhancer-binding activator of the genes for the CrcZ-family small RNAs (CrcZ, and CrcY or CrcX in some species). Those small RNAs act as decoys for the Hfq/Crc translational repressor: Hfq binds A-rich catabolite-activity motifs near the ribosome-binding sites of catabolic mRNAs through its distal face, and the catalytically inactive co-repressor Crc stabilises the repressive Hfq/RNA assemblies. When favoured carbon sources are scarce, CrcZ-family RNA levels rise, Hfq/Crc is sequestered, and translational repression of catabolic mRNAs is relieved. The module spans sensing, phosphotransfer, sigma-54-dependent small-RNA induction, and the translational repression step that the small RNAs antagonise. |
Signaling Pathway | COMPLETE | Pseudomonadaceae |
0 | carbon catabolite repression |
6 | 7 | 5 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/pseudomonad_cbr_crc_catabolite_control.yaml | |
Pseudomonas 2-ketogluconate loopMODULE:pseudomonad_2_ketogluconate_loopCONCRETE A reusable Pseudomonas peripheral glucose-catabolism module. A PQQ-dependent inner-membrane Gcd oxidizes periplasmic glucose to... [more...][less]A reusable Pseudomonas peripheral glucose-catabolism module. A PQQ-dependent inner-membrane Gcd oxidizes periplasmic glucose to D-glucono-1,5-lactone, which hydrolyzes to gluconate; a three-subunit Gad complex oxidizes gluconate to 2-ketogluconate; KguT imports it; KguK phosphorylates it; and KguD reduces the phosphorylated intermediate to 6-phosphogluconate. PQQ biosynthesis, porin-mediated glucose entry, PtxS regulation, the alternative gluconate-kinase route, and the downstream Entner-Doudoroff trunk are outside the boundary. |
Metabolic Pathway | COMPLETE | Pseudomonas |
0 | non-phosphorylated glucose catabolic process D-gluconate metabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 4/8 | 0 | ✗ | modules/pseudomonad_2_ketogluconate_loop.yaml | |
Pseudomonas pyoverdine non-proteinogenic precursor supplyMODULE:pseudomonas_pyoverdine_precursor_supplyCONCRETE A reusable Pseudomonas module for reactions that supply unusual amino-acid building blocks to the cytoplasmic pyoverdine NRPS assembly line. PvdA... [more...][less]A reusable Pseudomonas module for reactions that supply unusual amino-acid building blocks to the cytoplasmic pyoverdine NRPS assembly line. PvdA hydroxylates L-ornithine to produce N5-hydroxy-L-ornithine, and PvdH forms L-2,4-diaminobutyrate from L-aspartate 4-semialdehyde by PLP-dependent transamination. Hydroxyornithine acylation, NRPS assembly, ferribactin export, periplasmic maturation, secretion, ferripyoverdine uptake, and iron release are outside this module. |
Biological Process | COMPLETE | Pseudomonas |
0 | pyoverdine biosynthetic process |
3 | 2 | 2 | 0 | 0 | 0 | 4/4 | 0 | ✓ | modules/pseudomonas_pyoverdine_precursor_supply.yaml | |
Pseudomonas-type anabolic peptidoglycan recyclingMODULE:peptidoglycan_recyclingCONCRETE A reusable Gram-negative bacterial recycling route that imports soluble anhydromuropeptides, separates their GlcNAc, anhMurNAc, and stem-peptide... [more...][less]A reusable Gram-negative bacterial recycling route that imports soluble anhydromuropeptides, separates their GlcNAc, anhMurNAc, and stem-peptide components, and returns both MurNAc and the recovered peptide to peptidoglycan precursor synthesis. The sugar arm uses AnmK, MupP, AmgK, and MurU to regenerate UDP-MurNAc. This anabolic branch is characteristic of Pseudomonas and other bacteria that lack the MurQ catabolic diversion. Periplasmic generation of turnover fragments and downstream polymerization of peptidoglycan are outside the boundary. |
Metabolic Pathway | DRAFT | 3 | peptidoglycan turnover |
9 | 8 | 8 | 0 | 0 | 9 | 9/13 | 0 | ✗ | modules/peptidoglycan_recycling.yaml | ||
Purine base and nucleoside salvage, with oxidation of purine bases to urateMODULE:purine_salvage_and_catabolism The cytosolic handling of purine bases and nucleosides released by nucleic-acid and nucleotide turnover or taken up from outside the cell. A... [more...][less]The cytosolic handling of purine bases and nucleosides released by nucleic-acid and nucleotide turnover or taken up from outside the cell. A salvage arm recycles them into nucleotides, sparing costly de novo synthesis: phosphoribosyltransferases transfer the phosphoribosyl group of PRPP to adenine (adenine phosphoribosyltransferase, giving AMP), to hypoxanthine and guanine (hypoxanthine-guanine phosphoribosyltransferase, giving IMP and GMP) and, in fungi and bacteria, to xanthine (xanthine phosphoribosyltransferase, giving XMP); adenosine kinase phosphorylates adenosine to AMP. Interconverting deaminations and phosphorolysis route bases between these entry points: adenosine deaminase (animals) or adenine deaminase (fungi, bacteria) converts the adenine moiety to the hypoxanthine level, purine nucleoside phosphorylase releases hypoxanthine and guanine from inosine and guanosine, and guanine deaminase converts guanine to xanthine. An optional catabolic arm oxidises hypoxanthine and xanthine to urate, by molybdenum-dependent xanthine oxidoreductase in animals, plants and many bacteria, or, for xanthine, by an alpha-ketoglutarate-dependent xanthine dioxygenase found only in fungi. Some organisms lack the catabolic arm entirely: budding yeast has no xanthine oxidoreductase, xanthine dioxygenase or urate oxidase and only salvages purine bases. In humans, inherited defects define classic disorders: complete HPRT1 deficiency causes Lesch-Nyhan syndrome and partial deficiency gout/hyperuricemia; APRT deficiency causes 2,8-dihydroxyadenine nephrolithiasis; ADA and PNP deficiencies cause immunodeficiency through lymphotoxic deoxynucleotide accumulation; and XDH deficiency causes xanthinuria type I (XDH is the target of allopurinol and febuxostat). |
Metabolic Pathway | DRAFT | 0 | purine-containing compound salvage purine nucleobase metabolic process |
13 | 11 | 8 | 2 | 4 | 7 | 18/21 | 0 | ✗ | modules/purine_salvage_and_catabolism.yaml | ||
Purine nucleotide catabolism to urate (5'-nucleotidases / deaminases -> PNP -> XDH)MODULE:purine_nucleotide_catabolism Purine ribonucleotides are catabolised to the excretory end-product uric acid through a converging network of dephosphorylation, deamination and... [more...][less]Purine ribonucleotides are catabolised to the excretory end-product uric acid through a converging network of dephosphorylation, deamination and phosphorolysis reactions. AMP is either deaminated to IMP by AMP deaminase (AMPD1/2/3) or dephosphorylated to adenosine by a 5'-nucleotidase — the cytosolic AMP-preferring NT5C1A or the GPI-anchored cell-surface ecto-5'-nucleotidase NT5E (CD73), whose extracellular adenosine is also a major purinergic signal. Adenosine is deaminated to inosine by adenosine deaminase (ADA). IMP and GMP are dephosphorylated to inosine and guanosine by the cytosolic 5'-nucleotidase NT5C2. Purine-nucleoside phosphorylase (PNP) then removes the ribose from inosine, guanosine and their deoxy forms, giving hypoxanthine and guanine. Guanine is deaminated to xanthine by guanine deaminase (GDA), while hypoxanthine is oxidised to xanthine and xanthine to urate by xanthine dehydrogenase/oxidase (XDH). Defects across the pathway cause disease: ADA and PNP deficiencies cause severe combined / T-cell immunodeficiency, XDH deficiency causes xanthinuria, NT5E loss-of-function causes arterial calcification (ACDC), and activating NT5C2 mutations drive relapse in acute lymphoblastic leukaemia. |
Metabolic Pathway | DRAFT | 0 | purine nucleotide catabolic process purine-containing compound catabolic process urate biosynthetic process |
9 | 8 | 8 | 0 | 0 | 8 | 9/9 | 0 | ✗ | modules/purine_nucleotide_catabolism.yaml | ||
Purine ribonucleotide interconversion (IMP to AMP/GMP and their di- and triphosphates)MODULE:purine_nucleotide_interconversion Inosine monophosphate (IMP), the first complete purine nucleotide made by de novo synthesis or by salvage, is the branch point from which the... [more...][less]Inosine monophosphate (IMP), the first complete purine nucleotide made by de novo synthesis or by salvage, is the branch point from which the adenine and guanine ribonucleotides are made. Toward AMP, adenylosuccinate synthetase condenses IMP with L-aspartate using GTP to form adenylosuccinate, which adenylosuccinate lyase cleaves to AMP and fumarate. Toward GMP, IMP dehydrogenase oxidises IMP to xanthosine monophosphate (XMP) with NAD+ (the committed, rate-limiting step of guanine-nucleotide synthesis) and GMP synthase aminates XMP to GMP using the amide nitrogen of glutamine. The monophosphates are then phosphorylated by adenylate kinase (AMP to ADP) and guanylate kinase (GMP to GDP), and nucleoside-diphosphate kinase transfers the gamma-phosphate of ATP to GDP (and other diphosphates) to make GTP; ADP is converted to ATP mainly by energy metabolism. AMP deaminase hydrolytically deaminates AMP back to IMP; with adenylosuccinate synthetase and lyase this forms the purine nucleotide cycle, which in animal muscle buffers the adenylate energy charge and releases fumarate and ammonia. Because GTP is required to make AMP and ATP to make GMP, these reactions cross-regulate the adenine and guanine nucleotide pools. The enzymes are cytosolic and conserved from bacteria to fungi and animals, with lineage-specific isozymes (for example, muscle and liver adenylosuccinate synthetases and three AMP deaminases in mammals, and three expressed IMP dehydrogenases in budding yeast). Inherited defects of the human enzymes include ADSS1 distal myopathy, IMPDH1 retinitis pigmentosa, IMPDH2 neurodevelopmental dystonia, myoadenylate deaminase (AMPD1) deficiency and AMPD2 pontocerebellar hypoplasia; IMP dehydrogenase is the target of mycophenolic acid and ribavirin. |
Metabolic Pathway | DRAFT | 0 | purine ribonucleotide interconversion 'de novo' AMP biosynthetic process 'de novo' GMP biosynthetic process |
9 | 8 | 8 | 0 | 0 | 8 | 18/22 | 0 | ✗ | modules/purine_nucleotide_interconversion.yaml | ||
Pyrenoid-based CO2-concentrating mechanismMODULE:pyrenoid_ccmCONCRETE The pyrenoid-based CO2-concentrating mechanism (PCCM) of green algae, modeled on Chlamydomonas reinhardtii. Rubisco is condensed by a multivalent... [more...][less]The pyrenoid-based CO2-concentrating mechanism (PCCM) of green algae, modeled on Chlamydomonas reinhardtii. Rubisco is condensed by a multivalent linker protein into a liquid-like matrix (the pyrenoid) inside the chloroplast stroma. Thylakoid membrane tubules traverse the matrix. Bicarbonate accumulated in the stroma enters the thylakoid lumen through bestrophin-like channels and is dehydrated to CO2 by a lumenal carbonic anhydrase within the tubules, releasing CO2 into the Rubisco matrix. A starch sheath around the matrix limits CO2 back-diffusion, and a stromal LCIB/LCIC carbonic anhydrase complex at the pyrenoid periphery recaptures escaping CO2 as bicarbonate. The parts follow the six-step minimal-PCCM decomposition used in modeling and in plans to engineer a pyrenoid into C3 plant chloroplasts. Bicarbonate uptake across the plasma membrane and chloroplast envelope, and transcriptional induction under low CO2, are included as optional upstream parts. |
Biological Process | DRAFT | Chlamydomonas reinhardtii |
0 | pyrenoid-based CO2-concentrating mechanism pyrenoid |
9 | 14 | 8 | 0 | 0 | 7 | 17/17 | 0 | ✗ | modules/pyrenoid_ccm.yaml | |
Pyrimidine base and nucleoside salvageMODULE:pyrimidine_salvage Recycling of preformed pyrimidine bases and ribonucleosides, taken up from the environment or released by RNA and nucleotide turnover, into UMP and... [more...][less]Recycling of preformed pyrimidine bases and ribonucleosides, taken up from the environment or released by RNA and nucleotide turnover, into UMP and CMP. Uracil is converted directly to UMP by uracil phosphoribosyltransferase with PRPP. Uridine and cytidine are phosphorylated by uridine-cytidine kinase to UMP and CMP; alternatively, cytidine is deaminated to uridine by cytidine deaminase, and the ribonucleosides are cleaved to their free bases either by a nucleoside hydrolase (fungi and protists) or by uridine phosphorylase (animals and bacteria). Cytosine is deaminated to uracil by cytosine deaminase, an enzyme present in fungi and bacteria but absent from animals; this is why the antifungal prodrug 5-fluorocytosine is selectively toxic to fungi. CMP made by salvage is phosphorylated to CDP by UMP/CMP kinase, and UMP joins the de novo product for conversion to UTP and CTP. The same enzymes act on some deoxyribonucleosides (deoxycytidine is phosphorylated or cleaved), but thymidine salvage requires thymidine kinase, which animals and many bacteria have and budding and fission yeasts lack. Uptake of pyrimidine bases and nucleosides by plasma-membrane permeases precedes the module. |
Metabolic Pathway | DRAFT | Fungi |
0 | pyrimidine-containing compound salvage |
10 | 8 | 7 | 1 | 2 | 6 | 16/23 | 0 | ✗ | modules/pyrimidine_salvage.yaml | |
Pyrimidine nucleotide catabolism (5'-nucleotidase/deaminase/phosphorylase -> DPYD -> DPYS -> UPB1)MODULE:pyrimidine_nucleotide_catabolism Pyrimidine nucleotides are degraded through a sequence of dephosphorylation, deamination and phosphorolysis that liberates the free bases uracil... [more...][less]Pyrimidine nucleotides are degraded through a sequence of dephosphorylation, deamination and phosphorolysis that liberates the free bases uracil and thymine, followed by the three-step reductive ring-opening pathway that converts them to beta-alanine and beta-aminoisobutyrate. Pyrimidine mononucleotides (UMP, CMP) are dephosphorylated to uridine and cytidine by the erythrocyte-enriched cytosolic pyrimidine 5'-nucleotidase NT5C3A. Cytidine (and 2'-deoxycytidine) is deaminated to uridine (2'-deoxyuridine) by cytidine deaminase CDA. Uridine is phosphorolysed to uracil plus ribose-1-phosphate by uridine phosphorylase UPP1 (ubiquitous) or UPP2 (tissue-restricted paralog); thymidine is analogously phosphorolysed to thymine by thymidine phosphorylase TYMP. The liberated uracil and thymine then enter the conserved reductive catabolic pathway: dihydropyrimidine dehydrogenase DPYD reduces them (NADPH) to dihydrouracil/dihydrothymine, dihydropyrimidinase DPYS hydrolyses the ring to N-carbamyl-beta-alanine / N-carbamyl-beta-aminoisobutyrate, and beta-ureidopropionase UPB1 releases beta-alanine / beta-aminoisobutyrate (+ CO2 + NH3). This pathway also governs the activation and inactivation of pyrimidine-analog drugs: NT5C3A/CDA/UPP1/TYMP shape the fluoropyrimidine (5-FU, capecitabine) and cytidine-analog (gemcitabine, cytarabine) response, and DPYD loss-of-function causes severe 5-fluorouracil toxicity. Other deficiencies cause pyrimidine-5'-nucleotidase hemolytic anemia (NT5C3A), MNGIE (TYMP), and dihydropyrimidinuria (DPYD/DPYS/UPB1). |
Metabolic Pathway | DRAFT | 0 | pyrimidine nucleotide catabolic process uracil catabolic process beta-alanine biosynthetic process |
8 | 7 | 7 | 0 | 0 | 7 | 8/8 | 0 | ✗ | modules/pyrimidine_nucleotide_catabolism.yaml | ||
Pyrroloquinoline quinone biosynthesisMODULE:pqq_biosynthesis Pyrroloquinoline quinone (PQQ) is made from conserved glutamate and tyrosine residues in the short ribosomally synthesized precursor peptide PqqA.... [more...][less]Pyrroloquinoline quinone (PQQ) is made from conserved glutamate and tyrosine residues in the short ribosomally synthesized precursor peptide PqqA. A PqqD-family peptide chaperone presents PqqA to the radical-SAM enzyme PqqE, which forms the defining carbon-carbon cross-link. Proteolytic processing and PqqB-dependent oxygenation both contribute to formation of a late small-molecule precursor, although their relative order is unresolved. PqqC completes oxidative ring closure to mature PQQ. PQQ export and use by quinoprotein dehydrogenases are downstream of this module. |
Metabolic Pathway | DRAFT | Bacteria |
0 | pyrroloquinoline quinone biosynthetic process |
9 | 8 | 5 | 1 | 3 | 5 | 12/15 | 1 | ✓ | modules/pqq_biosynthesis.yaml | |
Pyruvate dehydrogenase bypass and acetate-dependent acetyl-CoA synthesisMODULE:pdh_bypass_acetyl_coa_synthesisABSTRACT The pyruvate dehydrogenase (PDH) bypass makes acetyl-CoA in the cytosol without the mitochondrial PDH complex. Acetaldehyde is oxidised by an... [more...][less]The pyruvate dehydrogenase (PDH) bypass makes acetyl-CoA in the cytosol without the mitochondrial PDH complex. Acetaldehyde is oxidised by an aldehyde dehydrogenase to acetate, and acetate is ligated to coenzyme A by an AMP-forming acetyl-CoA synthetase. The acetaldehyde comes either from pyruvate decarboxylase during growth on sugars or from alcohol dehydrogenase oxidising ethanol during growth on ethanol. Acetyl-CoA cannot cross organelle membranes, and some fungi, including budding yeast, lack ATP-citrate lyase. In those organisms this route is the main or only source of nucleocytosolic acetyl-CoA for fatty acid and sterol synthesis, lysine synthesis and histone acetylation, and it is essential. The same three reactions carry ethanol and acetate into central metabolism (via the glyoxylate cycle) after the diauxic shift. The acetate-activation step is the conserved acetyl-CoA synthetase found from bacteria to mammals. |
Metabolic Pathway | DRAFT | 0 | acetyl-CoA biosynthetic process |
8 | 6 | 3 | 2 | 4 | 2 | 10/11 | 0 | ✗ | modules/pdh_bypass_acetyl_coa_synthesis.yaml | ||
Pyruvate fates — pyruvate dehydrogenase complex and pyruvate carboxylaseMODULE:pyruvate_metabolism The two committed eukaryotic fates of pyruvate that feed the TCA cycle. (1) Oxidative decarboxylation by the mitochondrial pyruvate dehydrogenase... [more...][less]The two committed eukaryotic fates of pyruvate that feed the TCA cycle. (1) Oxidative decarboxylation by the mitochondrial pyruvate dehydrogenase complex (PDC) links glycolysis to the TCA cycle: pyruvate + CoA + NAD+ -> acetyl-CoA + CO2 + NADH. Pyruvate enters the matrix through the mitochondrial pyruvate carrier. The PDC is a giant mitochondrial-matrix multienzyme machine built on a 60-mer E2 (dihydrolipoyllysine-residue acetyltransferase) core, with the thiamine-diphosphate-dependent E1 decarboxylase (an alpha2-beta2 heterotetramer), the E3-binding structural subunit (protein X / E3BP) that anchors the dihydrolipoyl dehydrogenase E3, and E3 itself, which reoxidises the lipoyl arms and passes electrons to NAD+. The same subunit architecture is conserved from yeasts (PDA1, PDB1, LAT1, PDX1, LPD1) to animals (PDHA1, PDHB, DLAT, PDHX, DLD), and the E3 is shared with the 2-oxoglutarate and branched-chain 2-oxoacid dehydrogenases. PDC flux is switched off by phosphorylation of E1alpha by pyruvate dehydrogenase kinases and on by dephosphorylation by the phosphatases. (2) Carboxylation by the biotin-dependent pyruvate carboxylase (PC): pyruvate + HCO3- + ATP -> oxaloacetate, the principal anaplerotic reaction replenishing oxaloacetate and the committed first step of gluconeogenesis from pyruvate or lactate. PC is a mitochondrial-matrix enzyme in animals, where it is allosterically activated by acetyl-CoA, the PDC product, coordinating the two fates; in budding yeast the two PC isozymes are cytosolic, so the oxaloacetate they make must be imported into mitochondria to replenish the cycle. In humans, inherited defects cause severe lactic acidosis and neurological disease: PDHA1 (X-linked, the commonest), PDHB, DLAT and PDHX deficiencies cause pyruvate dehydrogenase complex deficiency (Leigh syndrome spectrum), PC deficiency causes lactic acidosis with hypoglycemia, and DLD deficiency (the shared E3) gives a combined phenotype. |
Metabolic Pathway | DRAFT | 0 | pyruvate metabolic process |
5 | 7 | 2 | 1 | 2 | 1 | 19/19 | 0 | ✗ | modules/pyruvate_metabolism.yaml | ||
RHG proteins, Diap1 and the Dark apoptosome in Drosophila caspase activationMODULE:dmel_rhg_apoptosome_caspase_activationCONCRETE In Drosophila cells, the initiator caspase Dronc is kept inactive by the inhibitor of apoptosis protein Diap1, an E3 ubiquitin ligase that binds... [more...][less]In Drosophila cells, the initiator caspase Dronc is kept inactive by the inhibitor of apoptosis protein Diap1, an E3 ubiquitin ligase that binds and ubiquitylates Dronc and effector caspases. Apoptotic stimuli induce the RHG proteins Reaper (Rpr), Head involution defective (Hid), Grim and Sickle (Skl), which share an N-terminal IAP-binding motif. They bind Diap1, displace the caspases and promote Diap1 degradation. Freed Dronc is recruited by the adaptor Dark into the apoptosome, a wheel-shaped complex in which Dronc is activated and then cleaves the effector caspases drICE and Dcp-1. The mitochondrial serine protease HtrA2 (Omi) also binds IAPs and can promote cell death. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | apoptotic process apoptosome |
5 | 8 | 4 | 0 | 0 | 2 | 9/9 | 0 | ✗ | modules/dmel_rhg_apoptosome_caspase_activation.yaml | |
RIG-I signaling pathway moduleMODULE:rig_i_signaling RIG-I detects viral RNA and signals through MAVS to activate TBK1/IKK-family kinases and IRF transcription factors that induce type I interferon... [more...][less]RIG-I detects viral RNA and signals through MAVS to activate TBK1/IKK-family kinases and IRF transcription factors that induce type I interferon responses. |
Signaling Pathway | DRAFT | metazoa |
6 | RIG-I signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 3/5 | 0 | ✓ | modules/rig_i_signaling.yaml | |
RISC-loading complexes and miRISC in Drosophila melanogasterMODULE:dmel_risc_loading_complexesCONCRETE Small RNA duplexes produced by Dicer are loaded into Argonaute proteins by RISC-loading complexes. In Drosophila the miRNA pathway uses Dicer-1... [more...][less]Small RNA duplexes produced by Dicer are loaded into Argonaute proteins by RISC-loading complexes. In Drosophila the miRNA pathway uses Dicer-1 with the dsRNA-binding partner Loquacious (Loqs-PB) and loads miRNAs mainly into AGO1, whereas the siRNA pathway uses Dicer-2 with R2D2, which senses duplex asymmetry and loads siRNAs into AGO2. FlyBase also defines an alternative siRNA loading complex in which Loqs (Loqs-PD isoform) partners Dicer-2 with AGO2. Mature miRNA-loaded AGO1 associates with the GW182 protein Gawky to form the miRNA-induced silencing complex (miRISC), which represses translation and promotes deadenylation and decay of target mRNAs. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | RISC-loading complex RISC complex |
6 | 4 | 3 | 1 | 2 | 1 | 1/7 | 0 | ✗ | modules/dmel_risc_loading_complexes.yaml | |
RNA exosome and nuclear exosome targeting complex in Drosophila melanogasterMODULE:dmel_rna_exosomeCONCRETE The RNA exosome is a 3'-5' exoribonuclease complex that processes and degrades many classes of RNA in the nucleus and cytoplasm. A catalytically... [more...][less]The RNA exosome is a 3'-5' exoribonuclease complex that processes and degrades many classes of RNA in the nucleus and cytoplasm. A catalytically inactive nine-subunit barrel, made of a six-subunit ring (including Ski6, Mtr3, Rrp42, Rrp45 and Rrp46) capped by Csl4, Rrp4 and Rrp40, channels RNA to the processive exonuclease and endonuclease Dis3 (Rrp44). The nuclear exosome also contains the distributive exonuclease Rrp6. Nuclear cofactors deliver substrates: the nuclear exosome targeting (NEXT) complex, formed by the RNA helicase Mtr4, a zinc-knuckle protein (CG4622, ZCCHC8 homolog) and an RRM protein (CG11454, RBM7 homolog), targets short-lived non-polyadenylated transcripts for decay. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | exosome (RNase complex) |
4 | 4 | 3 | 0 | 0 | 1 | 0/13 | 0 | ✗ | modules/dmel_rna_exosome.yaml | |
RNA polymerase II elongation complexes in Drosophila melanogasterMODULE:dmel_rnapii_elongation_complexesCONCRETE After initiation, RNA polymerase II pauses shortly downstream of most Drosophila promoters, held by DSIF (Spt4-Spt5) and NELF. Release into... [more...][less]After initiation, RNA polymerase II pauses shortly downstream of most Drosophila promoters, held by DSIF (Spt4-Spt5) and NELF. Release into productive elongation requires P-TEFb (Cdk9-CycT), which phosphorylates NELF, Spt5 and the polymerase C-terminal domain; P-TEFb is held inactive by Hexim within the 7SK snRNP and is also recruited within the super elongation complex (SEC), which carries the ELL elongation factor Su(Tpl). The related little elongation complex (LEC) promotes transcription of snRNA genes. During elongation, the PAF1 complex couples polymerase to co-transcriptional histone modification, FACT reorganizes nucleosomes in front of and behind the polymerase, and elongin stimulates the elongation rate. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | transcription elongation factor complex |
12 | 10 | 9 | 1 | 2 | 2 | 2/32 | 0 | ✗ | modules/dmel_rnapii_elongation_complexes.yaml | |
RNA polymerase II general transcription factors in Drosophila melanogasterMODULE:dmel_rnapii_general_transcription_factorsCONCRETE The general transcription factors TFIID, TFIIA, TFIIB, TFIIE, TFIIF and TFIIH assemble with RNA polymerase II on core promoters to form the... [more...][less]The general transcription factors TFIID, TFIIA, TFIIB, TFIIE, TFIIF and TFIIH assemble with RNA polymerase II on core promoters to form the preinitiation complex. TFIID, built from the TATA-box binding protein (TBP) and TBP-associated factors (TAFs), recognizes core promoter elements; TFIIA stabilizes TBP binding to DNA. TFIIF escorts polymerase into the complex and TFIIE recruits TFIIH. TFIIH contains the XPB (hay) translocase that opens promoter DNA, the XPD helicase, and the CDK-activating kinase (Cdk7, CycH, Mat1), which phosphorylates the polymerase C-terminal domain during initiation; TFIIH also acts in nucleotide excision repair. In Drosophila testis, paralogous testis-specific TAFs (tTAFs) and a germline TFIIA small subunit variant drive the spermatocyte transcription program. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | transcription preinitiation complex |
11 | 12 | 8 | 1 | 2 | 0 | 0/40 | 0 | ✗ | modules/dmel_rnapii_general_transcription_factors.yaml | |
RNase P and RNase MRP complexes in Drosophila melanogasterMODULE:dmel_rnase_p_mrpCONCRETE Ribonuclease P removes the 5' leader from precursor tRNAs. Nuclear RNase P is a ribonucleoprotein whose catalytic RNA (RNaseP:RNA) is bound by... [more...][less]Ribonuclease P removes the 5' leader from precursor tRNAs. Nuclear RNase P is a ribonucleoprotein whose catalytic RNA (RNaseP:RNA) is bound by several proteins; the related RNase MRP shares most of these proteins but has its own RNA (RNaseMRP:RNA) and cleaves other substrates, including pre-rRNA. In mitochondria, tRNA 5' processing is carried out by a protein-only RNase P made of a tRNA methyltransferase subunit (rswl, MRPP1 homolog), a short-chain dehydrogenase subunit (scu, MRPP2/HSD17B10 homolog) and the PRORP-type nuclease subunit (mldr). |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ribonuclease P complex ribonuclease MRP complex |
4 | 3 | 3 | 0 | 0 | 0 | 1/12 | 0 | ✗ | modules/dmel_rnase_p_mrp.yaml | |
Rab7- and HOPS-dependent membrane fusion at the plant vacuoleMODULE:plant_vacuole_fusionCONCRETE Cargo bound for the plant lytic vacuole, from prevacuolar compartments, the biosynthetic route and autophagy, arrives by membrane fusion with the... [more...][less]Cargo bound for the plant lytic vacuole, from prevacuolar compartments, the biosynthetic route and autophagy, arrives by membrane fusion with the tonoplast. The Mon1-Ccz1 complex activates the Rab7 GTPase (RabG3 in plants) on the incoming membrane, Rab7 recruits the HOPS tethering complex, and HOPS assembles the vacuolar SNAREs, the Qa-SNARE SYP22 with VTI11 and their partners, which fuse the two bilayers. This module is the green-lineage form of that step, written so that it can be evaluated in a plant genome. |
Biological Process | DRAFT | Viridiplantae |
7 | vacuole fusion HOPS complex |
5 | 7 | 4 | 0 | 0 | 3 | 0/13 | 0 | ✗ | modules/plant_vacuole_fusion.yaml | |
Rad9-Hus1-Rad1 (9-1-1) checkpoint clamp in Drosophila melanogasterMODULE:dmel_9_1_1_checkpoint_clampCONCRETE The 9-1-1 complex is a heterotrimeric ring of Rad9, Hus1 and Rad1 that is structurally related to the PCNA sliding clamp. An RFC-like clamp loader... [more...][less]The 9-1-1 complex is a heterotrimeric ring of Rad9, Hus1 and Rad1 that is structurally related to the PCNA sliding clamp. An RFC-like clamp loader places it at 5' recessed junctions of single-stranded DNA gaps and resected ends, where it helps recruit and activate the ATR kinase in the DNA damage and replication checkpoint. In Drosophila, the Hus1 ortholog is named Hus1-like. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | checkpoint clamp complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_9_1_1_checkpoint_clamp.yaml | |
Reductive pyrimidine degradationMODULE:pyrimidine_degradationCONCRETE A three-reaction pathway that degrades the pyrimidine bases uracil and thymine to beta-alanine or 3-aminoisobutanoate, carbon dioxide and ammonium.... [more...][less]A three-reaction pathway that degrades the pyrimidine bases uracil and thymine to beta-alanine or 3-aminoisobutanoate, carbon dioxide and ammonium. Dihydropyrimidine dehydrogenase first reduces the C5=C6 bond of the pyrimidine ring, dihydropyrimidinase hydrolytically opens the saturated ring to an N-carbamoyl-beta-amino acid, and beta-ureidopropionase (beta-alanine synthase) releases the beta-amino acid. The chemistry is conserved across bacteria and eukaryotes, but the first and third reactions are carried out by structurally distinct enzymes: a single-chain NADPH-dependent dehydrogenase in eukaryotes versus a two-subunit NADH-dependent enzyme in bacteria, and a nitrilase-superfamily beta-alanine synthase in animals, plants and amoebae versus an unrelated di-zinc M20-family enzyme in fungi. |
Metabolic Pathway | COMPLETE | amoebozoans animals bacteria eukaryotes fungi green plants |
0 | pyrimidine nucleobase catabolic process |
10 | 6 | 3 | 3 | 6 | 2 | 9/9 | 0 | ✗ | modules/pyrimidine_degradation.yaml | |
Reductive tricarboxylic acid cycleMODULE:reductive_tca_cycleABSTRACT The reductive TCA cycle (reverse Krebs, Arnon-Buchanan cycle), which fixes CO2 by running the oxidative TCA cycle backwards. Three steps are not... [more...][less]The reductive TCA cycle (reverse Krebs, Arnon-Buchanan cycle), which fixes CO2 by running the oxidative TCA cycle backwards. Three steps are not simply the reverse of their oxidative counterparts, and they are what define the cycle: citrate is cleaved by an ATP-dependent citrate lyase rather than made by citrate synthase; 2-oxoglutarate is formed by reductive carboxylation of succinyl-CoA by a ferredoxin-dependent 2-oxoglutarate synthase; and fumarate is reduced rather than succinate oxidized. A fourth ferredoxin-dependent carboxylation, pyruvate synthase, converts the acetyl-CoA released by citrate cleavage into pyruvate for biosynthesis. The cycle fixes two CO2 per turn and is markedly cheaper per carbon than the Calvin cycle, which is why it dominates in green sulfur bacteria and several Aquificae and epsilonproteobacteria; the price is that its ferredoxin-dependent carboxylases are oxygen-sensitive, confining it to anaerobic and microaerophilic niches. A sibling of MODULE:wood_ljungdahl_pathway, MODULE:hydroxypropionate_bicycle and MODULE:calvin_benson_bassham_cycle. |
Metabolic Pathway | DRAFT | 0 | reductive tricarboxylic acid cycle carbon fixation |
6 | 5 | 5 | 0 | 0 | 5 | 0/5 | 0 | ✗ | modules/reductive_tca_cycle.yaml | ||
Reelin signaling — RELN binding to VLDLR/LRP8, SRC-family phosphorylation of DAB1, PI3K and LIS1 effector branches, and CRL5(SOCS7) degradation of phospho-DAB1; RELN/VLDLR/LRP8/DAB1/FYN/SRC/PIK3R1/PAFAH1B1/SOCS7/CUL5/RNF7MODULE:reelin_signalingCONCRETE Reelin (RELN) is a large secreted glycoprotein made by Cajal-Retzius cells in the marginal zone of the developing cortex and by other neurons later... [more...][less]Reelin (RELN) is a large secreted glycoprotein made by Cajal-Retzius cells in the marginal zone of the developing cortex and by other neurons later in life. It controls where radially migrating neurons stop and so sets up the layers of the cerebral cortex, hippocampus and cerebellum. Reelin binds the ectodomains of two lipoprotein receptors of the LDL receptor family, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, LRP8), and clusters them. The cytoplasmic tails of both receptors carry an NPxY motif bound by the phosphotyrosine-binding domain of the adaptor Disabled-1 (DAB1). Receptor clustering brings DAB1 molecules together at the inner face of the plasma membrane, where the Src-family kinases FYN and SRC phosphorylate DAB1 on tyrosines; phosphorylated DAB1 in turn activates more Src-family kinase, giving a positive feedback loop. Tyrosine-phosphorylated DAB1 is a docking hub for downstream effectors. It binds the p85-alpha regulatory subunit (PIK3R1) of class IA phosphoinositide 3-kinase, which activates AKT and inhibits GSK3B; and it binds LIS1 (PAFAH1B1), the dynein regulator mutated in lissencephaly, linking the Reelin signal to the microtubule machinery of neuronal migration. Phosphorylated DAB1 is also the substrate of the signal's own off-switch. The substrate adaptor SOCS7 recognises phospho-DAB1 and recruits it to a cullin-5 RING ubiquitin ligase (CUL5 with the RING protein RNF7/RBX2 and the Elongin B/C adaptor), which polyubiquitinates DAB1 for proteasomal degradation and so stops neurons at their target layer. In the adult brain the same receptor-DAB1-kinase core modulates NMDA and AMPA receptor function at excitatory synapses and enhances long-term potentiation. Loss of RELN, of DAB1, or of both receptors produces the reeler phenotype in mice, and RELN mutations cause lissencephaly with cerebellar hypoplasia in humans. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | reelin-mediated signaling pathway |
7 | 11 | 6 | 0 | 0 | 6 | 5/11 | 0 | ✗ | modules/reelin_signaling.yaml | |
Renin-angiotensin cascade — renin (with the (pro)renin receptor) cleavage of angiotensinogen, ACE or chymase/cathepsin G formation of angiotensin II, the ACE2/neprilysin/PRCP angiotensin-(1-7) arm acting on MAS1, and the ENPEP/ANPEP aminopeptidase arm to angiotensin III and IVMODULE:renin_angiotensin_cascadeCONCRETE The renin-angiotensin cascade is the extracellular proteolytic pathway that generates the family of angiotensin peptide hormones from a single... [more...][less]The renin-angiotensin cascade is the extracellular proteolytic pathway that generates the family of angiotensin peptide hormones from a single precursor, angiotensinogen (AGT), a liver-secreted serpin-fold glycoprotein that does none of the cleaving itself. Renin (REN), an aspartic endopeptidase released by the juxtaglomerular cells of the kidney, cleaves the N-terminal Leu-Val bond of angiotensinogen and releases the inactive decapeptide angiotensin I; this is the rate-limiting step. On tissue surfaces renin and its zymogen prorenin bind the (pro)renin receptor ATP6AP2, which raises renin's catalytic efficiency and lets prorenin act without proteolytic activation. The zinc peptidyl-dipeptidase angiotensin-converting enzyme (ACE), anchored on endothelial cells and also shed into plasma, removes the C-terminal His-Leu dipeptide of angiotensin I to give the octapeptide angiotensin II, the principal effector, which acts on the AT1 and AT2 receptors. In tissues, angiotensin II is also formed independently of ACE by the mast-cell serine protease chymase (CMA1) and by neutrophil cathepsin G (CTSG). A counter-regulatory arm converts the pressor peptides into angiotensin-(1-7): the monocarboxypeptidase ACE2 removes the C-terminal phenylalanine of angiotensin II (its preferred substrate) and the C-terminal leucine of angiotensin I to give angiotensin-(1-9); neprilysin (MME) cleaves angiotensin I and angiotensin-(1-9) to angiotensin-(1-7), as ACE also does for angiotensin-(1-9); and the lysosomal prolylcarboxypeptidase PRCP releases the C-terminal phenylalanine of angiotensin II and III. Angiotensin-(1-7) is the agonist of the G protein-coupled receptor MAS1 and opposes angiotensin II with vasodilator and antiproliferative actions. A third arm trims angiotensin II from the N terminus: glutamyl aminopeptidase (aminopeptidase A, ENPEP) removes Asp1 to give angiotensin III, which still acts on the AT1 and AT2 receptors and dominates in the brain renin-angiotensin system, and alanyl aminopeptidase (aminopeptidase N, ANPEP) removes Arg1 of angiotensin III to give angiotensin IV. |
Biological Process | DRAFT | Homo sapiens |
0 | angiotensin maturation |
15 | 13 | 7 | 2 | 7 | 8 | 2/12 | 0 | ✗ | modules/renin_angiotensin_cascade.yaml | |
Replication origin licensing and activation in Drosophila melanogasterMODULE:dmel_replication_origin_licensing_activationCONCRETE Eukaryotic DNA replication starts in two steps that are separated in the cell cycle. In G1, the origin recognition complex (ORC) binds replication... [more...][less]Eukaryotic DNA replication starts in two steps that are separated in the cell cycle. In G1, the origin recognition complex (ORC) binds replication origins and, with Cdc6 and Cdt1 (Double parked in Drosophila), loads the MCM2-7 helicase core as an inactive double hexamer around double-stranded DNA; this is origin licensing. In S phase, the Dbf4-dependent kinase (Cdc7 with its regulatory subunit Chiffon) and cyclin-dependent kinases trigger the recruitment of Cdc45 and the four-subunit GINS complex onto MCM2-7, forming the active CMG (Cdc45-MCM-GINS) helicase that unwinds DNA at the replication fork. Restricting licensing to G1 and activation to S phase ensures that each origin fires only once per cell cycle. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | DNA replication initiation |
6 | 6 | 5 | 0 | 0 | 4 | 0/21 | 0 | ✗ | modules/dmel_replication_origin_licensing_activation.yaml | |
Replication-dependent histone pre-mRNA 3' end processing in Drosophila melanogasterMODULE:dmel_histone_mrna_3prime_processingCONCRETE Replication-dependent histone mRNAs are not polyadenylated; instead their 3' end is formed by a single endonucleolytic cleavage between a conserved... [more...][less]Replication-dependent histone mRNAs are not polyadenylated; instead their 3' end is formed by a single endonucleolytic cleavage between a conserved stem-loop and a purine-rich histone downstream element. The stem-loop binding protein (Slbp) binds the stem-loop, and the U7 snRNP, whose U7 snRNA base pairs with the downstream element and whose Sm ring contains the U7-specific Lsm10 and Lsm11, recruits FLASH and the histone pre-mRNA cleavage complex. This complex reuses the Cpsf73 endonuclease, Cpsf100 and Symplekin together with other CPSF and CstF subunits. In Drosophila these factors concentrate in the histone locus body. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | histone pre-mRNA 3'end processing complex |
5 | 4 | 4 | 0 | 0 | 1 | 0/19 | 0 | ✗ | modules/dmel_histone_mrna_3prime_processing.yaml | |
Respiratory chain and ATP synthase assembly factors in Drosophila melanogasterMODULE:dmel_respiratory_complex_assembly_factorsCONCRETE The complexes of the mitochondrial oxidative phosphorylation system are built from nuclear- and mitochondrially encoded subunits with the help of... [more...][less]The complexes of the mitochondrial oxidative phosphorylation system are built from nuclear- and mitochondrially encoded subunits with the help of dedicated assembly factors that are not part of the mature enzymes. Complex II (succinate dehydrogenase) assembly factors include SDHAF2-type proteins required for covalent flavinylation of the SdhA subunit and SDHAF3 and SDHAF4 homologs that protect the iron-sulfur subunit and intermediates. Complex III assembly requires the AAA ATPase Bcs1, which inserts the Rieske iron-sulfur protein, the LYR protein LYRM7 that chaperones it, and the UQCC proteins that support cytochrome b. HIG1 domain proteins associate with complexes III and IV and support respiratory supercomplex formation. ATP synthase (complex V) assembly factors include ATPAF1-type chaperones of the F1 domain, TMEM70 and the metalloprotease ATP23. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | mitochondrial respiratory chain complex assembly |
5 | 24 | 4 | 0 | 0 | 0 | 1/24 | 0 | ✗ | modules/dmel_respiratory_complex_assembly_factors.yaml | |
Retinal determination network moduleMODULE:retinal_determination_network The conserved gene regulatory network that specifies eye identity in bilaterians. A Pax6 paired/homeodomain selector transcription factor initiates... [more...][less]The conserved gene regulatory network that specifies eye identity in bilaterians. A Pax6 paired/homeodomain selector transcription factor initiates the program and induces expression of a Six-family homeodomain transcription factor (Sine oculis / SIX) and the Eyes absent (EYA) cofactor. EYA, a nuclear transcriptional coactivator with intrinsic protein phosphatase activity, binds SIX proteins and converts SIX-dependent repression into activation; Dachshund (DACH), a Ski/Sno-related nuclear cofactor, also complexes with EYA. The factors cross-regulate one another in positive feedback loops, so the network behaves as an interlocked circuit rather than a linear hierarchy. Misexpression of the Pax6, Six/Eya or Dachshund components can induce ectopic eye tissue in Drosophila, and the vertebrate orthologs (PAX6, SIX3/SIX6, EYA, DACH) act with the same epistatic logic in optic vesicle, retina and lens development. |
Developmental Process | DRAFT | Bilateria |
1 | eye development |
5 | 5 | 4 | 0 | 0 | 6 | 11/11 | 0 | ✗ | modules/retinal_determination_network.yaml | |
Retinoic acid receptor signaling pathway moduleMODULE:retinoic_acid_receptor_signaling Retinoic acid synthesis and transport feed RAR/RXR nuclear receptor complexes that switch chromatin-associated co-repressor/co-activator states to... [more...][less]Retinoic acid synthesis and transport feed RAR/RXR nuclear receptor complexes that switch chromatin-associated co-repressor/co-activator states to control developmental and differentiation genes. |
Signaling Pathway | DRAFT | metazoa |
7 | retinoic acid receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 2/5 | 0 | ✓ | modules/retinoic_acid_receptor_signaling.yaml | |
Retinoid visual cycle (11-cis-retinal regeneration across RPE and photoreceptors)MODULE:retinoid_visual_cycle Vision depends on continuous regeneration of the 11-cis-retinal chromophore that photobleaches to all-trans-retinal each time a photon isomerizes a... [more...][less]Vision depends on continuous regeneration of the 11-cis-retinal chromophore that photobleaches to all-trans-retinal each time a photon isomerizes a visual pigment. The classical (RPE) visual cycle recycles it across the photoreceptor and retinal-pigment-epithelium (RPE) cells. In photoreceptors, light isomerizes 11-cis-retinal bound to opsin to all-trans-retinal, which is released and reduced to all-trans-retinol by NADPH-dependent retinol dehydrogenases (RDH8 in the outer segment, RDH12 in the inner segment; this also detoxifies the reactive aldehyde). All-trans-retinol travels to the RPE, where lecithin:retinol acyltransferase (LRAT) esterifies it to all-trans-retinyl ester (the pathway's storage/committed form). The central RPE enzyme RPE65 then carries out the coupled ester-hydrolysis and trans-to-cis isomerization, producing 11-cis-retinol, which the NAD+-dependent 11-cis-retinol dehydrogenase RDH5 oxidizes to 11-cis-retinal for return to photoreceptors and recombination with opsin. The cellular retinaldehyde-binding protein RLBP1 (CRALBP) chaperones the hydrophobic 11-cis-retinoids through these steps, and RGR, an opsin-family photoisomerase in RPE/Muller cells, provides a light-driven route regenerating 11-cis-retinal from all-trans-retinal. RDH11 contributes broad retinaldehyde-reductase activity, and DHRS3 buffers retinaldehyde/retinoic-acid levels. Defects across the cycle cause inherited retinal dystrophies: RPE65 and LRAT (Leber congenital amaurosis, the RPE65 form treated by voretigene neparvovec gene therapy), RDH12 (LCA13), RDH5 (fundus albipunctatus), RLBP1 (retinitis punctata albescens / Bothnia dystrophy) and RGR (retinitis pigmentosa). |
Metabolic Pathway | DRAFT | 0 | visual perception retinol metabolic process |
9 | 8 | 8 | 0 | 0 | 5 | 9/9 | 0 | ✗ | modules/retinoid_visual_cycle.yaml | ||
Retromer (VPS35/VPS26A/VPS29) and SORL1 endosome-to-TGN retrograde sorting — clathrin/AP-2/DNM2 internalization, V-ATPase acidification, retromer cargo selection, and RAB9A/AP-1 TGN delivery vs. ESCRT/RAB7A/CTSD lysosomal proteolysisMODULE:retromer_endosome_to_tgn_retrieval Transmembrane sorting receptors — including the neuronal sortilin-related receptor SORL1 (SorLA/LR11, which binds amyloid precursor protein APP),... [more...][less]Transmembrane sorting receptors — including the neuronal sortilin-related receptor SORL1 (SorLA/LR11, which binds amyloid precursor protein APP), cation-independent mannose 6-phosphate receptors (IGF2R/CI-MPR), and Wntless (WLS) — continuously cycle between the trans-Golgi network (TGN), plasma membrane, and endosomes. Cell-surface SORL1-cargo complexes are internalized via clathrin-coated pits (AP2M1, CLTC) and dynamin-2 (DNM2) vesicle scission into early sorting endosomes acidified by V-ATPase (ATP6V1A). On early and maturing sorting endosome membranes, the heterotrimeric retromer cargo-selective complex (CSC), composed of VPS35, VPS26A, and VPS29, recognizes the cytoplasmic FANSHY sorting motif of SORL1 (and aromatic/hydrophobic motifs on CI-MPR and WLS) to partition receptor-cargo complexes into tubular retrograde carriers, actively protecting them from ESCRT-I (TSG101) multivesicular body incorporation and RAB7A-driven lysosomal degradation. Downstream delivery and receptor sorting at the trans-Golgi network are mediated by the TGN/endosomal clathrin adaptor complex AP-1 (AP1B1, AP1G1; PMID:23415225) together with the complementary late-endosome-to-TGN small GTPase RAB9A (which recruits the dynein effector NDE1 to transport late-endosomal receptors to the TGN; PMID:8164745, PMID:34793709, PMID:15078902). When retromer function (VPS35/VPS26A/VPS29) or SORL1 sorting is impaired — a hallmark pathogenic mechanism in Alzheimer disease and Parkinson disease — sorting receptors and their cargo fail to return to the TGN, remain in maturing endosomes, and are routed via TSG101 and RAB7A into lysosomes for proteolytic cleavage (CTSD). |
Transport Step | DRAFT | 0 | retrograde transport, endosome to Golgi cargo adaptor activity receptor-mediated endocytosis endosome to lysosome transport |
8 | 14 | 7 | 0 | 0 | 7 | 21/21 | 0 | ✗ | Agent Based | modules/retromer_endosome_to_tgn_retrieval.yaml | |
Retromer complex in Drosophila melanogasterMODULE:dmel_retromerCONCRETE Retromer retrieves transmembrane cargo from endosomes and returns it to the trans-Golgi network or to the plasma membrane. Its cargo-selective core... [more...][less]Retromer retrieves transmembrane cargo from endosomes and returns it to the trans-Golgi network or to the plasma membrane. Its cargo-selective core is a heterotrimer of Vps35, Vps26 and Vps29 that recognizes sorting motifs in cargo tails; it associates with sorting nexins, including the SNX-BAR proteins Snx1 and Snx6, which bind endosomal phosphoinositides and shape membrane tubules. In Drosophila, retromer recycles the Wnt cargo receptor Wntless (Wls) to the Golgi, which is needed for Wingless secretion, and it also maintains rhodopsin and other cargo in photoreceptors. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | retromer complex |
3 | 2 | 2 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/dmel_retromer.yaml | |
Rho protein signal transduction pathway moduleMODULE:rho_gprotein_signaling Rho-family GTPase signaling uses GEFs, GAPs, and GTP-bound Rho switches to regulate actomyosin organization, adhesion, polarity, migration, and... [more...][less]Rho-family GTPase signaling uses GEFs, GAPs, and GTP-bound Rho switches to regulate actomyosin organization, adhesion, polarity, migration, and cytokinesis. |
Signaling Pathway | DRAFT | metazoa |
4 | Rho protein signal transduction |
4 | 6 | 3 | 0 | 0 | 2 | 1/4 | 0 | ✓ | modules/rho_gprotein_signaling.yaml | |
Riboflavin (vitamin B2) uptake and FMN/FAD cofactor synthesis (SLC52A1/2/3 -> RFK -> FLAD1)MODULE:riboflavin_uptake_and_cofactor_synthesis Riboflavin (vitamin B2) is the precursor of the flavin coenzymes FMN and FAD, which are the redox cofactors of dozens of flavoenzymes in... [more...][less]Riboflavin (vitamin B2) is the precursor of the flavin coenzymes FMN and FAD, which are the redox cofactors of dozens of flavoenzymes in mitochondrial fatty-acid and amino-acid oxidation, the respiratory chain, one-carbon and folate metabolism, and many oxidoreductases. Humans cannot synthesise riboflavin and must take it up from the diet, then convert it intracellularly to the active cofactors. Dietary and cellular riboflavin uptake is mediated by the three plasma-membrane SLC52 riboflavin transporters: SLC52A3 (RFVT3), the principal intestinal apical absorptive transporter; SLC52A2 (RFVT2), broadly expressed including brain; and SLC52A1 (RFVT1), important in placenta for maternal-fetal transfer. In the cytosol riboflavin kinase (RFK) phosphorylates riboflavin (ATP) to flavin mononucleotide (FMN), and FAD synthase (FLAD1) then adenylylates FMN (ATP) to flavin adenine dinucleotide (FAD). Defects in the transporters cause riboflavin transporter deficiency: SLC52A2/SLC52A3 loss-of-function causes Brown-Vialetto-Van Laere syndrome / Fazio- Londe disease (childhood sensorimotor neuronopathy with deafness and bulbar palsy, treatable with high-dose riboflavin), and maternal SLC52A1 deficiency causes transient neonatal multiple acyl-CoA dehydrogenase deficiency; FLAD1 deficiency causes a riboflavin-responsive lipid-storage myopathy / MADD-like disorder. |
Metabolic Pathway | DRAFT | 0 | riboflavin transport FMN biosynthetic process FAD biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/riboflavin_uptake_and_cofactor_synthesis.yaml | ||
Ribonucleotide reductase in Drosophila melanogasterMODULE:dmel_ribonucleotide_reductaseCONCRETE Class I ribonucleotide reductase converts ribonucleoside diphosphates to deoxyribonucleoside diphosphates, the rate-limiting step in supplying... [more...][less]Class I ribonucleotide reductase converts ribonucleoside diphosphates to deoxyribonucleoside diphosphates, the rate-limiting step in supplying dNTPs for DNA replication and repair. It is a complex of a large R1 subunit (RnrL), which contains the catalytic site and the allosteric sites that control activity and substrate specificity, and a small R2 subunit (RnrS), which carries the diferric-tyrosyl radical cofactor that starts catalysis. Electrons are supplied by thioredoxin or glutaredoxin. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | ribonucleoside-diphosphate reductase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_ribonucleotide_reductase.yaml | |
Rice momilactone A biosynthesisMODULE:rice_momilactone_biosynthesisCONCRETE Biosynthesis of the rice diterpenoid momilactone A from geranylgeranyl diphosphate. Cyclases construct a syn-pimaradiene scaffold, cytochrome P450... [more...][less]Biosynthesis of the rice diterpenoid momilactone A from geranylgeranyl diphosphate. Cyclases construct a syn-pimaradiene scaffold, cytochrome P450 enzymes oxidize it, and short-chain dehydrogenases support lactone and ketone formation. The chromosome 4 biosynthetic gene cluster supplies only part of this pathway: additional P450 enzymes are encoded on chromosomes 2, 6, and 1. Momilactones participate in plant chemical defense and allelopathy. An optional C20-hydroxylation branch records an activity implicated in momilactone B production; a complete ordered route to B is not represented. |
Metabolic Pathway | DRAFT | Oryza sativa subsp. japonica |
0 | momilactone diterpenoid biosynthesis chromosome 4 momilactone biosynthetic gene cluster |
16 | 10 | 11 | 2 | 4 | 7 | 1/8 | 0 | ✓ | modules/rice_momilactone_biosynthesis.yaml | |
RidA reactive enamine/imine detoxificationMODULE:rida_reactive_enamine_detoxificationCONCRETE A cytosolic metabolic damage-control module in which RidA accelerates hydrolytic deamination of reactive enamine/imine intermediates generated by... [more...][less]A cytosolic metabolic damage-control module in which RidA accelerates hydrolytic deamination of reactive enamine/imine intermediates generated by PLP-dependent enzymes such as threonine dehydratase, protecting isoleucine biosynthesis and other PLP enzyme pathways from covalent damage. |
Metabolic Pathway | DRAFT | Escherichia coli |
0 | 2-iminobutanoate/2-iminopropanoate deaminase activity threonine deaminase activity L-isoleucine biosynthetic process |
1 | 2 | 0 | 0 | 0 | 1 | 1/2 | 0 | ✗ | modules/rida_reactive_enamine_detoxification.yaml | |
Rod-Zw10-Zwilch (RZZ) complex in Drosophila melanogasterMODULE:dmel_rzz_complexCONCRETE The RZZ complex, made of Rough deal (Rod), Zw10 and Zwilch, assembles on unattached kinetochores in prometaphase. It recruits the Mad1-Mad2... [more...][less]The RZZ complex, made of Rough deal (Rod), Zw10 and Zwilch, assembles on unattached kinetochores in prometaphase. It recruits the Mad1-Mad2 checkpoint proteins and is therefore required for the spindle assembly checkpoint, and it recruits dynein-dynactin through the adaptor Spindly. Once microtubules attach, dynein strips RZZ and checkpoint proteins from the kinetochore along kinetochore fibres, which helps silence the checkpoint. Rod and Zw10 were first identified in Drosophila through mutants with chromosome segregation defects. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | RZZ complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_rzz_complex.yaml | |
Root ground-tissue radial patterning by the SHORT-ROOT-SCARECROW-BIRD moduleMODULE:root_radial_patterning_shr_scrCONCRETE Radial patterning of the Arabidopsis root ground tissue is organised by a mobile GRAS-domain transcriptional regulator. SHORT-ROOT (SHR) is... [more...][less]Radial patterning of the Arabidopsis root ground tissue is organised by a mobile GRAS-domain transcriptional regulator. SHORT-ROOT (SHR) is transcribed in the stele but the protein moves through plasmodesmata into the single adjacent cell layer (endodermis, cortex/endodermis initial (CEI) and quiescent centre (QC)). There it is captured in the nucleus by the related GRAS protein SCARECROW (SCR), with which it forms a head-to-head heterodimer, and by BIRD/INDETERMINATE-DOMAIN (IDD) C2H2 zinc-finger transcription factors such as JACKDAW (JKD/IDD10) and MAGPIE (MGP/IDD3). The BIRD zinc fingers ZF1-ZF3 contact DNA while ZF3-ZF4 dock into a groove on SHR, so the SHR-SCR heterodimer acts as a transcriptional coregulator brought to target promoters by BIRD proteins. Nuclear retention limits SHR movement to one layer, and the SHR-SCR-BIRD complex activates SCR itself (a positive feedback loop), MGP and other BIRDs (a feed-forward loop), and the D-type cyclin CYCD6;1. CYCD6;1 binds and activates CDKB1 kinases that phosphorylate RETINOBLASTOMA-RELATED (RBR), relieving RBR repression of SCR; this nested feed-forward loop triggers the formative asymmetric periclinal division of the CEI daughter that produces separate endodermis and cortex layers. SHR-SCR also specify endodermal identity, and SCR is required cell-autonomously for QC identity, providing the niche context in which the QC transcription factor WOX5 maintains the surrounding stem cells. Middle-cortex formation later in development reuses the SHR-SCR-CYCD6;1 module. |
Developmental Process | DRAFT | Arabidopsis thaliana |
0 | root radial pattern formation asymmetric cell division |
6 | 9 | 5 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/root_radial_patterning_shr_scr.yaml | |
S-adenosylmethionine (SAM) cycle — SAM synthesis / transmethylation / SAH hydrolysis (MAT1A/GNMT/AHCY); hypermethioninemiasMODULE:sam_cycle The S-adenosylmethionine (SAM) arm of the methionine cycle generates and recycles the universal biological methyl donor. Methionine... [more...][less]The S-adenosylmethionine (SAM) arm of the methionine cycle generates and recycles the universal biological methyl donor. Methionine adenosyltransferase (liver MAT1A; extrahepatic MAT2A) condenses L-methionine with ATP to form S-adenosyl-L-methionine (SAM). SAM then donates its methyl group in the many transmethylation reactions of SAM-dependent methyltransferases — of which glycine N-methyltransferase (GNMT), the abundant hepatic enzyme methylating glycine to sarcosine, is the major regulator of the SAM:SAH ratio (cellular methylation capacity) — each producing S-adenosyl-L-homocysteine (SAH). Adenosylhomocysteinase (AHCY, SAH hydrolase) then hydrolyses SAH to L-homocysteine + adenosine, relieving the potent SAH product-inhibition of methyltransferases. Homocysteine is then either remethylated back to methionine (methionine synthase MTR / betaine-homocysteine methyltransferase), closing the cycle, or committed to transsulfuration (CBS) toward cysteine — reactions curated in the homocysteine-metabolism module. Inherited defects of the three SAM-arm enzymes all cause hypermethioninemia: MAT1A (MAT I/III deficiency, usually benign, severe forms with CNS demyelination), GNMT (GNMT deficiency, mild hepatopathy), and AHCY (S-adenosylhomocysteine hydrolase / SAHH deficiency, with elevated SAH/SAM, myopathy, developmental delay and liver disease). |
Metabolic Pathway | DRAFT | 0 | L-methionine cycle |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/sam_cycle.yaml | ||
SCF-Slimb ubiquitin ligase in Drosophila melanogasterMODULE:dmel_scf_slimb_ubiquitin_ligaseCONCRETE SCF-Slimb is a cullin-RING E3 ubiquitin ligase in which the F-box protein Supernumerary limbs (Slimb, the beta-TrCP ortholog) recognizes... [more...][less]SCF-Slimb is a cullin-RING E3 ubiquitin ligase in which the F-box protein Supernumerary limbs (Slimb, the beta-TrCP ortholog) recognizes phosphorylated degron motifs and the Cul1-Roc1a core transfers ubiquitin to the bound substrate. SkpA bridges the F-box of Slimb to Cul1. Slimb targets include Armadillo in Wingless signalling, Cubitus interruptus in Hedgehog signalling, the centriole duplication kinase Plk4 and the clock protein Period, so SCF-Slimb restrains several signalling pathways and centriole number. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | SCF ubiquitin ligase complex |
4 | 3 | 3 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/dmel_scf_slimb_ubiquitin_ligase.yaml | |
SCIMP-scaffolded TLR tyrosine phosphorylation moduleMODULE:scimp_tlr_tyrosine_kinase_scaffoldABSTRACT A non-TIR adaptor branch of Toll-like receptor signalling in macrophages. After LPS activates TLR4 (see modules/tlr4_md2_lps_signaling.yaml), the... [more...][less]A non-TIR adaptor branch of Toll-like receptor signalling in macrophages. After LPS activates TLR4 (see modules/tlr4_md2_lps_signaling.yaml), the palmitoylated transmembrane adaptor SCIMP binds the TLR4 TIR domain. SCIMP carries the Src-family kinase LYN constitutively on its proline-rich region and, once its tyrosines are phosphorylated, recruits SYK through both SYK SH2 domains. LYN and SYK phosphorylate TLR4 on its TIR domain (mouse Y672, human Y674), and SCIMP recruits ERK1/2 to TLR4 in membrane ruffles, leading to c-FOS activation and a selective IL-6 and IL-12p40 response. CSK, docking on a separate SCIMP phosphotyrosine, provides negative feedback. The branch runs alongside the TIRAP-MYD88 and TRAM-TRIF branches and does not replace them. |
Signaling Pathway | DRAFT | mammals |
0 | toll-like receptor 4 signaling pathway |
6 | 7 | 5 | 0 | 0 | 6 | 7/8 | 0 | ✗ | modules/scimp_tlr_tyrosine_kinase_scaffold.yaml | |
SMC5/6 complex in Drosophila melanogasterMODULE:dmel_smc5_6_complexCONCRETE The SMC5/6 complex is the third eukaryotic SMC complex, acting in DNA repair by homologous recombination, in the resolution of recombination and... [more...][less]The SMC5/6 complex is the third eukaryotic SMC complex, acting in DNA repair by homologous recombination, in the resolution of recombination and replication intermediates, and in the maintenance of repetitive DNA such as the rDNA and heterochromatin. It is built on an SMC5-SMC6 heterodimer bridged by the kleisin Nse4, which binds the Nse1-Nse3 pair (Nse3 is a MAGE-family protein, encoded in Drosophila by MAGE). The SUMO ligase subunit Nse2 binds the SMC arms. Drosophila has two Nse2 paralogs, Quijote (qjt) and Cervantes (cerv), which define two variants of the complex. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Smc5-Smc6 complex |
6 | 4 | 3 | 1 | 2 | 0 | 0/7 | 0 | ✗ | modules/dmel_smc5_6_complex.yaml | |
SREBP signaling — sterol-regulated ER-to-Golgi escort and two-step cleavage of SREBP; SCAP/INSIG/MBTPS1/MBTPS2/SREBF1/SREBF2MODULE:srebp_signaling The SREBP pathway couples membrane sterol levels to transcription of the genes for cholesterol and fatty-acid synthesis and LDL uptake. SREBP... [more...][less]The SREBP pathway couples membrane sterol levels to transcription of the genes for cholesterol and fatty-acid synthesis and LDL uptake. SREBP precursors (SREBF1 and SREBF2) are ER-membrane proteins whose N-terminal basic helix-loop-helix leucine-zipper transcription factor domain is held on the cytosolic face of the ER. Their C-terminal regulatory domain binds the WD-repeat domain of SCAP, which carries a sterol-sensing domain and escorts SREBP from the ER to the Golgi in COPII vesicles. When ER cholesterol is high, cholesterol binding to SCAP and oxysterol (25-hydroxycholesterol) binding to the ER-resident INSIG proteins (INSIG1, INSIG2) lock SCAP-SREBP into an INSIG-bound complex that the COPII coat cannot recognise, so SREBP stays in the ER. When sterols fall, SCAP is released, SCAP-SREBP is packaged into COPII vesicles and moves to the Golgi. There SREBP is cleaved sequentially: site-1 protease (MBTPS1, a subtilisin-like serine protease) cuts in the luminal loop, and site-2 protease (MBTPS2, an intramembrane zinc metalloprotease) then cuts within the first transmembrane segment. The released N-terminal fragment enters the nucleus and activates genes bearing sterol regulatory elements, including HMGCR, LDLR and INSIG1 itself, closing a negative feedback loop. In mammals SREBF2 preferentially drives cholesterol synthesis, the SREBF1c transcript fatty-acid synthesis, and SREBF1a both. |
Signaling Pathway | DRAFT | 0 | SREBP signaling pathway |
6 | 10 | 5 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/srebp_signaling.yaml | ||
SREBP-SCAP complex in Drosophila melanogasterMODULE:dmel_srebp_scap_complexCONCRETE SREBP is a membrane-bound basic helix-loop-helix leucine zipper transcription factor held in the endoplasmic reticulum by its escort protein SCAP.... [more...][less]SREBP is a membrane-bound basic helix-loop-helix leucine zipper transcription factor held in the endoplasmic reticulum by its escort protein SCAP. When lipid levels fall, SCAP carries SREBP to the Golgi, where two proteolytic cleavages release the N-terminal transcription factor domain, which enters the nucleus and activates genes of lipid synthesis. In Drosophila, which cannot make sterols, SREBP processing is controlled by phosphatidylethanolamine rather than by sterols, and SREBP mainly regulates fatty acid synthesis. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | SREBP-SCAP complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_srebp_scap_complex.yaml | |
SRP-dependent co-translational translocation into the ERMODULE:er_cotranslational_translocationCONCRETE Most secretory and membrane proteins enter the endoplasmic reticulum while they are being made. The signal recognition particle (SRP) binds the... [more...][less]Most secretory and membrane proteins enter the endoplasmic reticulum while they are being made. The signal recognition particle (SRP) binds the signal sequence or first transmembrane segment as it leaves the ribosome, the SRP receptor at the ER membrane captures the SRP-ribosome complex, and the two GTPases hand the ribosome to the Sec61 channel, through which the chain is threaded into the lumen or released laterally into the membrane. This module is the eukaryote-wide protein core of that pathway, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
12 | SRP-dependent cotranslational protein targeting to membrane protein targeting to ER |
5 | 10 | 4 | 0 | 0 | 2 | 6/10 | 0 | ✗ | modules/er_cotranslational_translocation.yaml | |
SRP-dependent cotranslational targeting in Drosophila melanogasterMODULE:dmel_srp_cotranslational_targetingCONCRETE The signal recognition particle (SRP) recognizes signal sequences and transmembrane segments as they emerge from the ribosome, slows elongation and... [more...][less]The signal recognition particle (SRP) recognizes signal sequences and transmembrane segments as they emerge from the ribosome, slows elongation and delivers the ribosome-nascent chain complex to the SRP receptor on the endoplasmic reticulum membrane. SRP is a ribonucleoprotein built on the 7SL RNA. Its Alu domain (SRP9 and SRP14) arrests elongation, and its S domain (SRP19, SRP54, SRP68 and SRP72) binds the signal sequence through the methionine-rich domain of the GTPase SRP54. The receptor is a heterodimer of the GTPases SRalpha and SRbeta. GTP-dependent interaction of SRP54 with SRalpha transfers the nascent chain to the Sec61 translocon, and reciprocal GTP hydrolysis releases SRP from its receptor. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | SRP-dependent cotranslational protein targeting to membrane |
6 | 5 | 5 | 0 | 0 | 1 | 0/8 | 0 | ✗ | modules/dmel_srp_cotranslational_targeting.yaml | |
STRIPAK complex in Drosophila melanogasterMODULE:dmel_stripak_complexCONCRETE The striatin-interacting phosphatase and kinase (STRIPAK) complex is a large, conserved assembly built around a PP2A phosphatase whose regulatory B... [more...][less]The striatin-interacting phosphatase and kinase (STRIPAK) complex is a large, conserved assembly built around a PP2A phosphatase whose regulatory B subunit is a striatin. In Drosophila the striatin is Connector of kinase to AP-1 (Cka), which binds the PP2A scaffold (A) subunit Pp2A-29B and the catalytic subunit Microtubule star (Mts) together with Mob4, Strip, Slmap and Fgop2. Ccm3 links germinal-centre kinase III family kinases to the complex. STRIPAK restrains the Hippo pathway by dephosphorylating the Hippo kinase, and also acts in JNK signaling, axon transport, synapse development and centrosome positioning. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | FAR/SIP/STRIPAK complex |
4 | 4 | 3 | 0 | 0 | 1 | 2/9 | 0 | ✗ | modules/dmel_stripak_complex.yaml | |
SWR1-type Domino H2Av exchange complex in Drosophila melanogasterMODULE:dmel_swr1_domino_complexCONCRETE The SWR1-type complex deposits the histone variant H2Av into nucleosomes in exchange for H2A. Its catalytic subunit is the SWR1-family ATPase... [more...][less]The SWR1-type complex deposits the histone variant H2Av into nucleosomes in exchange for H2A. Its catalytic subunit is the SWR1-family ATPase Domino; in Drosophila the Domino-B isoform forms this complex, whereas Domino-A is part of the Tip60 complex. The complex shares with Tip60 the AAA+ ATPases Pontin and Reptin, YL-1, DMAP1, Gas41, Bap55 and the MRG15 module, and contains the actin-related protein Arp6. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | Swr1 complex |
6 | 5 | 5 | 0 | 0 | 0 | 0/12 | 0 | ✗ | modules/dmel_swr1_domino_complex.yaml | |
Salicylic acid biosynthesis (isochorismate route) and NPR1-dependent defence signallingMODULE:salicylic_acid_biosynthesis_npr1_signalingCONCRETE After pathogen attack Arabidopsis makes most of its salicylic acid (SA) from chorismate through isochorismate. In the chloroplast stroma,... [more...][less]After pathogen attack Arabidopsis makes most of its salicylic acid (SA) from chorismate through isochorismate. In the chloroplast stroma, isochorismate synthase 1 (ICS1, also SID2/EDS16) isomerizes chorismate to isochorismate; this is the committed, pathogen-induced step, and its paralog ICS2 contributes little. The MATE transporter EDS5 exports isochorismate to the cytosol, where the GH3 amidotransferase PBS3 conjugates it with glutamate to isochorismate-9-glutamate, which decomposes, spontaneously or with the help of the acyltransferase EPS1, into SA. SA is perceived by the NPR protein family: the paralogs NPR3 and NPR4 bind SA with high affinity and act as CUL3-ligase adaptors that control NPR1 turnover, while NPR1 itself has been reported to bind SA more weakly, although the relative roles of NPR1 and NPR3/NPR4 as SA receptors are debated. SA-induced changes in cellular redox reduce cytoplasmic NPR1 oligomers to monomers that enter the nucleus, where NPR1 acts as a transcription coregulator. Sumoylated NPR1 switches from WRKY repressors to TGA transcription factors and activates defence genes such as PR1, and NPR1 directly induces a set of WRKY transcription factor genes. One of these, WRKY70, is a sequence-specific transcription factor that promotes SA-induced pathogenesis-related gene expression, represses jasmonate-responsive genes and, together with WRKY54, restrains SA biosynthesis, forming a negative feedback loop. Together these steps drive local resistance and systemic acquired resistance (SAR) against biotrophic pathogens. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | salicylic acid biosynthetic process systemic acquired resistance, salicylic acid mediated signaling pathway |
4 | 3 | 3 | 0 | 0 | 3 | 3/3 | 0 | ✗ | modules/salicylic_acid_biosynthesis_npr1_signaling.yaml | |
Salt Overly Sensitive (SOS) pathway (SOS3/CBL4 - SOS2/CIPK24 - SOS1 Na+/H+ antiporter)MODULE:sos_salt_toleranceABSTRACT The Salt Overly Sensitive (SOS) pathway is a calcium-decoding kinase relay that drives Na+ extrusion from plant cells under salinity. A... [more...][less]The Salt Overly Sensitive (SOS) pathway is a calcium-decoding kinase relay that drives Na+ extrusion from plant cells under salinity. A salt-induced cytosolic Ca2+ signal is sensed by N-myristoylated calcineurin B-like (CBL) EF-hand calcium sensors: SOS3/CBL4 predominantly in roots and SCaBP8/CBL10 in shoots. The Ca2+-bound CBL binds the C-terminal NAF/FISL motif of the CBL-interacting protein kinase SOS2/CIPK24, relieving its autoinhibition and recruiting it to the plasma membrane. The CBL-CIPK24 complex phosphorylates the C-terminal autoinhibitory domain of SOS1/NHX7, an electroneutral plasma-membrane Na+/H+ antiporter, relieving its autoinhibition so that SOS1 uses the proton-motive force to export Na+ to the apoplast; SOS1 also controls long-distance Na+ partitioning at the xylem/symplast boundary. The module ends at SOS1-mediated Na+ efflux. The salt-sensing upstream step (GIPC-mediated Ca2+ influx), SOS2 regulation by ABI2, 14-3-3 proteins and GI, the vacuolar CBL10-CIPK24 branch and NHX-type vacuolar antiporters, and HKT1-mediated xylem Na+ retrieval are outside this module's boundary. |
Signaling Pathway | DRAFT | land plants |
0 | intracellular sodium ion homeostasis cellular response to salt stress |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/sos_salt_tolerance.yaml | |
Satellite phage P4 molecular piracy of helper myovirus P2 morphogenetic, packaging, and lysis machineryMODULE:phage_p4_p2_molecular_piracyCONCRETE A cross-genome molecular piracy module in which satellite bacteriophage P4 (Enterobacteria phage P4, 11.6 kb, lacking genes for structural capsid,... [more...][less]A cross-genome molecular piracy module in which satellite bacteriophage P4 (Enterobacteria phage P4, 11.6 kb, lacking genes for structural capsid, tail, terminase, or lysis proteins) hijacks the morphogenetic, DNA-packaging, and host-lysis apparatus of a coinfecting or lysogenic Peduoviridae helper phage such as Escherichia phage P2 (33.5 kb). The piracy program operates across four tightly coupled stages: (1) Helper prophage derepression, in which P4 derepression protein Epsilon binds the P2 immunity repressor C to prevent operator binding and induce P2 prophage excision and lytic gene expression, while P4 replicates its own 11.6-kb genome autonomously via its bifunctional primase-helicase-origin-binding protein Alpha; (2) Cross-genome late transcriptional transactivation and antitermination, in which the P4 tandem-Ogr-domain zinc-finger protein Delta (paralleling P2's own late activator Ogr) binds the alpha-CTD of host Escherichia coli RNA polymerase to activate P2's four morphogenetic and lysis promoters (PP, PO, PV, PJ), while P4 polarity suppression protein Psu binds and hyper-oligomerizes host transcription termination factor Rho to prevent premature termination across the hijacked P2 late operons; (3) Capsid size redirection, in which P4 protein Sid polymerizes into an external dodecahedral cage around assembling P2 gpN major capsid hexamers and gpO internal protease/scaffold subunits, redirecting procapsid geometry from the helper's T=7 head (60 nm, 35-kb capacity) to a threefold smaller T=4 head (45 nm, 11.6-kb capacity) that physically excludes the full-length P2 helper genome; and (4) Cos-site packaging piracy, in which P4 carries an identical 19-bp 5'-cohesive cos site recognized by the P2 terminase complex (small endonuclease subunit gpM and large ATPase subunit gpP), packaging the 11.6-kb P4 genome through the P2 gpQ portal into the Sid-constricted T=4 capsid before P2 tail attachment and lysis. |
Biological Process | COMPLETE | Bacteriophage P2 Caudoviricetes Enterobacteria phage P4 |
0 | release from viral latency viral DNA genome replication transcription antitermination viral capsid assembly viral procapsid maturation viral DNA genome packaging, 5' extended cos packaging |
5 | 11 | 4 | 0 | 0 | 4 | 11/11 | 0 | ✗ | modules/phage_p4_p2_molecular_piracy.yaml | |
Sec61 translocon and associated complexes in Drosophila melanogasterMODULE:dmel_sec61_transloconCONCRETE The Sec61 complex is the protein-conducting channel of the endoplasmic reticulum membrane. Its alpha subunit forms an hourglass-shaped pore with a... [more...][less]The Sec61 complex is the protein-conducting channel of the endoplasmic reticulum membrane. Its alpha subunit forms an hourglass-shaped pore with a lateral gate through which signal sequences and transmembrane segments of nascent polypeptides enter the lipid bilayer; the small beta and gamma subunits stabilize the channel. Sec61 receives ribosome-nascent chain complexes from the SRP receptor for cotranslational translocation, and with the Sec62-Sec63 complex it also translocates proteins post-translationally. Translocon-associated proteins such as TRAM and the TRAP complex assist the insertion and translocation of particular substrates. Drosophila has three Sec61 gamma genes, Sec61gamma, CG8860 and the testis-expressed CG13426, giving alternative forms of the channel. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | translocon complex |
7 | 6 | 3 | 1 | 3 | 0 | 0/9 | 0 | ✗ | modules/dmel_sec61_translocon.yaml | |
Septin complexes in Drosophila melanogasterMODULE:dmel_septin_complexesCONCRETE Septins are GTP-binding proteins that assemble into hetero-oligomeric complexes, which polymerize into filaments and rings at the cell cortex.... [more...][less]Septins are GTP-binding proteins that assemble into hetero-oligomeric complexes, which polymerize into filaments and rings at the cell cortex. These structures act as scaffolds and diffusion barriers and are prominent at the cleavage furrow and the cellularization front. The best-characterized Drosophila septin complex contains Septin1, Septin2 and Peanut (Pnut), was purified from embryos and forms filaments in vitro; Pnut is needed for cytokinesis in proliferating tissues. Septin4 and Septin5, paralogs of Septin1 and Septin2, form a second complex with Pnut. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | septin complex |
3 | 2 | 0 | 1 | 2 | 0 | 5/5 | 0 | ✗ | modules/dmel_septin_complexes.yaml | |
Serotonin and melatonin biosynthesis (Trp -> 5-HTP -> serotonin -> N-acetylserotonin -> melatonin)MODULE:serotonin_melatonin_biosynthesis Serotonin (5-hydroxytryptamine) and the pineal hormone melatonin are the indoleamine products of a four-step pathway from the essential amino acid... [more...][less]Serotonin (5-hydroxytryptamine) and the pineal hormone melatonin are the indoleamine products of a four-step pathway from the essential amino acid L-tryptophan. Tryptophan hydroxylase - the neuronal isoform TPH2 in brainstem raphe serotonergic neurons, the peripheral isoform TPH1 in gut enterochromaffin cells, pineal gland and skin - catalyses the rate-limiting hydroxylation of L-tryptophan to 5-hydroxy-L-tryptophan (5-HTP) using tetrahydrobiopterin (BH4), O2 and a non-heme Fe(II) centre. The shared aromatic-L-amino-acid decarboxylase (DDC/AADC, curated with the catecholamine pathway) decarboxylates 5-HTP to serotonin. In the pineal gland (and retina) serotonin is then converted to melatonin in two further steps that are gated by the circadian clock: serotonin N-acetyltransferase (AANAT, the "timezyme") N-acetylates serotonin to N-acetylserotonin using acetyl-CoA - the sharply night-elevated, cAMP/14-3-3-regulated rate-controlling step - and acetylserotonin O-methyltransferase (ASMT/HIOMT) O-methylates N-acetylserotonin to melatonin using S-adenosyl-L-methionine. Serotonin acts as a central and enteric neurotransmitter and platelet mediator, while melatonin signals darkness/photoperiod. Variants across the pathway are studied in mood, autism- spectrum and sleep phenotypes. |
Metabolic Pathway | DRAFT | 0 | serotonin biosynthetic process melatonin biosynthetic process indolalkylamine biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/serotonin_melatonin_biosynthesis.yaml | ||
Sevenless receptor tyrosine kinase signaling in Drosophila melanogasterMODULE:dmel_sevenless_signalingCONCRETE Sevenless is a receptor tyrosine kinase expressed in a subset of cells of the developing eye that is required for the R7 photoreceptor to adopt its... [more...][less]Sevenless is a receptor tyrosine kinase expressed in a subset of cells of the developing eye that is required for the R7 photoreceptor to adopt its fate. It is activated by Bride of sevenless, a seven-pass transmembrane ligand on the neighbouring R8 cell. The activated receptor recruits the adaptor Drk (Grb2), the docking protein Daughter of sevenless and the tyrosine phosphatase Corkscrew, which together activate Son of sevenless and Ras. Ras drives the Raf-MEK (Dsor1)-ERK (Rolled) cascade, aided by the scaffolds Ksr and Cnk. ERK phosphorylates the ETS factors Pointed (activating it) and Yan/Aop (relieving its repression), and induces Phyllopod, which with the E3 ligase Seven in absentia targets the repressor Tramtrack for degradation, allowing neuronal R7 differentiation. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | sevenless signaling pathway R7 cell fate commitment |
8 | 17 | 7 | 0 | 0 | 6 | 7/17 | 0 | ✗ | modules/dmel_sevenless_signaling.yaml | |
Sex-steroid biosynthesis and androgen activation — HSD17B3/CYP19A1/SRD5A2MODULE:sex_steroid_biosynthesis The C19 androgen precursors made in the gonads and adrenal (androstenedione, from the CYP17A1 17,20-lyase reaction) are converted into the active... [more...][less]The C19 androgen precursors made in the gonads and adrenal (androstenedione, from the CYP17A1 17,20-lyase reaction) are converted into the active sex steroids by three endoplasmic-reticulum-membrane enzymes. The testis-specific 17beta-hydroxysteroid dehydrogenase type 3 (HSD17B3) reduces the 17-keto group of androstenedione to give testosterone, the principal circulating androgen. Testosterone then has two activation fates in target tissues: the microsomal cytochrome P450 aromatase (CYP19A1) aromatizes the A-ring of C19 androgens to the C18 estrogens (androstenedione -> estrone, testosterone -> 17beta-estradiol), the committed and rate-limiting step of estrogen synthesis; and steroid 5alpha-reductase type 2 (SRD5A2) irreversibly reduces the C4-C5 double bond of testosterone to 5alpha-dihydrotestosterone (DHT), the most potent androgen, in prostate and genital skin. Inherited defects define disorders of sex development and hormone imbalance: HSD17B3 (46,XY DSD, 17beta-HSD3 deficiency), CYP19A1 (aromatase deficiency / aromatase excess syndrome; CYP19A1 is also the aromatase-inhibitor breast-cancer drug target) and SRD5A2 (5alpha-reductase-2 deficiency 46,XY DSD; the finasteride/dutasteride target for benign prostatic hyperplasia and androgenetic alopecia). |
Metabolic Pathway | DRAFT | 0 | steroid hormone biosynthetic process androgen biosynthetic process estrogen biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/sex_steroid_biosynthesis.yaml | ||
Shikimate pathway to chorismateMODULE:bacterial_shikimate_chorismate_biosynthesisCONCRETE Seven-step shikimate pathway that converts phosphoenolpyruvate and D-erythrose 4-phosphate to chorismate in bacteria, fungi, plants and... [more...][less]Seven-step shikimate pathway that converts phosphoenolpyruvate and D-erythrose 4-phosphate to chorismate in bacteria, fungi, plants and apicomplexan protists. DAHP synthase condenses the two central-carbon precursors and is the main point of feedback control; 3-dehydroquinate synthase, 3-dehydroquinate dehydratase, shikimate dehydrogenase, shikimate kinase and EPSP synthase then build 5-enolpyruvylshikimate 3-phosphate, and chorismate synthase performs a reduced-flavin-dependent elimination to give chorismate. The reaction chain is invariant, but its enzyme architecture differs by lineage: bacteria use separate enzymes (with either type I or type II dehydroquinases), plants fuse dehydroquinase and shikimate dehydrogenase in one polypeptide, and fungi and apicomplexa carry the five central activities on a single pentafunctional AROM polypeptide. In plants the pathway is plastidic; in fungi it is cytosolic. Chorismate is the branch point for phenylalanine, tyrosine, tryptophan, folate, ubiquinone and other aromatic compounds, which are outside this module. |
Metabolic Pathway | COMPLETE | apicomplexans bacteria fungi green plants |
0 | chorismate biosynthetic process |
20 | 14 | 13 | 3 | 6 | 10 | 30/30 | 0 | ✗ | modules/bacterial_shikimate_chorismate_biosynthesis.yaml | |
Sialic acid (N-acetylneuraminate) metabolism (biosynthesis, activation, transport, catabolism)MODULE:sialic_acid_metabolism Sialic acids (in humans chiefly N-acetylneuraminate, Neu5Ac) are the negatively charged nine-carbon sugars that cap most cell-surface and secreted... [more...][less]Sialic acids (in humans chiefly N-acetylneuraminate, Neu5Ac) are the negatively charged nine-carbon sugars that cap most cell-surface and secreted glycoconjugates, governing cell-cell recognition, receptor masking, serum-protein half-life and pathogen interactions. Their metabolism forms a compact cytosol-to- organelle pathway. Biosynthesis starts with the bifunctional, feedback-controlled enzyme GNE, whose epimerase domain converts UDP-N-acetylglucosamine to N-acetylmannosamine (ManNAc) and whose kinase domain phosphorylates ManNAc to ManNAc-6-phosphate. The sialic-acid synthase NANS then condenses ManNAc-6-P with phosphoenolpyruvate to N-acetylneuraminate-9-phosphate, which the HAD phosphatase NANP dephosphorylates to free Neu5Ac. In the nucleus, CMAS activates Neu5Ac with CTP to the sugar-nucleotide donor CMP-Neu5Ac; the Golgi antiporter SLC35A1 imports CMP-Neu5Ac into the Golgi lumen (in exchange for CMP) to supply the sialyltransferases that decorate glycans. CMP-Neu5Ac feedback-inhibits GNE, keeping flux matched to demand. On the catabolic side, the lysosomal sialidase NEU1 (acting within the CTSA/GLB1 lysosomal multienzyme complex) removes terminal sialic acids from glycoconjugates during turnover, the lysosomal H+/sialic acid symporter sialin (SLC17A5) exports the released free sialic acid to the cytosol for reuse by CMAS, and the cytosolic aldolase NPL cleaves free Neu5Ac to ManNAc + pyruvate, recycling the amino sugar. Inherited defects at nearly every step cause disease: GNE myopathy and sialuria (GNE), NANS-CDG, SLC35A1-CDG (CDG-IIf), sialidosis (NEU1), free sialic acid storage disorders (Salla disease and infantile sialic acid storage disease; SLC17A5) and an NPL-related myopathy. Several of these respond to ManNAc or sialic-acid supplementation. |
Metabolic Pathway | DRAFT | 0 | N-acetylneuraminate biosynthetic process N-acetylneuraminate catabolic process |
9 | 8 | 8 | 0 | 0 | 8 | 7/8 | 0 | ✗ | modules/sialic_acid_metabolism.yaml | ||
Signal peptidase complex in Drosophila melanogasterMODULE:dmel_signal_peptidase_complexCONCRETE The signal peptidase complex in the endoplasmic reticulum membrane cleaves N-terminal signal peptides from secretory and membrane proteins as they... [more...][less]The signal peptidase complex in the endoplasmic reticulum membrane cleaves N-terminal signal peptides from secretory and membrane proteins as they are translocated. Its catalytic subunit, SEC11 (encoded in Drosophila by twr), is a membrane-anchored serine protease whose active site faces the ER lumen. The accessory subunits SPCS1, SPCS2 and SPCS3 (Spase12, Spase25 and Spase22-23) are required for activity and stability of the complex; SPCS3 also helps select substrates. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | signal peptidase complex |
3 | 2 | 2 | 0 | 0 | 0 | 4/4 | 0 | ✗ | modules/dmel_signal_peptidase_complex.yaml | |
Single-gene bacteriophage lysis (peptidoglycan biosynthesis inhibition and envelope destabilization)MODULE:phage_single_gene_lysisABSTRACT A reusable module representing single-gene lysis (SGL) systems of small single-stranded DNA (Microviridae) and single-stranded RNA (Fiersviridae /... [more...][less]A reusable module representing single-gene lysis (SGL) systems of small single-stranded DNA (Microviridae) and single-stranded RNA (Fiersviridae / Leviviricetes) bacteriophages. Unlike double-stranded DNA phages that deploy multigene holin-endolysin-spanin cassettes to degrade existing peptidoglycan, small-genome phages encode a single lysis protein—frequently overlapping essential structural or replication genes or embedded within the virion maturation protein—that triggers host bacteriolysis during cell division. Two principal mechanistic branches are represented: (1) "protein antibiotic" SGL proteins that directly inhibit conserved cytoplasmic or inner-membrane enzymes of the host peptidoglycan precursor pathway, exemplified by phiX174 protein E (which forms a transmembrane ternary YES complex with host phospho-N-acetylmuramoyl-pentapeptide-transferase MraY and the peptidyl-prolyl isomerase chaperone SlyD to block lipid I synthesis) and Qbeta maturation/lysis protein A2 (which binds and inhibits host UDP-N-acetylglucosamine 1-carboxyvinyltransferase MurA in a closed conformation to block the first committed step of murein synthesis); and (2) small transmembrane membrane-destabilizing SGL proteins such as MS2 protein L, which insert into inner-outer membrane adhesion sites and induce autolysis without inhibiting murein precursor enzymes. |
Biological Process | COMPLETE | Viruses |
0 | viral release via suppression of host peptidoglycan biosynthetic process viral release from host cell by cytolysis |
5 | 3 | 1 | 1 | 3 | 3 | 3/3 | 0 | ✗ | modules/phage_single_gene_lysis.yaml | |
Siphovirus long flexible non-contractile tail assembly and receptor adsorptionMODULE:phage_siphovirus_tail_assemblyCONCRETE A morphogenetic assembly and host-entry pathway conserved across siphoviruses (long non-contractile tailed bacteriophages of class Caudoviricetes)... [more...][less]A morphogenetic assembly and host-entry pathway conserved across siphoviruses (long non-contractile tailed bacteriophages of class Caudoviricetes) and homologous to the inner tail-tube/baseplate-hub core of contractile myoviruses and type VI secretion systems. Assembly begins at the distal tip with the host entry-receptor attachment protein gpJ, which sequentially recruits the tail tip initiator proteins gpI, gpL (an [4Fe-4S] cluster-binding hub component), and gpK (a peptidoglycan-active NlpC/P60-domain protein) together with the tape measure protein gpH and gpM. The chaperone gpG and its programmed -1 ribosomal frameshift fusion product gpGT coat the alpha-helical tape measure protein gpH and recruit the major tail tube subunit gpV, which polymerizes into 31 to 32 stacked hexameric rings along the gpH scaffold until reaching its N-terminus. The hexameric terminator protein gpU caps the completed tube, gpH is proteolytically matured to gpH*, and the tail completion protein gpZ renders the mature tail competent to join the gpW/gpFII-plugged DNA-filled head. Optional side tail fibers (Stf, folded with the Tfa chaperone) attach to the collar/tail to mediate rapid reversible primary adsorption before irreversible gpJ engagement of the outer membrane receptor triggers gpH*-mediated DNA ejection across the host envelope. |
Biological Process | COMPLETE | Caudoviricetes Escherichia phage lambda |
0 | viral tail assembly viral head-tail joining entry receptor-mediated virion attachment to host cell symbiont genome ejection through host cell envelope, long flexible tail mechanism |
7 | 12 | 6 | 0 | 0 | 4 | 13/13 | 0 | ✗ | modules/phage_siphovirus_tail_assembly.yaml | |
Siroheme biosynthesis from uroporphyrinogen IIIMODULE:siroheme_biosynthesis Biosynthesis of siroheme, the iron-containing isobacteriochlorin prosthetic group of assimilatory sulfite and nitrite reductases, from the common... [more...][less]Biosynthesis of siroheme, the iron-containing isobacteriochlorin prosthetic group of assimilatory sulfite and nitrite reductases, from the common tetrapyrrole precursor uroporphyrinogen III. Three reactions are required: S-adenosyl-L-methionine-dependent bis-methylation of uroporphyrinogen III at C-2 and C-7 to precorrin-2, NAD(P)+-dependent dehydrogenation of precorrin-2 to sirohydrochlorin, and insertion of ferrous iron into sirohydrochlorin to give siroheme. The chemistry is conserved in bacteria, fungi and plants, but the enzyme architecture differs. In enterobacteria a single multifunctional siroheme synthase (CysG) carries all three activities, with the methylase in its C-terminal region and the dehydrogenase and chelatase sharing an N-terminal region. Fungi split the pathway between a monofunctional uroporphyrinogen-III methyltransferase (Met1-type) and a bifunctional dehydrogenase-ferrochelatase (Met8-type) that uses a single active site for both reactions. Bacillus and plants use separate enzymes for every step, including a small SirB-type sirohydrochlorin ferrochelatase that in plants is located in the plastid. Uroporphyrinogen III synthesis is shared with heme, chlorophyll and cobalamin biosynthesis and lies upstream of this module; incorporation of siroheme into sulfite reductase lies downstream. |
Metabolic Pathway | DRAFT | 0 | siroheme biosynthetic process |
6 | 7 | 2 | 1 | 3 | 4 | 2/7 | 0 | ✗ | modules/siroheme_biosynthesis.yaml | ||
Slit-Robo signaling pathway moduleMODULE:slit_robo_signalingABSTRACT Slits are secreted leucine-rich-repeat glycoproteins that bind Roundabout (Robo) receptors on migrating cells and axons. Slit-Robo signaling is... [more...][less]Slits are secreted leucine-rich-repeat glycoproteins that bind Roundabout (Robo) receptors on migrating cells and axons. Slit-Robo signaling is best known as the repulsive cue that keeps axons from crossing, or recrossing, the CNS midline, and it also patterns the lateral position of longitudinal axon pathways. |
Signaling Pathway | DRAFT | Bilateria |
1 | Roundabout signaling pathway |
3 | 2 | 2 | 0 | 0 | 1 | 0/9 | 0 | ✗ | modules/slit_robo_signaling.yaml | |
SlyD-assisted nickel insertion for E. coli NiFe hydrogenasesMODULE:nife_hydrogenase_nickel_insertionCONCRETE A nickel-metallocenter maturation submodule in which the cytosolic metallochaperone SlyD binds nickel through its histidine/cysteine-rich tail,... [more...][less]A nickel-metallocenter maturation submodule in which the cytosolic metallochaperone SlyD binds nickel through its histidine/cysteine-rich tail, stimulates nickel release from HypB, and supports nickel insertion into NiFe hydrogenase large subunits. SlyD's FKBP peptidyl-prolyl isomerase activity and general IF-domain holdase activity are real but separable from this hydrogenase nickel-insertion role. |
Biological Process | DRAFT | Escherichia coli |
0 | nickel chaperone activity protein maturation |
1 | 1 | 0 | 0 | 0 | 0 | 1/2 | 0 | ✗ | modules/nife_hydrogenase_nickel_insertion.yaml | |
Small nucleolar ribonucleoprotein complexes in Drosophila melanogasterMODULE:dmel_small_nucleolar_rnpsCONCRETE Small nucleolar ribonucleoproteins (snoRNPs) guide chemical modification and processing of ribosomal RNA in the nucleolus. Box H/ACA snoRNPs... [more...][less]Small nucleolar ribonucleoproteins (snoRNPs) guide chemical modification and processing of ribosomal RNA in the nucleolus. Box H/ACA snoRNPs contain a guide RNA and four core proteins, the pseudouridine synthase dyskerin (Nop60B in Drosophila), Gar1, Nhp2 and Nop10, and convert target uridines into pseudouridine. Box C/D snoRNPs contain the methyltransferase fibrillarin with Nop56, Nop58 and a 15.5K protein and catalyse 2'-O-methylation of target nucleotides. The U3 box C/D snoRNP instead acts in early pre-rRNA cleavage within the small-subunit processome. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | sno(s)RNA-containing ribonucleoprotein complex |
3 | 2 | 2 | 0 | 0 | 0 | 0/8 | 0 | ✗ | modules/dmel_small_nucleolar_rnps.yaml | |
Specification of floral meristem identity at the Arabidopsis shoot apexMODULE:floral_meristem_identityCONCRETE After floral induction the Arabidopsis shoot apical meristem becomes an indeterminate inflorescence meristem whose lateral primordia must be... [more...][less]After floral induction the Arabidopsis shoot apical meristem becomes an indeterminate inflorescence meristem whose lateral primordia must be assigned floral, rather than shoot, fate. Floral integrators supply the input: the florigen FT, a PEBP-family protein made in leaves, reaches the apex and acts as a transcriptional coactivator of the bZIP factor FD to activate APETALA1 (AP1) and the MADS-box integrators SOC1 and FRUITFULL (FUL); SOC1 (as a heterodimer with AGL24) binds the LEAFY (LFY) promoter and activates it, and FUL promotes the reproductive transition partially redundantly with SOC1. LFY, a plant-specific DNA-binding transcription factor, directly induces AP1 in the floral anlagen, and AP1 in turn up-regulates LFY, so the two lock in floral fate through positive feedback. The SQUAMOSA-clade MADS factors AP1, CAULIFLOWER (CAL) and FUL act partially redundantly in this step (ap1 cal ful triple mutants make no flowers); AP1 also acts as a master repressor in the young flower, directly silencing the flowering-time/inflorescence genes SOC1, AGL24 and SVP so that the shoot program does not continue in floral meristems. The F-box protein UNUSUAL FLORAL ORGANS (UFO) binds LFY and DNA to form a LFY-UFO transcriptional complex that redirects LFY to region-specific targets in the young flower. TERMINAL FLOWER1 (TFL1), a PEBP paralog of FT, is expressed in the centre of the inflorescence meristem and acts as an FD-dependent corepressor that keeps LFY and AP1 out of the shoot apex, maintaining indeterminate inflorescence identity; AP1 and LFY reciprocally repress TFL1 in floral primordia. The A-class factor APETALA2 contributes to floral meristem establishment alongside AP1. Floral organ identity (the ABCE program activated later by LFY, UFO and AP1 together with SEP proteins), the leaf-side photoperiod pathway that produces FT, and the age, vernalization and gibberellin pathways converging on the integrators are separate modules. |
Developmental Process | DRAFT | Arabidopsis thaliana |
0 | floral meristem identity specification (closest GO term) floral meristem determinacy |
5 | 11 | 4 | 0 | 0 | 8 | 10/10 | 0 | ✗ | modules/floral_meristem_identity.yaml | |
Sphingomyelin cycle (ceramide <-> sphingomyelin interconversion)MODULE:sphingomyelin_cycle Sphingomyelin (SM) is the most abundant sphingolipid of the plasma membrane and a defining component of lipid rafts and the myelin sheath. The... [more...][less]Sphingomyelin (SM) is the most abundant sphingolipid of the plasma membrane and a defining component of lipid rafts and the myelin sheath. The "sphingomyelin cycle" is the reversible interconversion of SM and ceramide, which couples membrane-lipid homeostasis to ceramide/diacylglycerol signalling. In the synthetic direction the sphingomyelin synthases SGMS1 (trans-Golgi) and SGMS2 (plasma membrane) transfer a phosphocholine head group from phosphatidylcholine (PC) to ceramide, producing SM + diacylglycerol (DAG) — simultaneously consuming the pro-apoptotic lipid ceramide and generating the pro-mitogenic lipid DAG. In the hydrolytic direction, sphingomyelinases (SM phosphodiesterases) cleave SM back to ceramide + phosphocholine, generating the ceramide second messenger. Human cells use several, distinguished by pH optimum and location: the lysosomal acid sphingomyelinase SMPD1 (turnover and the ASMase/ceramide stress pathway; Niemann-Pick A/B on deficiency), and the Mg2+-dependent neutral sphingomyelinases SMPD3 (nSMase2, the major stress-responsive plasma-membrane/Golgi enzyme controlling ceramide signalling, exosome secretion and bone mineralization), SMPD4 (nSMase3, ER/Golgi/nuclear-envelope) and SMPD2 (nSMase1, ER; note its preferred cellular substrate is lyso-platelet-activating factor, so its bulk-SMase role is limited). The ceramide produced feeds the ceramidase/sphingosine-1-phosphate rheostat and re-acylation pathways. Inherited defects illustrate the pathway: SMPD1 Niemann-Pick disease, SGMS2 and SMPD3 skeletal dysplasias, and SMPD4 a neurodevelopmental disorder with microcephaly. |
Metabolic Pathway | DRAFT | 0 | sphingomyelin biosynthetic process sphingomyelin catabolic process |
5 | 4 | 4 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/sphingomyelin_cycle.yaml | ||
Sphingosine-1-phosphate rheostat (ceramide -> sphingosine -> S1P -> exit)MODULE:sphingosine_1_phosphate_rheostat The "sphingolipid rheostat" is the interconversion of the bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), whose... [more...][less]The "sphingolipid rheostat" is the interconversion of the bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), whose relative levels set the balance between cell death/growth arrest (ceramide, sphingosine) and survival/proliferation/migration (S1P). Ceramide is hydrolysed to sphingosine plus a free fatty acid by ceramidases: the alkaline ceramidases ACER1 (ER, skin), ACER2 (Golgi) and ACER3 (ER/Golgi, broadly expressed) act here, complementing the acid (ASAH1, lysosomal) and neutral (ASAH2) ceramidases curated elsewhere. Sphingosine is then phosphorylated with ATP to S1P by the sphingosine kinases SPHK1 (cytosolic, translocating to the plasma membrane; pro-survival/pro-inflammatory) and SPHK2 (nuclear/ER/mitochondrial; its nuclear S1P inhibits HDAC1/2). S1P has two fates. It is reversibly dephosphorylated back to sphingosine by the ER S1P phosphatases SGPP1 and SGPP2 (recycling sphingosine for re-acylation to ceramide and damping S1P signalling), or it is IRREVERSIBLY cleaved by the PLP-dependent ER lyase SGPL1 to (2E)-hexadecenal + phosphoethanolamine — the sole exit from sphingolipid metabolism, which also builds the tissue-to-blood S1P gradient that governs lymphocyte egress. Inherited defects illustrate the pathway's importance: ACER3 childhood leukodystrophy and SGPL1 sphingosine-phosphate-lyase insufficiency syndrome (steroid-resistant nephrotic syndrome with adrenal insufficiency); the S1P axis is also the target of the immunomodulator fingolimod (FTY720, an SPHK2 substrate). |
Metabolic Pathway | DRAFT | 0 | sphingosine metabolic process sphingolipid catabolic process |
5 | 5 | 4 | 0 | 0 | 4 | 8/8 | 0 | ✗ | modules/sphingosine_1_phosphate_rheostat.yaml | ||
Stomatal lineage progression and spacing (EPF-ERECTA-YODA-MAPK and SPCH/MUTE/FAMA-SCRM)MODULE:stomatal_lineage_developmentCONCRETE In the Arabidopsis leaf epidermis, stomata are produced by a dedicated cell lineage whose successive transitions are driven by three closely... [more...][less]In the Arabidopsis leaf epidermis, stomata are produced by a dedicated cell lineage whose successive transitions are driven by three closely related group Ia bHLH transcription factors, each acting as a heterodimer with the broadly expressed group IIIb bHLHs SCREAM/ICE1 (SCRM) and SCRM2. SPEECHLESS (SPCH) initiates the lineage by driving the asymmetric entry division of a meristemoid mother cell, MUTE terminates the self-renewing asymmetric divisions of the meristemoid and converts it into a guard mother cell (GMC), and FAMA drives the single symmetric GMC division and guard cell differentiation, then locks in guard cell fate with RETINOBLASTOMA-RELATED. Lineage entry and spacing are restrained by cell-cell signalling: the secreted cysteine-rich peptide EPF2, produced by early lineage cells, binds the leucine-rich-repeat receptor kinase ERECTA in a complex with the non-catalytic co-receptor TOO MANY MOUTHS (TMM); ligand binding recruits SERK co-receptor kinases and activates the MAPKKK YODA, which phosphorylates MKK4/MKK5, which in turn activate MPK3/MPK6. MPK3/MPK6, docked onto SCRM through its KiDoK motif and recruited with YODA to the cortex by the polarity scaffold BASL, phosphorylate SPCH and SCRM and promote their degradation, limiting lineage entry. Because SPCH-SCRM directly activates EPF2 and TMM, the circuit forms a negative feedback loop that self-organizes stomatal density and the one-cell spacing rule. The related peptide EPF1, perceived mainly by ERL1, acts later on spacing divisions, and the positive peptide stomagen (EPFL9) competes with EPF2 for ERECTA-TMM. Brassinosteroid (via BIN2 inhibition of YODA), CO2 (via CRSP cleavage of EPF2) and other environmental inputs converge on this module. |
Developmental Process | DRAFT | Arabidopsis thaliana |
0 | stomatal complex development stomatal lineage progression stomatal complex patterning |
11 | 10 | 10 | 0 | 0 | 8 | 11/11 | 0 | ✗ | modules/stomatal_lineage_development.yaml | |
Streptococcus pyogenes FbaB covalent surface-adhesin module (CnaB2 isopeptide domain; SpyTag/SpyCatcher origin)MODULE:spytag_spycatcher This module describes the multidomain group A Streptococcus (Streptococcus pyogenes) surface adhesin FbaB (gene fba2; UniProtKB:Q8G9G1) and, in... [more...][less]This module describes the multidomain group A Streptococcus (Streptococcus pyogenes) surface adhesin FbaB (gene fba2; UniProtKB:Q8G9G1) and, in particular, its CnaB2 / SpaA-like prealbumin-fold domain, which autocatalytically forms an intramolecular Lys-Asp isopeptide bond. FbaB is a major virulence factor of invasive M3/M18 GAS strains: it is covalently anchored to the peptidoglycan cell wall via a C-terminal LPXTG sortase motif, binds host fibronectin through C-terminal fibronectin-binding repeats to mediate adhesion to and invasion of host cells, carries an N-terminal thioester (TED) domain of the kind that covalently captures host proteins in related streptococcal adhesins, and uses the CnaB2 isopeptide bond to gain the mechanical, thermal and chemical stability inferred to be needed for force-bearing engagement of host fibronectin during invasion. The CnaB2 domain (residues ~462-541; the region crystallized in PDB 9OJ3 and earlier FbaB-CnaB2 structures) is the natural scaffold that was split and engineered into the widely used SpyTag/SpyCatcher covalent protein-conjugation system (SpyTag = reactive Asp-bearing peptide; SpyCatcher = Lys-bearing protein partner; catalytic Glu), with SpyTag003/SpyCatcher003 being the third-generation variant in PDB 9OJ3. The module is grounded in a single natural gene product, FbaB; SpyTag and SpyCatcher are engineered fragments of this one protein, not separate genes. |
Module | DRAFT | Streptococcus pyogenes (group A Streptococcus) |
0 | fibronectin binding adhesion of symbiont to host cell |
5 | 4 | 4 | 0 | 0 | 3 | 1/1 | 0 | ✗ | modules/spytag_spycatcher.yaml | |
Strigolactone perception and D14-MAX2-SMXL signalling in shoot-branching controlMODULE:strigolactone_signaling_shoot_branchingCONCRETE Strigolactones (SLs) are carotenoid-derived hormones that inhibit axillary bud outgrowth. In Arabidopsis thaliana, SL is perceived by the... [more...][less]Strigolactones (SLs) are carotenoid-derived hormones that inhibit axillary bud outgrowth. In Arabidopsis thaliana, SL is perceived by the alpha/beta-hydrolase receptor DWARF14 (D14), which binds and slowly hydrolyses the butenolide D-ring. SL binding changes the conformation of D14 so that it associates with the F-box protein MORE AXILLARY GROWTH2 (MAX2) in an SCF(MAX2) E3 ubiquitin ligase and with the SMAX1-LIKE co-repressors SMXL6, SMXL7 and SMXL8. The SMXLs are then polyubiquitinated and degraded by the proteasome, and D14 itself is degraded as negative feedback. In the absence of SL, the nuclear SMXL6/7/8 proteins repress target genes by recruiting TOPLESS-related co-repressors through an EAR motif, and SMXL6 can also bind target promoters itself. Their removal de-represses the bud-expressed TCP transcription factor BRANCHED1 (BRC1), which keeps buds dormant, in part by activating HD-ZIP genes that raise abscisic acid in the bud. SL-triggered SMXL degradation also reduces PIN1 accumulation and auxin transport in the stem, which inhibits bud activation in parallel with BRC1. The sister karrikin pathway uses the same F-box protein, MAX2, with the D14 paralog KAI2 and the SMAX1/SMXL2 repressors. That pathway, SL biosynthesis (D27, MAX3, MAX4, MAX1) and the auxin-transport branch are outside this module. |
Signaling Pathway | DRAFT | Arabidopsis thaliana |
0 | cellular response to strigolactone regulation of secondary shoot formation |
5 | 7 | 4 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/strigolactone_signaling_shoot_branching.yaml | |
Survival motor neuron (SMN) complex in Drosophila melanogasterMODULE:dmel_smn_complexCONCRETE The survival motor neuron (SMN) complex assembles the heptameric Sm protein ring onto the Sm site of spliceosomal snRNAs in the cytoplasm, the key... [more...][less]The survival motor neuron (SMN) complex assembles the heptameric Sm protein ring onto the Sm site of spliceosomal snRNAs in the cytoplasm, the key step of Sm-class snRNP biogenesis. SMN oligomerizes and binds Gemin2, which holds a pentamer of Sm proteins; Gemin5 recognizes the snRNA, and Gemin3 is a DEAD-box helicase subunit. Drosophila has a reduced set of Gemin proteins compared with vertebrates and carries three Gemin4 paralogs (Glos/Gemin4a, Gem4b, Gem4c); FlyBase defines SMN complex variants that differ in which Gemin4 paralog they contain. Loss of Smn in flies causes defects in snRNP assembly, motor function and viability, modelling spinal muscular atrophy. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | SMN complex |
6 | 4 | 2 | 1 | 3 | 0 | 2/7 | 0 | ✗ | modules/dmel_smn_complex.yaml | |
Synaptic vesicle cycle (umbrella)MODULE:synaptic_vesicle_cycleCONCRETE The life cycle of the synaptic vesicle at a presynaptic terminal, modeled as an organelle lifecycle with five stages: (1) neurotransmitter loading,... [more...][less]The life cycle of the synaptic vesicle at a presynaptic terminal, modeled as an organelle lifecycle with five stages: (1) neurotransmitter loading, in which the V-ATPase acidifies the lumen and a vesicular transporter fills the vesicle; (2) reserve-pool clustering, in which synapsins tether loaded vesicles into a phase-separated cluster from which they are mobilised on demand; (3) exocytosis, in which vesicles are recruited to the active zone, primed by Munc13/Munc18-1, and fused by the SNARE machinery when synaptotagmin senses Ca2+ entering through Cav2 channels; (4) endocytosis, in which vesicle membrane and proteins are retrieved by clathrin-dependent or ultrafast/bulk routes and re-formed by dynamin fission and auxilin/HSC70 uncoating; and (5) maturation, in which the regenerated vesicle regains its full protein complement and is returned to the loading stage. Stages 1, 3 and 4 are elaborated in separate modules; this umbrella carries the cycle topology and the hallmark machinery of each stage. Exemplars are human; the cycle is conserved at metazoan chemical synapses. Grounded in GO:0099504 (synaptic vesicle cycle). |
Organelle Lifecycle | DRAFT | metazoa |
0 | synaptic vesicle cycle |
6 | 8 | 5 | 0 | 0 | 5 | 15/20 | 0 | ✗ | modules/synaptic_vesicle_cycle.yaml | |
Synaptic vesicle endocytosis and vesicle regenerationMODULE:synaptic_vesicle_endocytosisCONCRETE The retrieval stage of the synaptic vesicle cycle, in which vesicle membrane and resident proteins deposited in the presynaptic plasma membrane by... [more...][less]The retrieval stage of the synaptic vesicle cycle, in which vesicle membrane and resident proteins deposited in the presynaptic plasma membrane by exocytosis are recovered and re-formed into release-competent vesicles at the presynaptic endocytic zone. In the classical clathrin-mediated route, the AP-2 adaptor complex, the neuron-specific assembly protein AP180 and the synaptotagmin-sorting adaptor stonin-2 recognise vesicle cargo and PI(4,5)P2 and nucleate a clathrin coat; BAR-domain proteins (endophilin, amphiphysin, syndapin) shape the invaginating membrane and recruit the GTPase dynamin, which constricts and severs the neck; synaptojanin-1 hydrolyses PI(4,5)P2 and auxilin recruits HSC70 to strip the clathrin coat, yielding a naked vesicle ready for re-acidification and loading. The same coat, curvature, fission and uncoating machinery is reused when membrane is first retrieved by clathrin-independent ultrafast or bulk endocytosis and vesicles are then regenerated by clathrin-dependent budding from a synaptic endosome. The module conforms, with stated deviations, to the generic MODULE:vesicle_coat_budding motif. Exemplars are human. Grounded in GO:0048488 (synaptic vesicle endocytosis). |
Biological Process | DRAFT | metazoa |
9 | synaptic vesicle endocytosis |
7 | 14 | 4 | 1 | 2 | 3 | 22/32 | 0 | ✗ | modules/synaptic_vesicle_endocytosis.yaml | |
Synaptic vesicle exocytosis (docking, priming, Ca2+-triggered fusion)MODULE:synaptic_vesicle_exocytosisCONCRETE The release stage of the synaptic vesicle cycle at the presynaptic active zone. Loaded vesicles are recruited to the active zone by the vesicle... [more...][less]The release stage of the synaptic vesicle cycle at the presynaptic active zone. Loaded vesicles are recruited to the active zone by the vesicle GTPase Rab3 and its effector RIM, which together with ELKS scaffolds tether vesicles and position them near voltage-gated Ca2+ channels. Munc13 and Munc18-1 then prime the vesicle by opening syntaxin-1 and templating assembly of the trans-SNARE complex (syntaxin-1 / SNAP-25 / synaptobrevin-2). An action potential opens Cav2 channels; the resulting Ca2+ microdomain is sensed by synaptotagmin-1, which relieves the complexin clamp and drives full SNARE zippering and fusion-pore opening, releasing transmitter. NSF with alpha-SNAP finally disassembles the cis-SNARE complex so the SNAREs can be reused. The inner pair -> fuse -> recycle bundle conforms to the generic MODULE:snare_fusion_cycle motif. Exemplars are human; the machinery is conserved across metazoan chemical synapses. Grounded in GO:0016079 (synaptic vesicle exocytosis). |
Biological Process | DRAFT | metazoa |
2 | synaptic vesicle exocytosis |
10 | 14 | 7 | 1 | 2 | 6 | 17/31 | 0 | ✗ | modules/synaptic_vesicle_exocytosis.yaml | |
T cell receptor signaling pathway moduleMODULE:t_cell_receptor_signaling The proximal T cell receptor (TCR) signaling pathway, from antigen engagement at the plasma membrane to calcium/NFAT-driven transcription.... [more...][less]The proximal T cell receptor (TCR) signaling pathway, from antigen engagement at the plasma membrane to calcium/NFAT-driven transcription. Peptide-MHC binding by the clonotypic TCR alpha/beta chains is transmitted by the invariant CD3 and CD3 zeta subunits, whose ITAMs are phosphorylated by the Src-family kinase LCK, carried to the complex by the MHC-matched coreceptor (CD4 or CD8) and kept primed by the phosphatase CD45. Doubly phosphorylated ITAMs dock the tandem SH2 domains of ZAP70, which LCK then activates. ZAP70 phosphorylates the transmembrane scaffold LAT and the cytosolic adaptor SLP-76 (LCP2), which the adaptor GADS bridges into the TCR signalosome; the signalosome recruits PLC gamma 1 and the Tec kinase ITK that activates it. PLC gamma 1 hydrolyses PIP2 to IP3 and DAG; IP3-driven calcium entry activates calcineurin, which dephosphorylates NFAT so that it enters the nucleus and activates target genes. The Ras-MAPK/AP-1 and PKC-theta/NF-kappaB branches that also leave the LAT signalosome are outside this module and are modelled in their own modules. Leaf molecular functions follow the ADAPTIVE_IMMUNITY gene reviews of each member. |
Signaling Pathway | DRAFT | jawed vertebrates |
2 | T cell receptor signaling pathway |
8 | 13 | 5 | 1 | 2 | 4 | 19/19 | 0 | ✗ | modules/t_cell_receptor_signaling.yaml | |
TGF-beta receptor-SMAD signaling pathway moduleMODULE:tgfb_smad_signaling A compact TGF-beta/SMAD signaling module. A dimeric TGF-beta family ligand binds type II and type I serine/threonine kinase receptors, the type II... [more...][less]A compact TGF-beta/SMAD signaling module. A dimeric TGF-beta family ligand binds type II and type I serine/threonine kinase receptors, the type II receptor activates the type I receptor, the type I receptor phosphorylates receptor-regulated SMADs, and SMAD complexes accumulate in the nucleus to regulate transcription. The module is grounded in GO:0007179. TGFB1 is anchored to PAINT TGF-beta-family nodes; receptors and SMADs are included as curated UniProt exemplars without PTN ancestry where local seed rows were not available. |
Signaling Pathway | DRAFT | metazoa |
2 | transforming growth factor beta receptor signaling pathway |
5 | 4 | 4 | 0 | 0 | 3 | 4/6 | 0 | ✗ | modules/tgfb_smad_signaling.yaml | |
TLR2-heterodimer lipopeptide sensing moduleMODULE:tlr2_heterodimer_lipopeptide_signalingABSTRACT Recognition of bacterial lipopeptides by TLR2 heterodimers and the first steps of the MyD88-dependent signal. LBP and CD14 deliver the lipopeptide;... [more...][less]Recognition of bacterial lipopeptides by TLR2 heterodimers and the first steps of the MyD88-dependent signal. LBP and CD14 deliver the lipopeptide; TLR2 pairs with TLR1 for triacylated or with TLR6 for diacylated lipopeptides; the PIP2-anchored sorting adaptor TIRAP recruits MYD88, which recruits the kinase IRAK4. Downstream TRAF6, TAK1 and NF-kappaB steps are shared with other MyD88-dependent TLRs and are modelled in the toll-like receptor signaling module. |
Signaling Pathway | DRAFT | mammals |
0 | toll-like receptor TLR1:TLR2 signaling pathway toll-like receptor TLR6:TLR2 signaling pathway |
7 | 7 | 4 | 1 | 2 | 3 | 7/9 | 0 | ✗ | modules/tlr2_heterodimer_lipopeptide_signaling.yaml | |
TLR4-MD-2 lipopolysaccharide sensing moduleMODULE:tlr4_md2_lps_signalingABSTRACT Recognition of bacterial lipopolysaccharide (LPS) by the TLR4-MD-2 receptor and its two adaptor branches. LBP and CD14 deliver monomeric LPS; MD-2... [more...][less]Recognition of bacterial lipopolysaccharide (LPS) by the TLR4-MD-2 receptor and its two adaptor branches. LBP and CD14 deliver monomeric LPS; MD-2 binds lipid A in its hydrophobic pocket and TLR4 transmits the signal; the receptor first signals through TIRAP-MYD88 at the plasma membrane and, after endocytosis, through TRAM-TRIF from endosomes. This is the module where GO:0001875 lipopolysaccharide immune receptor activity belongs. |
Signaling Pathway | DRAFT | mammals |
0 | toll-like receptor 4 signaling pathway |
6 | 9 | 3 | 1 | 2 | 2 | 9/12 | 0 | ✗ | modules/tlr4_md2_lps_signaling.yaml | |
TNF-mediated signaling pathway moduleMODULE:tnf_signaling TNF binding to TNF receptor complexes nucleates TRADD, RIPK, and TRAF signaling assemblies that balance NF-kappaB activation, inflammatory gene... [more...][less]TNF binding to TNF receptor complexes nucleates TRADD, RIPK, and TRAF signaling assemblies that balance NF-kappaB activation, inflammatory gene expression, survival, and death decisions. |
Signaling Pathway | DRAFT | metazoa |
10 | tumor necrosis factor-mediated signaling pathway |
5 | 9 | 4 | 0 | 0 | 3 | 5/9 | 0 | ✓ | modules/tnf_signaling.yaml | |
TOR complexes TORC1 and TORC2 in Drosophila melanogasterMODULE:dmel_tor_complexesCONCRETE The serine/threonine kinase TOR acts in two distinct complexes. TORC1, defined by the substrate-recruiting subunit Raptor, is rapamycin-sensitive,... [more...][less]The serine/threonine kinase TOR acts in two distinct complexes. TORC1, defined by the substrate-recruiting subunit Raptor, is rapamycin-sensitive, is activated by amino acids and growth factors through the Rag and Rheb GTPases, and promotes growth by phosphorylating S6 kinase and the translation inhibitor 4E-BP (Thor) while repressing autophagy. TORC2, defined by Rictor and Sin1 together with Lst8, phosphorylates Akt at its hydrophobic motif and contributes to growth control and cytoskeletal regulation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | TOR complex |
3 | 2 | 2 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/dmel_tor_complexes.yaml | |
TORC1 nutrient- and growth-factor-sensing machinery in Drosophila melanogasterMODULE:dmel_torc1_nutrient_sensingCONCRETE TORC1 is activated on the lysosome surface only when two inputs coincide. Amino acid sufficiency is relayed through the heterodimeric Rag GTPases... [more...][less]TORC1 is activated on the lysosome surface only when two inputs coincide. Amino acid sufficiency is relayed through the heterodimeric Rag GTPases (RagA-B with RagC-D), which are anchored to the lysosome by the pentameric Ragulator complex and recruit TORC1 when RagA-B is GTP-bound. The GATOR1 complex (Iml1, Nprl2, Nprl3) acts as a GTPase-activating protein for RagA-B and so inhibits TORC1, and the GATOR2 complex (Mio, Wdr24, Wdr59, Seh1 and Sec13) inhibits GATOR1. Growth-factor and energy signals are relayed through the TSC1-TSC2 complex (Tsc1 and Gigas), a GTPase-activating protein for the small GTPase Rheb, which directly activates TORC1. In Drosophila, GATOR1 and GATOR2 regulate TORC1 activity in the ovary and other tissues, and TSC mutations cause cell overgrowth. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | regulation of TORC1 signaling |
7 | 6 | 6 | 0 | 0 | 4 | 4/18 | 0 | ✗ | modules/dmel_torc1_nutrient_sensing.yaml | |
TRAIL-activated apoptotic signaling — TNFSF10 ligation of TRAIL-R1/R2, FADD/caspase-8 DISC assembly restrained by c-FLIP and decoy receptors, and type I (direct executioner caspase) versus type II (BID/mitochondrial) caspase amplificationMODULE:trail_apoptotic_signalingCONCRETE TRAIL (TNFSF10, Apo2L) is a TNF-family ligand that exists as a type II transmembrane protein and as a shed soluble form; both act as homotrimers. A... [more...][less]TRAIL (TNFSF10, Apo2L) is a TNF-family ligand that exists as a type II transmembrane protein and as a shed soluble form; both act as homotrimers. A TRAIL trimer binds the two death-domain receptors TRAIL-R1 (DR4, TNFRSF10A) and TRAIL-R2 (DR5, TNFRSF10B), which form homomeric and heteromeric ligand-receptor clusters at the plasma membrane. The receptor death domains recruit the adaptor FADD through death-domain contacts, and FADD in turn recruits procaspase-8 (and, where expressed, procaspase-10) through death-effector-domain contacts, forming the TRAIL death-inducing signaling complex (DISC). Proximity-induced dimerisation activates caspase-8 at the DISC. The catalytically inactive caspase-8 paralog c-FLIP (CFLAR) is recruited to the same FADD platform and restrains caspase-8 activation, and the decoy receptors TRAIL-R3 (TNFRSF10C, which lacks an intracellular domain) and TRAIL-R4 (TNFRSF10D, which carries a truncated death domain) can bind TRAIL without assembling a DISC and protect cells when overexpressed. Active caspase-8 then propagates the signal by one of two routes. In type I cells enough caspase-8 is generated at the DISC to cleave and activate the executioner caspases-3 and -7 directly. In type II cells caspase-8 output is limiting and must be amplified through the mitochondrial pathway: caspase-8 cleaves the BH3-only protein BID to truncated tBID, which moves to mitochondria and activates BAX/BAK-dependent outer membrane permeabilisation, cytochrome c release, apoptosome assembly and caspase-9 activation, which then feeds the same executioner caspases. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | TRAIL-activated apoptotic signaling pathway |
16 | 12 | 11 | 2 | 4 | 10 | 10/12 | 0 | ✗ | modules/trail_apoptotic_signaling.yaml | |
TRAPP complexes in Drosophila melanogasterMODULE:dmel_trapp_complexesCONCRETE Transport protein particle (TRAPP) complexes are multisubunit guanine nucleotide exchange factors for Rab GTPases in the secretory and autophagic... [more...][less]Transport protein particle (TRAPP) complexes are multisubunit guanine nucleotide exchange factors for Rab GTPases in the secretory and autophagic pathways. A shared core, in which Bet3, Bet5 and Trs23 form the catalytic surface for Rab1 nucleotide exchange, is extended with Trs20, Trs31, Trs33 and the Trs20-like CG9067. Addition of the large subunits Trs120 (SIDL) and Trs130 (brunelleschi, brun) forms TRAPPII, which acts at the Golgi and in Drosophila is required for male meiotic cytokinesis; addition of Trs85 (gryzun, gry) and the TRAPPC11, TRAPPC12 and TRAPPC13 homologs forms TRAPPIII, which acts in ER-to-Golgi transport and autophagy. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | TRAPP complex |
6 | 4 | 3 | 1 | 2 | 0 | 0/13 | 0 | ✗ | modules/dmel_trapp_complexes.yaml | |
Taurine / hypotaurine biosynthesis and transport (CDO1 -> CSAD / ADO; SLC6A6)MODULE:taurine_biosynthesis_and_transport Taurine is one of the most abundant free amino acids in mammalian tissues, essential for bile-salt conjugation, osmoregulation, membrane... [more...][less]Taurine is one of the most abundant free amino acids in mammalian tissues, essential for bile-salt conjugation, osmoregulation, membrane stabilisation, calcium handling and mitochondrial tRNA modification; it is supplied both by endogenous biosynthesis from cysteine and by cellular uptake. The main biosynthetic route starts with cysteine dioxygenase (CDO1), which oxidises L-cysteine to 3-sulfino-L-alanine (cysteinesulfinate) using O2 and a non-heme Fe(II) centre — the committed, rate-limiting step of cysteine catabolism. Cysteinesulfinic acid decarboxylase (CSAD), a PLP-dependent enzyme, then decarboxylates cysteinesulfinate to hypotaurine. A parallel route is provided by 2-aminoethanethiol (cysteamine) dioxygenase (ADO), which oxidises cysteamine (derived from coenzyme A / pantetheine turnover) directly to hypotaurine; ADO is additionally the N-terminal cysteine dioxygenase of the Cys/N-degron oxygen-sensing pathway. Hypotaurine from either route is oxidised to taurine. Cells that synthesise little taurine rely on the plasma-membrane Na+/Cl- -coupled taurine transporter SLC6A6 (TauT) to import it. Defects illustrate the pathway's importance: SLC6A6 loss-of-function causes taurine-deficiency retinal degeneration and cardiomyopathy, and CDO1 is frequently epigenetically silenced in cancer. |
Metabolic Pathway | DRAFT | 0 | taurine biosynthetic process sulfur amino acid catabolic process taurine transmembrane transport |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/taurine_biosynthesis_and_transport.yaml | ||
Tdrd3-Top3beta topoisomerase complex in Drosophila melanogasterMODULE:dmel_tdrd3_top3b_complexCONCRETE Topoisomerase 3-beta (TOP3B) is a type IA topoisomerase that can act on both DNA and RNA. It forms a conserved complex with the Tudor-domain... [more...][less]Topoisomerase 3-beta (TOP3B) is a type IA topoisomerase that can act on both DNA and RNA. It forms a conserved complex with the Tudor-domain protein TDRD3, which stimulates its activity, recruits it to messenger ribonucleoprotein complexes and links it to the fragile X protein FMRP. In Drosophila, Top3beta and Tdrd3 associate with each other and with Fmr1, and the complex has been implicated in synapse formation and in mRNA translation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | DNA topoisomerase III-beta-TDRD3 complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_tdrd3_top3b_complex.yaml | |
Temperate Bacteriophage Lysis-Lysogeny Decision, Prophage Integration, and InductionMODULE:phage_temperate_latency_switchCONCRETE A reusable module capturing the regulatory decision (`GO:0098689`), establishment (`GO:0019043`), maintenance (`GO:0019044`), and induction/release... [more...][less]A reusable module capturing the regulatory decision (`GO:0098689`), establishment (`GO:0019043`), maintenance (`GO:0019044`), and induction/release (`GO:0019046`, `GO:0032359`) of viral latency (lysogeny) in temperate bacteriophages. Two orthogonal variant axes are modeled: (1) the bistable lysis-lysogeny decision circuit (`CI`/`Cro`/`CII`/`CIII` host-protease sensing in lambdoid phages, `C` repressor/Cox switch in P2-like phages, and the arbitrium `AimP`/`AimR`/`AimX` peptide quorum-sensing circuit in Bacillus SPbeta/phi3T phages), and (2) the prophage maintenance state (`GO:0075713` site-specific integrated chromosomal prophage via tyrosine/serine integrase vs. `GO:0075720` extrachromosomal circular or `GO:0075530` linear telomeric plasmid prophage in P1 and N15 vs. replicative transposition prophage integration via DDE transposase `GO:0004803` / `GO:0015074` in Mu-like phages). |
Biological Process | COMPLETE | Bacteria Viruses |
0 | latency-replication decision viral latency release from viral latency |
8 | 6 | 2 | 2 | 5 | 1 | 4/5 | 1 | ✗ | modules/phage_temperate_latency_switch.yaml | |
Temperate phage lysogenic-lytic decision, transcription antitermination, and prophage integration/excisionMODULE:phage_temperate_lysogeny_switchCONCRETE A coupled gene-regulatory and site-specific recombination module that governs the bistable decision between prophage latency (lysogeny) and... [more...][less]A coupled gene-regulatory and site-specific recombination module that governs the bistable decision between prophage latency (lysogeny) and productive lytic development in lambdoid temperate bacteriophages. Early transcription initiated at promoters PL and PR is extended past intrinsic and Rho-dependent terminators by the nut-site antitermination protein N, expressing the CII transcriptional activator, its FtsH-inhibiting stabilizer CIII, and the integrative/recombinational genes. High CII activity activates promoters PRE (driving synthesis of the CI immunity repressor), PI (driving synthesis of the tyrosine integrase Int), and PaQ (antisense inhibition of late antiterminator Q), establishing integrated proviral latency in which CI dimers cooperatively repress PL and PR while maintaining PRM. Conversely, low CII activity permits Cro accumulation at OR3/OL3 and Q-mediated antitermination of the late PR' transcript, committing the phage to lytic replication and virion morphogenesis. Host SOS DNA damage activates RecA* coprotease-stimulated autocleavage of CI, derepressing PL and PR so that Int and the directionality factor Xis catalyze excisive recombination (attL x attR) to release the prophage genome for lytic replication. |
Biological Process | COMPLETE | Caudoviricetes Escherichia phage lambda |
0 | latency-replication decision establishment of integrated proviral latency maintenance of viral latency provirus excision |
9 | 8 | 8 | 0 | 0 | 10 | 8/8 | 0 | ✗ | modules/phage_temperate_lysogeny_switch.yaml | |
Terminin telomere-capping complex in Drosophila melanogasterMODULE:dmel_terminin_telomere_cappingCONCRETE Drosophila telomeres are maintained by retrotransposons rather than telomerase, and their capping is sequence-independent. The terminin complex... [more...][less]Drosophila telomeres are maintained by retrotransposons rather than telomerase, and their capping is sequence-independent. The terminin complex binds chromosome ends and prevents them from being recognised as DNA breaks and fused. It contains HOAP (encoded by caravaggio, cav) with HipHop, which together with HP1 form the HipHop-HOAP subcomplex, and the MTV subcomplex of Modigliani (Moi), Verrocchio (Ver) and Tea, which also associates with HOAP. Loss of terminin subunits causes telomere fusions. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | nuclear telomere cap complex |
3 | 2 | 2 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/dmel_terminin_telomere_capping.yaml | |
Tetrahydrobiopterin (BH4) biosynthesis and regenerationMODULE:tetrahydrobiopterin_metabolism Tetrahydrobiopterin (BH4, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential reduced-pteridine cofactor for the aromatic amino acid... [more...][less]Tetrahydrobiopterin (BH4, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin) is an essential reduced-pteridine cofactor for the aromatic amino acid hydroxylases (phenylalanine hydroxylase PAH, tyrosine hydroxylase TH, and the tryptophan hydroxylases TPH1/TPH2), for the nitric oxide synthases, and for alkylglycerol monooxygenase. This module covers the two arms of BH4 homeostasis. (1) De novo biosynthesis, a short cytosolic three-step pathway from GTP: GTP cyclohydrolase I (GCH1) opens the imidazole ring of GTP to give 7,8-dihydroneopterin 3'-triphosphate (the committed, feedback-regulated step); 6-pyruvoyltetrahydropterin synthase (PTS/PTPS) converts this to 6-pyruvoyl-5,6,7,8-tetrahydropterin; and sepiapterin reductase (SPR) carries out the NADPH-dependent reductions that yield BH4. (2) Regeneration (recycling), which is required because each turn of an aromatic amino acid hydroxylase oxidises BH4 to pterin-4a-carbinolamine (4a-hydroxy-BH4): pterin-4a-carbinolamine dehydratase (PCBD1/PCD) dehydrates this to quinonoid dihydrobiopterin, and dihydropteridine reductase (QDPR/DHPR) reduces the quinonoid dihydrobiopterin back to BH4 using NADH. Because the hydroxylases turn over far faster than de novo synthesis, the PCBD1-QDPR salvage loop supplies most of the BH4 used at steady state. Inherited defects of GCH1, PTS, SPR, PCBD1 or QDPR all cause BH4 deficiency, presenting as BH4-deficient hyperphenylalaninemia (atypical/"malignant" PKU) and/or monoamine-neurotransmitter deficiency (dopa-responsive dystonia, catecholamine and serotonin deficiency), a distinct and separately treatable group of disorders from PAH-deficient classical PKU. PCBD1 additionally moonlights as DCoH, the dimerization cofactor / transcriptional coactivator of the HNF1 transcription factors. |
Metabolic Pathway | DRAFT | 0 | tetrahydrobiopterin biosynthetic process tetrahydrobiopterin metabolic process |
7 | 6 | 6 | 0 | 0 | 6 | 8/10 | 0 | ✗ | modules/tetrahydrobiopterin_metabolism.yaml | ||
Thiamine (vitamin B1) uptake and diphosphate activation (SLC19A2/A3 -> TPK1 -> SLC25A19; THTPA)MODULE:thiamine_uptake_and_activation Humans cannot synthesise thiamine (vitamin B1) and must take it up from the diet, then convert it to its active cofactor form thiamine diphosphate... [more...][less]Humans cannot synthesise thiamine (vitamin B1) and must take it up from the diet, then convert it to its active cofactor form thiamine diphosphate (ThDP, also called thiamine pyrophosphate, TPP), which is required by pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, branched-chain 2-oxoacid dehydrogenase and transketolase. Free thiamine is imported across the plasma membrane by the two high-affinity SLC19 thiamine transporters THTR1 (SLC19A2) and THTR2 (SLC19A3). In the cytosol thiamine pyrophosphokinase TPK1 transfers a diphosphate group from ATP (physiologically UTP is the preferred donor) to thiamine, producing ThDP. ThDP is then delivered to the mitochondrial matrix by the inner-membrane carrier SLC25A19 to supply the matrix dehydrogenases. Cellular thiamine triphosphate (ThTP), a minor phosphorylated form, is hydrolysed back to ThDP by the cytosolic thiamine triphosphatase THTPA, contributing to phosphothiamine homeostasis. Defects in this module cause thiamine-responsive megaloblastic anaemia (SLC19A2 / Rogers syndrome), biotin-thiamine-responsive basal ganglia disease (SLC19A3), thiamine metabolism dysfunction syndrome 5 / episodic encephalopathy (TPK1) and Amish lethal microcephaly / THMD4 (SLC25A19). |
Metabolic Pathway | DRAFT | 0 | thiamine metabolic process thiamine transport thiamine diphosphate biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/thiamine_uptake_and_activation.yaml | ||
Thylakoid light reactionsMODULE:thylakoid_light_reactions The light-driven electron transport and photophosphorylation half of oxygenic photosynthesis, as a taxon-neutral decomposition: light harvesting by... [more...][less]The light-driven electron transport and photophosphorylation half of oxygenic photosynthesis, as a taxon-neutral decomposition: light harvesting by the antenna, water oxidation at photosystem II, plastoquinol oxidation and proton translocation by the cytochrome b6f complex, the inter-photosystem mobile carrier, P700 photo-oxidation and ferredoxin reduction at photosystem I, NADPH production by ferredoxin-NADP+ reductase, and ATP synthesis from the proton-motive force. Phrased as functions, complexes and pathway segments rather than a fixed gene list, so it can represent cyanobacterial, algal and plant implementations. Carbon fixation is a separate module (MODULE:calvin_benson_bassham_cycle), which consumes the ATP and NADPH this module supplies. Photoprotection and cyclic/pseudocyclic electron balancing stay with the parent MODULE:oxygenic_photosynthesis, since they regulate the ratio between the two halves rather than belonging to either. Anoxygenic photosynthesis (single reaction center, non-water electron donors) is out of scope. |
Biological Process | DRAFT | 0 | photosynthesis, light reaction photosynthetic electron transport chain |
10 | 8 | 7 | 1 | 2 | 5 | 1/4 | 5 | ✗ | modules/thylakoid_light_reactions.yaml | ||
Thymidylate (dTMP -> dTTP) synthesis; thymidylate synthase / dUTPase / dTMP kinaseMODULE:thymidylate_synthesis Thymidylate synthesis is the route that makes the DNA-specific precursor dTTP, distinguishing DNA (thymine) from RNA (uracil) precursors. dUTP... [more...][less]Thymidylate synthesis is the route that makes the DNA-specific precursor dTTP, distinguishing DNA (thymine) from RNA (uracil) precursors. dUTP diphosphatase (DUT) hydrolyses dUTP to dUMP + diphosphate, which both keeps the cellular dUTP:dTTP ratio low (preventing mutagenic uracil misincorporation into DNA) and supplies dUMP as substrate. Thymidylate synthase (TYMS) then reductively methylates dUMP to dTMP, using 5,10-methylenetetrahydrofolate as the one-carbon donor (oxidised to dihydrofolate, regenerated by DHFR) — the sole de novo source of dTMP. Thymidylate kinase (DTYMK) phosphorylates dTMP to dTDP, the essential step common to both the de novo and salvage routes; nucleoside diphosphate kinase then makes dTTP. This pathway is a central target of chemotherapy — TYMS is inhibited by the 5-fluorouracil metabolite FdUMP and by antifolates (raltitrexed, pemetrexed), and the folate cofactor supply is targeted by methotrexate — because rapidly dividing cells depend on de novo dTTP for DNA replication. Perturbing the balance (e.g. DUT loss, TYMS inhibition) causes dUTP accumulation, uracil misincorporation and DNA damage. |
Metabolic Pathway | DRAFT | 0 | dTMP biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/thymidylate_synthesis.yaml | ||
Thyroid-stimulating hormone signaling pathway moduleMODULE:tsh_signaling Secreted heterodimeric thyroid-stimulating hormone (thyrotropin, TSH), assembled in anterior pituitary thyrotrophs from the... [more...][less]Secreted heterodimeric thyroid-stimulating hormone (thyrotropin, TSH), assembled in anterior pituitary thyrotrophs from the receptor-specificity-determining beta subunit TSHB (PANTHER:PTHR11515:SF5) and the common glycoprotein hormone alpha subunit CGA (PANTHER:PTHR11509:SF0), binds the extracellular leucine-rich-repeat domain of the thyroid-stimulating hormone receptor (TSHR, PANTHER:PTHR24372:SF0) at the basolateral plasma membrane of thyroid follicular cells. Hormone binding induces a conformational push-pull shift in the TSHR extracellular domain that activates the seven-transmembrane bundle to couple primarily to heterotrimeric Gs (GNAS, PANTHER:PTHR10218:SF357)—stimulating adenylyl cyclase and cAMP-dependent thyroid hormone synthesis and secretion—and at higher hormone occupancy to Gq/11 (GNAQ, PANTHER:PTHR10218:SF329) to activate phospholipase C-beta and dual oxidase-dependent iodide organification, executing the thyroid-stimulating hormone signaling pathway (GO:0038194). |
Signaling Pathway | DRAFT | Euteleostomi |
2 | thyroid-stimulating hormone signaling pathway |
3 | 5 | 2 | 0 | 0 | 1 | 3/5 | 0 | ✗ | modules/tsh_signaling.yaml | |
Tip60 histone acetyltransferase and exchange complex in Drosophila melanogasterMODULE:dmel_tip60_complexCONCRETE The Drosophila Tip60 complex combines the activities that budding yeast splits between NuA4 and SWR1. Its MYST-family acetyltransferase Tip60... [more...][less]The Drosophila Tip60 complex combines the activities that budding yeast splits between NuA4 and SWR1. Its MYST-family acetyltransferase Tip60 acetylates nucleosomal histone H4 and the H2A variant H2Av, and the SWR1-family ATPase Domino exchanges phosphorylated H2Av for unmodified H2Av, which links the complex to DNA damage responses. The complex also contains the AAA+ ATPases Pontin and Reptin, the Tra1 homolog Nipped-A, actin, and chromatin-reader subunits including MRG15, Brd8 and Gas41. It contributes to transcriptional regulation, DNA repair and cell-cycle control. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | NuA4 histone acetyltransferase complex |
5 | 4 | 4 | 0 | 0 | 0 | 1/16 | 0 | ✗ | modules/dmel_tip60_complex.yaml | |
Toll signaling pathway in Drosophila melanogasterMODULE:dmel_toll_signalingCONCRETE The Toll pathway is activated when an extracellular serine protease cascade cleaves the pro-domain of the cytokine-like ligand Spaetzle, allowing... [more...][less]The Toll pathway is activated when an extracellular serine protease cascade cleaves the pro-domain of the cytokine-like ligand Spaetzle, allowing it to bind the Toll receptor. In the early embryo, a maternally supplied cascade (Gastrulation defective, Snake and Easter), spatially restricted by the Pipe sulfotransferase in the ventral follicle cells, generates ventral Spaetzle and establishes the dorsal-ventral axis. In the immune response, pattern-recognition proteins (PGRP-SA, GNBP1, GNBP3) and the virulence sensor Persephone activate ModSP, Grass and Hayan, converging on the Spaetzle-processing enzyme. Activated Toll recruits the adaptors MyD88 and Tube and the kinase Pelle, which lead to degradation of the IkB protein Cactus and nuclear entry of the NF-kappaB factors Dorsal and Dif. Related Toll receptors such as Toll-7, bound by neurotrophin-like Spaetzle family ligands, act in the nervous system. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | Toll signaling pathway |
10 | 33 | 7 | 1 | 2 | 5 | 12/36 | 0 | ✗ | modules/dmel_toll_signaling.yaml | |
Toll-like receptor innate immune signaling pathway moduleMODULE:toll_like_receptor_signaling A compact Toll-like receptor (TLR) signaling module. Ligand-bound TLRs recruit TIR-domain adaptors such as MYD88, activate IRAK kinases and TRAF6... [more...][less]A compact Toll-like receptor (TLR) signaling module. Ligand-bound TLRs recruit TIR-domain adaptors such as MYD88, activate IRAK kinases and TRAF6 ubiquitin ligase scaffolds, and route the signal through TAK1/IKK and MAPK branches to NF-kappaB, AP-1, and inflammatory gene expression. The module is grounded in GO:0002224 and includes PTN anchors for TRAF6-family ubiquitin-ligase and innate-immune roles where local PAINT seed rows support them. |
Signaling Pathway | DRAFT | metazoa |
2 | toll-like receptor signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 5/5 | 0 | ✗ | modules/toll_like_receptor_signaling.yaml | |
Tonoplast proton pumping and solute transport in plantsMODULE:plant_tonoplast_transportCONCRETE The plant vacuole membrane, the tonoplast, carries two proton pumps, the V-ATPase and the pyrophosphate-energized H+-PPase, whose gradient drives... [more...][less]The plant vacuole membrane, the tonoplast, carries two proton pumps, the V-ATPase and the pyrophosphate-energized H+-PPase, whose gradient drives the uptake of ions and metabolites by antiporters, while aquaporins and channels let water and ions move between the cytosol and the vacuole. This module is the green-lineage core of tonoplast transport beyond the V-ATPase, written so that it can be evaluated in a plant genome. |
Biological Process | DRAFT | Viridiplantae |
12 | vacuolar transmembrane transport plant-type vacuole membrane |
8 | 7 | 7 | 0 | 0 | 2 | 0/14 | 0 | ✗ | modules/plant_tonoplast_transport.yaml | |
TopAI-YjhQ toxin-antitoxin neutralizationMODULE:topai_yjhq_toxin_antitoxinCONCRETE A protein-sequestration module for the Escherichia coli topAI-yjhQ toxin-antitoxin pair in which YjhQ acts as the antitoxin for TopAI/YjhX. YjhQ... [more...][less]A protein-sequestration module for the Escherichia coli topAI-yjhQ toxin-antitoxin pair in which YjhQ acts as the antitoxin for TopAI/YjhX. YjhQ binding neutralizes TopAI toxicity and relieves TopAI-mediated inhibition of topoisomerase I. YjhQ's predicted GNAT-family acetyltransferase chemistry remains substrate-unknown and is outside this toxin-sequestering module. |
Regulatory Step | DRAFT | Escherichia coli |
0 | TopAI-YjhQ toxin-antitoxin neutralization |
1 | 2 | 0 | 0 | 0 | 1 | 1/2 | 0 | ✗ | modules/topai_yjhq_toxin_antitoxin.yaml | |
Torso receptor tyrosine kinase signaling in Drosophila melanogasterMODULE:dmel_torso_signalingCONCRETE Torso is a receptor tyrosine kinase that is uniformly distributed in the early embryo membrane but activated only at the anterior and posterior... [more...][less]Torso is a receptor tyrosine kinase that is uniformly distributed in the early embryo membrane but activated only at the anterior and posterior poles, where it specifies the terminal structures. Local activation depends on Torso-like, which is deposited at the poles by follicle cells and acts together with eggshell components (Nasrat/fs(1)N, Polehole/fs(1)M3 and Closca) to allow activation of Torso by its ligand Trunk. Torso signals through Drk, Sos and Ras to the Raf-MEK (Dsor1)-ERK (Rolled) cascade. ERK phosphorylation relieves repression by Capicua, which with the corepressor Groucho represses the terminal gap genes tailless and huckebein outside the poles. In the larval prothoracic gland, Torso is activated by prothoracicotropic hormone (PTTH) to trigger ecdysone production and the onset of metamorphosis. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | torso signaling pathway terminal region determination |
10 | 22 | 7 | 1 | 2 | 6 | 6/22 | 0 | ✗ | modules/dmel_torso_signaling.yaml | |
TreS-Mak-GlgE branched alpha-glucan biosynthesisMODULE:tres_mak_glge_branched_alpha_glucan_biosynthesisCONCRETE A reusable bacterial pathway that channels trehalose into branched alpha-glucan. Trehalose synthase operating in the catabolic direction forms... [more...][less]A reusable bacterial pathway that channels trehalose into branched alpha-glucan. Trehalose synthase operating in the catabolic direction forms maltose, maltokinase converts maltose to alpha-maltose 1-phosphate, GlgE uses that activated donor to extend alpha-1,4-glucan chains by maltosyl units, and GlgB introduces alpha-1,6 branches. TreS and Mak may be separate proteins or domains of one fusion protein; that architectural variation does not change the four reaction roles. |
Metabolic Pathway | DRAFT | bacteria |
3 | alpha-glucan biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 3/7 | 0 | ✗ | modules/tres_mak_glge_branched_alpha_glucan_biosynthesis.yaml | |
TreY/TreZ trehalose biosynthesis from alpha-glucanMODULE:trey_trez_trehalose_biosynthesis A reusable two-reaction bacterial and archaeal pathway that makes trehalose from the reducing ends of alpha-1,4-glucans such as glycogen, starch... [more...][less]A reusable two-reaction bacterial and archaeal pathway that makes trehalose from the reducing ends of alpha-1,4-glucans such as glycogen, starch and maltooligosaccharides. TreY (maltooligosyl trehalose synthase) rearranges the reducing-end alpha-1,4 glucosidic bond into an alpha,alpha-1,1 bond, giving maltooligosyltrehalose; TreZ (malto-oligosyltrehalose trehalohydrolase) then hydrolyses the adjacent alpha-1,4 bond to release trehalose and an alpha-glucan two glucose units shorter. Alpha-glucan synthesis and remodeling, the alternative OtsA/OtsB and TreS trehalose routes, and trehalose degradation are outside the boundary. |
Metabolic Pathway | COMPLETE | 1 | trehalose biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/trey_trez_trehalose_biosynthesis.yaml | ||
Trehalose synthesis via trehalose 6-phosphate and trehalase hydrolysisMODULE:trehalose_metabolismCONCRETE Trehalose (alpha-D-glucopyranosyl alpha-D-glucopyranoside) is a non-reducing glucose disaccharide used as a reserve carbohydrate and stress... [more...][less]Trehalose (alpha-D-glucopyranosyl alpha-D-glucopyranoside) is a non-reducing glucose disaccharide used as a reserve carbohydrate and stress protectant by fungi, bacteria, invertebrates and plants. This module covers its synthesis through the phosphorylated intermediate and its hydrolysis. A retaining glycosyltransferase of GT-20 family, trehalose-6-phosphate synthase (TPS, OtsA), transfers glucose from UDP-glucose to glucose 6-phosphate to form alpha,alpha-trehalose 6-phosphate (T6P). A HAD-superfamily trehalose-6-phosphate phosphatase (TPP, OtsB) then removes the phosphate to release free trehalose. The phosphatase is either a standalone OtsB-type enzyme (bacteria, plants) or the C-terminal phosphatase domain of a larger TPS2-type protein that also carries an inactive GT-20-like domain (fungi). In yeasts the two catalytic subunits form a cytosolic trehalose synthase complex together with large TSL1/TPS3-type regulatory subunits, which also carry GT-20-like domains and are needed for full activity and stability of the complex. Trehalose is hydrolysed to two glucose molecules by trehalases. A cytosolic glycoside hydrolase family 37 neutral trehalase mobilises intracellular trehalose, and an extracellular or periplasmic trehalase (GH65 acid trehalase in budding yeast, GH37 TreA in enterobacteria) hydrolyses external trehalose. T6P also acts as a signalling metabolite (for example as a hexokinase inhibitor in budding yeast), which is a separate role of the pathway intermediate. The other trehalose routes (TreY/TreZ and TreS from alpha-glucans, trehalose phosphorylases), the supply of UDP-glucose and glucose 6-phosphate, and trehalose transport are outside the boundary. |
Metabolic Pathway | DRAFT | 0 | trehalose metabolic process |
10 | 7 | 5 | 2 | 4 | 3 | 13/17 | 0 | ✗ | modules/trehalose_metabolism.yaml | ||
Trehalose synthesis, transport and breakdown in Drosophila melanogasterMODULE:dmel_trehalose_metabolismCONCRETE Trehalose, a glucose disaccharide, is the main circulating sugar in insect hemolymph. In the fat body, trehalose-6-phosphate synthase 1 (Tps1), a... [more...][less]Trehalose, a glucose disaccharide, is the main circulating sugar in insect hemolymph. In the fat body, trehalose-6-phosphate synthase 1 (Tps1), a bifunctional enzyme with synthase and phosphatase domains, makes trehalose from UDP-glucose and glucose-6-phosphate. Trehalose leaves the fat body and enters target cells through the facilitative transporter Tret1, and in target tissues trehalase (Treh) hydrolyses it into two glucose molecules for glycolysis and other uses. Trehalose levels buffer hemolymph sugar and protect against stress. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | trehalose biosynthetic process trehalose catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/dmel_trehalose_metabolism.yaml | |
Triacylglycerol synthesis for lipid droplet formationMODULE:lipid_droplet_neutral_lipid_storageCONCRETE Lipid droplets form in the endoplasmic reticulum membrane when neutral lipids, chiefly triacylglycerol and sterol esters, are made between the two... [more...][less]Lipid droplets form in the endoplasmic reticulum membrane when neutral lipids, chiefly triacylglycerol and sterol esters, are made between the two leaflets, coalesce into a lens and bud toward the cytosol as an oil core covered by a phospholipid monolayer. The committed step of triacylglycerol storage is the acylation of diacylglycerol, catalysed in eukaryotes by two unrelated acyl-CoA-dependent enzyme families, DGAT1 and DGAT2, either of which can supply a droplet. This module is the eukaryote-wide core of that step, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
3 | triglyceride biosynthetic process lipid droplet formation |
5 | 3 | 2 | 1 | 2 | 1 | 5/8 | 0 | ✗ | modules/lipid_droplet_neutral_lipid_storage.yaml | |
Tricarboxylic acid cycleMODULE:tca_cycleCONCRETE A taxon-neutral module for the oxidative tricarboxylic acid (TCA) cycle, covering acetyl-CoA entry through citrate synthase, citrate/isocitrate... [more...][less]A taxon-neutral module for the oxidative tricarboxylic acid (TCA) cycle, covering acetyl-CoA entry through citrate synthase, citrate/isocitrate interconversion by aconitase, oxidative decarboxylation of isocitrate to 2-oxoglutarate and of 2-oxoglutarate to succinyl-CoA, substrate-level phosphorylation by succinyl-CoA ligase, succinate oxidation by respiratory complex II, fumarate hydration, and malate oxidation to regenerate oxaloacetate. The chemistry is conserved between bacteria, where the cycle runs in the cytoplasm and complex II sits in the plasma membrane, and eukaryotes, where it runs in the mitochondrial matrix and complex II sits in the inner mitochondrial membrane. The enzyme implementations differ at several steps: citrate synthase is a hexameric type II enzyme in many Gram-negative bacteria and a dimeric type I enzyme in mitochondria; the isocitrate step uses NADP-dependent isocitrate dehydrogenases in many bacteria but an allosterically regulated NAD-dependent hetero-oligomeric isocitrate dehydrogenase in eukaryotic mitochondria; the eukaryotic 2-oxoglutarate dehydrogenase complex carries an extra adaptor subunit that recruits the E3 component; and malate can be oxidized by NAD-dependent malate dehydrogenase or by membrane-associated malate:quinone oxidoreductases. Paralogous isozymes in other compartments (peroxisomal or cytosolic citrate synthase, malate dehydrogenase and NADP-isocitrate dehydrogenase) serve the glyoxylate cycle, NADPH supply or redox shuttles rather than the oxidative cycle. |
Metabolic Pathway | DRAFT | 0 | tricarboxylic acid cycle |
17 | 14 | 12 | 2 | 4 | 8 | 58/58 | 0 | ✓ | modules/tca_cycle.yaml | ||
Troponin complex in Drosophila melanogasterMODULE:dmel_troponin_complexCONCRETE Troponin is the calcium sensor of the thin filament in striated muscle. It is a complex of three subunits bound to tropomyosin: troponin C binds... [more...][less]Troponin is the calcium sensor of the thin filament in striated muscle. It is a complex of three subunits bound to tropomyosin: troponin C binds calcium, troponin I inhibits actomyosin interaction at rest, and troponin T anchors the complex to tropomyosin. When calcium binds troponin C, the inhibition by troponin I is relieved and tropomyosin moves to expose myosin-binding sites on actin, allowing contraction. Drosophila has single genes for troponin I (wings up A, wupA) and troponin T (upheld, up), each producing many muscle-specific isoforms by alternative splicing, and five troponin C genes expressed in different muscles; in the indirect flight muscle TpnC4 and TpnC41C are used, with TpnC4 linked to stretch activation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | troponin complex |
9 | 7 | 3 | 1 | 5 | 1 | 1/7 | 0 | ✗ | modules/dmel_troponin_complex.yaml | |
Tryptophan catabolism to ommochrome pigments in Drosophila melanogasterMODULE:dmel_ommochrome_biosynthesisCONCRETE The brown ommochrome eye pigment xanthommatin is made from tryptophan through the kynurenine pathway, which in insects is also the main route of... [more...][less]The brown ommochrome eye pigment xanthommatin is made from tryptophan through the kynurenine pathway, which in insects is also the main route of tryptophan catabolism. Tryptophan 2,3-dioxygenase (vermilion) opens the indole ring to give N-formylkynurenine, kynurenine formamidase (Kfase) releases kynurenine, and kynurenine 3-monooxygenase (cinnabar) hydroxylates it to 3-hydroxykynurenine. 3-Hydroxykynurenine is imported into pigment granules of the eye and other tissues by the White-Scarlet ABC transporter, where it is condensed to xanthommatin; this last step requires the heme peroxidase Cardinal. Mutations in v, cn, w, st and cd give the classic eye-colour phenotypes that lack or reduce brown pigment. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | ommochrome biosynthetic process L-tryptophan catabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 0/6 | 0 | ✗ | modules/dmel_ommochrome_biosynthesis.yaml | |
Tus-dependent bacterial MnmA tRNA wobble-uridine thiolationMODULE:bacterial_mnma_trna_thiolation A Tus-dependent bacterial sulfur-relay module that mobilizes sulfur from cysteine and passes it through TusA, the TusBCD complex, and TusE to MnmA,... [more...][less]A Tus-dependent bacterial sulfur-relay module that mobilizes sulfur from cysteine and passes it through TusA, the TusBCD complex, and TusE to MnmA, which installs 2-thiouridine at the wobble uridine of substrate tRNAs. Sulfur mobilization, carrier handoffs, complex-mediated transfer, and tRNA thiolation are modeled as separate substantive roles. |
Biological Process | DRAFT | Gammaproteobacteria |
0 | tRNA wobble position uridine thiolation |
6 | 7 | 5 | 0 | 0 | 4 | 7/7 | 0 | ✗ | modules/bacterial_mnma_trna_thiolation.yaml | |
Type I interferon signaling pathway moduleMODULE:type_i_interferon_signaling Type I interferons engage IFNAR receptor complexes and JAK1/TYK2 kinases to activate STAT1-STAT2-IRF9 transcriptional complexes that induce... [more...][less]Type I interferons engage IFNAR receptor complexes and JAK1/TYK2 kinases to activate STAT1-STAT2-IRF9 transcriptional complexes that induce antiviral gene programs. |
Signaling Pathway | DRAFT | metazoa |
8 | type I interferon-mediated signaling pathway |
4 | 8 | 3 | 0 | 0 | 2 | 5/8 | 0 | ✓ | modules/type_i_interferon_signaling.yaml | |
Type II interferon signaling pathway moduleMODULE:type_ii_interferon_signaling Interferon-gamma engages IFNGR receptor complexes and JAK1/JAK2 kinases to activate STAT1-dependent transcriptional programs for macrophage... [more...][less]Interferon-gamma engages IFNGR receptor complexes and JAK1/JAK2 kinases to activate STAT1-dependent transcriptional programs for macrophage activation and cell-mediated immunity. |
Signaling Pathway | DRAFT | metazoa |
7 | type II interferon-mediated signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 3/6 | 0 | ✓ | modules/type_ii_interferon_signaling.yaml | |
Type-II (dissociated) fatty-acid synthesis, bacterial and mitochondrialMODULE:type_ii_fatty_acid_synthesis A reusable dissociated fatty-acid synthase (FAS II) pathway in which each reaction is catalysed by a separate enzyme acting on acyl chains carried... [more...][less]A reusable dissociated fatty-acid synthase (FAS II) pathway in which each reaction is catalysed by a separate enzyme acting on acyl chains carried by a free acyl carrier protein (ACP). Malonyl-CoA formed by acetyl-CoA carboxylase is loaded onto ACP, an acyl-ACP chain is initiated, and the chain is iteratively elongated through condensation, beta-keto reduction, dehydration, and enoyl reduction. The same architecture operates in bacteria (and plastids) and, as a conserved, endosymbiont-derived system, in the mitochondrial matrix of eukaryotes, where it is independent of the cytosolic type I FAS and its best-defined product is octanoyl-ACP, the precursor of lipoic acid. Mitochondrial FAS II uses a homomeric multidomain acetyl-CoA carboxylase, a mitochondrial ACP and partly unrelated reductase and dehydratase families. An optional FabA/FabB branch introduces and extends cis unsaturation in bacteria. Enzyme-family, cofactor and compartment variants are represented explicitly rather than collapsed into a type-I fatty-acid synthase. |
Metabolic Pathway | DRAFT | 2 | fatty acid biosynthetic process |
33 | 22 | 14 | 7 | 18 | 11 | 28/36 | 0 | ✓ | modules/type_ii_fatty_acid_synthesis.yaml | ||
Tyramine and octopamine biosynthesis in Drosophila melanogasterMODULE:dmel_tyramine_octopamine_biosynthesisCONCRETE Octopamine, the insect counterpart of noradrenaline, and its precursor tyramine are monoamine neurotransmitters and neurohormones. Tyrosine is... [more...][less]Octopamine, the insect counterpart of noradrenaline, and its precursor tyramine are monoamine neurotransmitters and neurohormones. Tyrosine is decarboxylated to tyramine by tyrosine decarboxylase: Tdc2 in neurons and Tdc1 in non-neural tissues. Tyramine beta-hydroxylase (Tbh), a copper monooxygenase of the dopamine beta-hydroxylase family that acts inside secretory vesicles, then hydroxylates tyramine to octopamine. Loss of Tbh removes octopamine and causes female sterility from a failure of ovulation, and loss of Tdc2 removes both amines from the nervous system. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | octopamine biosynthetic process tyramine biosynthetic process |
3 | 4 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✗ | modules/dmel_tyramine_octopamine_biosynthesis.yaml | |
UDP-glucose and UDP-galactose biosynthesisMODULE:udp_glucose_and_udp_galactose_biosynthesisCONCRETE Bacterial module for de novo production of UDP-glucose from the central glucose 6-phosphate pool and its reversible interconversion with... [more...][less]Bacterial module for de novo production of UDP-glucose from the central glucose 6-phosphate pool and its reversible interconversion with UDP-galactose. Three reactions make up the module: phosphoglucomutase isomerizes glucose 6-phosphate to alpha-D-glucose 1-phosphate, UTP--glucose-1-phosphate uridylyltransferase (GalU) activates glucose 1-phosphate as UDP-glucose, and NAD-dependent UDP-glucose 4-epimerase (GalE) interconverts UDP-glucose and UDP-galactose. The phosphoglucomutase step is supplied by non-homologous or distantly related enzyme families that differ between lineages: a PGM1-type phosphoglucomutase (Escherichia coli Pgm), a PGM2-type phosphoglucomutase (Bacillus subtilis PgcA), or a bifunctional phosphomannomutase/phosphoglucomutase (Pseudomonas aeruginosa AlgC). The activated hexoses feed lipopolysaccharide core, teichoic acid and glycolipid anchors, capsular and exopolysaccharides, trehalose and other glycoconjugates; those consuming pathways, and galactose uptake and catabolism, are outside this module. |
Metabolic Pathway | COMPLETE | bacteria |
3 | UDP-alpha-D-glucose biosynthetic process UDP-galactose biosynthetic process |
7 | 5 | 3 | 1 | 3 | 2 | 9/9 | 0 | ✓ | modules/udp_glucose_and_udp_galactose_biosynthesis.yaml | |
UDP-glucuronate and UDP-xylose biosynthesis in Drosophila melanogasterMODULE:dmel_udp_glucuronate_xylose_biosynthesisCONCRETE UDP-glucuronic acid and UDP-xylose are the sugar donors for proteoglycan glycosaminoglycan chains and for other glucuronidated and xylosylated... [more...][less]UDP-glucuronic acid and UDP-xylose are the sugar donors for proteoglycan glycosaminoglycan chains and for other glucuronidated and xylosylated molecules. UDP-glucose pyrophosphorylase (Ugp) makes UDP-glucose from glucose-1-phosphate and UTP, and UDP-glucose 6-dehydrogenase (Sugarless, sgl) oxidises it to UDP-glucuronic acid in the cytosol. The nucleotide-sugar transporter Fringe connection (frc) imports UDP-glucuronic acid and other UDP sugars into the ER and Golgi lumen, where UDP-glucuronic acid decarboxylase (Uxs) converts UDP-glucuronic acid to UDP-xylose. Sugarless and Fringe connection were identified genetically through their requirement for Wingless and other heparan sulfate proteoglycan-dependent signalling. |
Metabolic Pathway | DRAFT | Drosophila melanogaster |
0 | UDP-glucuronate biosynthetic process UDP-D-xylose biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/dmel_udp_glucuronate_xylose_biosynthesis.yaml | |
Ubiquinone (coenzyme Q) biosynthesis in bacteria and mitochondriaMODULE:ubiquinone_biosynthesis De novo biosynthesis of ubiquinone (coenzyme Q) from 4-hydroxybenzoate and a long-chain all-trans-polyprenyl diphosphate in bacteria and in the... [more...][less]De novo biosynthesis of ubiquinone (coenzyme Q) from 4-hydroxybenzoate and a long-chain all-trans-polyprenyl diphosphate in bacteria and in the mitochondria of eukaryotes. A dedicated trans-prenyltransferase sets the tail length (homomeric IspB or Coq1, or a heterotetrameric Dps1/Dlp1 or PDSS1/PDSS2 enzyme). The aromatic head group comes from chorismate via UbiC in bacteria, and from tyrosine in fungi, where aminotransferases form 4-hydroxyphenylpyruvate and an aldehyde dehydrogenase (Hfd1) oxidizes 4-hydroxybenzaldehyde to 4-hydroxybenzoate. UbiA-family prenyltransferases (UbiA in the bacterial membrane, Coq2 in the mitochondrial inner membrane) attach the tail. The ring then undergoes one decarboxylation, three hydroxylations, two O-methylations and one C-methylation, in lineage-specific order: bacteria decarboxylate first with prFMN-dependent UbiD (cofactor from UbiX) and use UbiI/UbiH/UbiF or Coq7 hydroxylases, whereas the mitochondrial CoQ synthome hydroxylates C5 with Coq6, O-methylates with Coq3, performs a C1 oxidative decarboxylation with Coq4, then C-methylates (Coq5), hydroxylates C6 (Coq7) and O-methylates again (Coq3). Accessory factors (UbiJ, UbiK and UbiB in bacteria; Coq8, Coq9 and the mitochondrial ferredoxin system in eukaryotes) organize the hydrophobic intermediates or supply electrons. Oxygen-independent UbiT/UbiU/UbiV implementations, C5-C20 prenyl diphosphate synthesis, and coenzyme Q transport and use are outside the module. |
Metabolic Pathway | DRAFT | 8 | ubiquinone biosynthetic process |
30 | 30 | 16 | 6 | 13 | 13 | 46/63 | 0 | ✓ | modules/ubiquinone_biosynthesis.yaml | ||
Urea cycle (vertebrate hepatic ureagenesis, Krebs-Henseleit cycle)MODULE:urea_cycle The urea cycle (ornithine cycle / Krebs-Henseleit cycle) is the principal pathway for the detoxification of waste nitrogen in ureotelic... [more...][less]The urea cycle (ornithine cycle / Krebs-Henseleit cycle) is the principal pathway for the detoxification of waste nitrogen in ureotelic vertebrates, converting ammonia (arising largely from amino-acid catabolism) plus bicarbonate and aspartate-derived nitrogen into urea for renal excretion. In mammals it operates predominantly in periportal hepatocytes and spans two compartments: the first two committed steps are mitochondrial and the last three are cytosolic, so the pathway is physically split across the inner mitochondrial membrane and requires two dedicated mitochondrial carriers. The cycle proper comprises six enzymes. N-acetylglutamate synthase (NAGS) produces N-acetyl-L-glutamate (NAG), the obligate allosteric activator of carbamoyl phosphate synthetase 1 and therefore the regulatory gate of the whole pathway. Carbamoyl phosphate synthetase 1 (CPS1) condenses ammonia, bicarbonate and two ATP into carbamoyl phosphate in the matrix. Ornithine transcarbamylase (OTC) transfers the carbamoyl group to L-ornithine to give L-citrulline. Citrulline is exported to the cytosol in exchange for ornithine by the mitochondrial ornithine/citrulline carrier SLC25A15 (ORNT1). In the cytosol argininosuccinate synthase (ASS1) condenses citrulline with L-aspartate (the second nitrogen donor, supplied to the cytosol by the citrin aspartate/glutamate carrier SLC25A13) at the expense of ATP to form argininosuccinate; argininosuccinate lyase (ASL) cleaves this to L-arginine and fumarate; and arginase 1 (ARG1) hydrolyses arginine to urea and L-ornithine, regenerating the ornithine that re-enters mitochondria to close the cycle. The fumarate released by ASL links the urea cycle to the TCA cycle and, via aspartate regeneration, to the "aspartate-argininosuccinate shunt". Inherited deficiency of any of the six enzymes, of the two transporters (SLC25A15, SLC25A13), or of NAGS causes a urea cycle disorder presenting with hyperammonemia. The same enzyme chemistry, used biosynthetically rather than for nitrogen disposal, also produces arginine de novo (the arginine biosynthetic pathway) in tissues and organisms lacking a complete ureotelic cycle. |
Metabolic Pathway | DRAFT | 0 | urea cycle |
9 | 8 | 8 | 0 | 0 | 8 | 10/11 | 0 | ✗ | modules/urea_cycle.yaml | ||
Ureide pathway - nitrogen recovery from allantoin via urea to ammoniaMODULE:ureide_urea_catabolism The ureide pathway recovers the four nitrogen atoms of the purine ring as ammonium. In organisms that keep urate oxidase, urate made by purine... [more...][less]The ureide pathway recovers the four nitrogen atoms of the purine ring as ammonium. In organisms that keep urate oxidase, urate made by purine catabolism is oxidised to 5-hydroxyisourate, which 5-hydroxyisourate hydrolase and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline (OHCU) decarboxylase convert to (S)-allantoin. Organisms without these enzymes, such as budding yeasts, can import allantoin from outside and enter the pathway at this point. Allantoinase opens the hydantoin ring to give allantoate. The allantoate is then split along one of two chemical routes. In the first, allantoicase releases urea and (S)-ureidoglycolate, and ureidoglycolate lyase releases a second urea and glyoxylate. In the second, used by plants and many bacteria, allantoate amidohydrolase and ureidoglycine aminohydrolase release ammonium directly, and ureidoglycolate is either split by the lyase or fully hydrolysed by ureidoglycolate amidohydrolase without making urea. The urea is then broken down in one of two ways. Most fungi, plants and many bacteria use a nickel-dependent urease, which hydrolyses urea in one step. Saccharomycetes yeasts instead use urea amidolyase, a biotin-dependent enzyme with two domains: urea carboxylase makes allophanate from urea, bicarbonate and ATP, and allophanate hydrolase converts allophanate to ammonium and CO2. The glyoxylate carbon goes to the glyoxylate cycle. In fungi and animals the enzymes are soluble, and in some organisms the urate oxidase steps are peroxisomal; in plants the steps after allantoin take place in the endoplasmic reticulum. |
Metabolic Pathway | DRAFT | 0 | allantoin catabolic process urea catabolic process |
19 | 12 | 12 | 3 | 6 | 9 | 10/20 | 0 | ✗ | modules/ureide_urea_catabolism.yaml | ||
Usp12/46 deubiquitinase complex in Drosophila melanogasterMODULE:dmel_usp46_deubiquitinase_complexCONCRETE Usp12-46 is the single Drosophila ortholog of the human ubiquitin-specific proteases USP12 and USP46. As in humans, it forms a complex with two... [more...][less]Usp12-46 is the single Drosophila ortholog of the human ubiquitin-specific proteases USP12 and USP46. As in humans, it forms a complex with two WD40 proteins, Uaf1 (WDR48) and Wdr20, which bind the catalytic domain and stimulate its deubiquitinase activity. In Drosophila, Usp12-46 with Uaf1 and Wdr20 has been reported to deubiquitylate and stabilize signalling components, including the Notch receptor and Arrow in Wingless signalling. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | peptidase complex |
4 | 3 | 3 | 0 | 0 | 0 | 3/3 | 0 | ✗ | modules/dmel_usp46_deubiquitinase_complex.yaml | |
V-ATPase acidification of vacuoles and lysosomesMODULE:vacuolar_atpase_acidificationCONCRETE The vacuolar H+-ATPase (V-ATPase) acidifies the lumen of lysosomes, lytic vacuoles, endosomes and other organelles of the endomembrane system. It... [more...][less]The vacuolar H+-ATPase (V-ATPase) acidifies the lumen of lysosomes, lytic vacuoles, endosomes and other organelles of the endomembrane system. It is a rotary motor: ATP hydrolysis by the soluble V1 sector (subunits A, B, C, D, E, F, G, H) turns a central rotor that spins the membrane V0 proteolipid ring (c subunits, with a, d and e) past the a subunit, moving protons into the lumen. This module is the eukaryote-wide subunit set, written so that it can be evaluated in any genome. |
Biological Process | DRAFT | Eukaryota |
13 | vacuolar acidification proton-transporting V-type ATPase complex |
4 | 12 | 3 | 0 | 0 | 1 | 15/15 | 0 | ✗ | modules/vacuolar_atpase_acidification.yaml | |
VEGFR signaling pathway moduleMODULE:vegfr_signaling VEGF ligands activate endothelial VEGF receptor tyrosine kinases, coupling receptor phosphorylation to PLC-gamma, PI3K, and migration programs that... [more...][less]VEGF ligands activate endothelial VEGF receptor tyrosine kinases, coupling receptor phosphorylation to PLC-gamma, PI3K, and migration programs that drive vascular growth and permeability. |
Signaling Pathway | DRAFT | metazoa |
10 | vascular endothelial growth factor receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 4/6 | 0 | ✓ | modules/vegfr_signaling.yaml | |
VHL-Elongin B/C-Cul2 ubiquitin ligase in Drosophila melanogasterMODULE:dmel_vcb_ubiquitin_ligaseCONCRETE The VCB complex consists of the von Hippel-Lindau tumour suppressor protein (Vhl) bound to the adaptor heterodimer Elongin B and Elongin C.... [more...][less]The VCB complex consists of the von Hippel-Lindau tumour suppressor protein (Vhl) bound to the adaptor heterodimer Elongin B and Elongin C. Together with Cul2 and the RING protein Roc1a it forms a cullin-RING E3 ubiquitin ligase in which Vhl is the substrate receptor. Its best-known substrates are hypoxia-inducible factor alpha subunits (Sima in Drosophila) after prolyl hydroxylation in normoxia, so the ligase couples oxygen availability to HIF-alpha degradation. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | VCB complex Cul2-RING ubiquitin ligase complex |
4 | 3 | 3 | 0 | 0 | 1 | 5/5 | 0 | ✗ | modules/dmel_vcb_ubiquitin_ligase.yaml | |
Vacuolar H+-ATPase in Drosophila melanogasterMODULE:dmel_vacuolar_atpaseCONCRETE The vacuolar H+-ATPase (V-ATPase) is a rotary proton pump that acidifies lysosomes, endosomes, the Golgi and secretory vesicles, and in specialized... [more...][less]The vacuolar H+-ATPase (V-ATPase) is a rotary proton pump that acidifies lysosomes, endosomes, the Golgi and secretory vesicles, and in specialized epithelia such as the Malpighian tubules and midgut energizes the plasma membrane for transport. The cytosolic V1 domain hydrolyses ATP at three catalytic sites in an A3B3 hexamer, and the central rotor (subunits D, F and d) transmits rotation to a ring of proteolipid c subunits in the membrane V0 domain. The V0 a subunit provides the proton path together with the c ring, and peripheral stalks of E and G subunits, with C and H, hold the stator. Reversible dissociation of V1 from V0 regulates activity. In Drosophila many subunits are encoded by paralogous genes, some with tissue- or testis-restricted expression, and the accessory proteins Ac45 and ATP6AP2 associate with V0. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | proton-transporting V-type ATPase complex |
11 | 36 | 10 | 0 | 0 | 0 | 0/36 | 0 | ✗ | modules/dmel_vacuolar_atpase.yaml | |
Vacuolar sorting receptor cycle in plantsMODULE:plant_vacuolar_sorting_receptor_cycleCONCRETE Soluble hydrolases bound for the plant lytic vacuole carry sorting signals that vacuolar sorting receptors (VSRs) recognise at the trans-Golgi... [more...][less]Soluble hydrolases bound for the plant lytic vacuole carry sorting signals that vacuolar sorting receptors (VSRs) recognise at the trans-Golgi network and prevacuolar compartment. The receptor-cargo complex travels to the prevacuolar compartment, where cargo is released, and the retromer complex of Vps35, Vps26 and Vps29 returns the receptors for another round. This module is the green-lineage form of that cycle. |
Biological Process | DRAFT | Viridiplantae |
5 | protein targeting to vacuole retromer complex |
4 | 5 | 3 | 0 | 0 | 1 | 0/14 | 0 | ✗ | modules/plant_vacuolar_sorting_receptor_cycle.yaml | |
Valine and isoleucine distal catabolism (acyl-CoA dehydrogenase -> propionyl-CoA)MODULE:valine_isoleucine_distal_catabolism After the shared, mitochondrial branched-chain aminotransferase (BCAT2) and branched-chain alpha-ketoacid dehydrogenase (BCKDH) steps deaminate and... [more...][less]After the shared, mitochondrial branched-chain aminotransferase (BCAT2) and branched-chain alpha-ketoacid dehydrogenase (BCKDH) steps deaminate and oxidatively decarboxylate the three branched-chain amino acids to their acyl-CoA thioesters, valine and isoleucine follow their own distal degradation routes in the mitochondrial matrix that converge on propionyl-CoA. In the VALINE route, isobutyryl-CoA is dehydrogenated by isobutyryl-CoA dehydrogenase (ACAD8, an FAD enzyme feeding electrons to ETF) to methacrylyl-CoA; the crotonase ECHS1 (curated elsewhere) hydrates this to (S)-3-hydroxyisobutyryl-CoA, which the crotonase-superfamily hydrolase HIBCH deacylates to free 3-hydroxyisobutyrate + CoA (a step thought to detoxify the reactive methacrylyl-CoA). 3-Hydroxy- isobutyrate dehydrogenase (HIBADH, NAD+) then oxidises it to (S)-methylmalonate semialdehyde, and the CoA-acylating aldehyde dehydrogenase ALDH6A1 (methylmalonate-semialdehyde dehydrogenase) oxidatively decarboxylates that to propionyl-CoA. In the ISOLEUCINE route, 2-methylbutyryl-CoA is dehydrogenated by the short/branched-chain acyl-CoA dehydrogenase ACADSB (FAD -> ETF) to tiglyl-CoA; ECHS1 hydrates it, and HSD17B10 (the moonlighting SDR protein MRPP2/HADH2, in its 2-methyl-3-hydroxybutyryl-CoA dehydrogenase role, NAD+) oxidises 2-methyl-3-hydroxybutyryl-CoA to 2-methylacetoacetyl-CoA, which the thiolase ACAT1 (curated elsewhere) cleaves to propionyl-CoA + acetyl-CoA. The propionyl-CoA produced by both routes enters the propionyl-CoA -> methylmalonyl-CoA -> succinyl-CoA anaplerotic pathway (PCC/MUT). Inherited defects at each step cause distinct organic acidurias (ACAD8: isobutyryl-CoA dehydrogenase deficiency; ACADSB: 2-methylbutyryl-CoA dehydrogenase deficiency; HIBCH and ALDH6A1: valine-pathway neurometabolic disease; HSD17B10: X-linked MHBD deficiency, which also impairs the protein's separate mitochondrial RNase P role). |
Metabolic Pathway | DRAFT | 0 | L-valine catabolic process L-isoleucine catabolic process |
7 | 6 | 6 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/valine_isoleucine_distal_catabolism.yaml | ||
Variobactin and variochelin photoreactive lipopeptide siderophore biosynthesis and transportMODULE:variochelin_siderophore_biosynthesis_and_uptake A conserved hybrid polyketide synthase / nonribosomal peptide synthetase (PKS/NRPS) biosynthetic and iron-transport module (the var gene cluster)... [more...][less]A conserved hybrid polyketide synthase / nonribosomal peptide synthetase (PKS/NRPS) biosynthetic and iron-transport module (the var gene cluster) in soil and rhizosphere Variovorax species (exemplified by Variovorax paradoxus P4B GenBank KT362218 producing variobactin A/B, and Variovorax boronicumulans and Variovorax sp. H002 producing variochelins A-E). Downstream of the unreviewed starter NRPS Var3 (ALG65336.1, loading the N-acyl-arginine starter unit), the cytoplasmic hybrid PKS/NRPS/TauD megasynthase Var4 (VarG) extends the N-acyl-arginine starter with a malonate/methylmalonate ketide unit, reduces the beta-keto group, condenses the ketide-extended intermediate with the position-3 aspartate monomer loaded in trans on Var5 (ALG65340.1), and beta-hydroxylates that aspartate residue via its C-terminal TauD domain to install the photoreactive beta-hydroxyaspartate (Hya; reported as L-erythro-Hya for TauD-type hydroxylases in PMID:38590537, though L-threo-Hya was earlier reported for variochelin A in PMID:27023373) ligand; the bimodular NRPS Var6 elongates and epimerizes two internal peptide monomers (established as D-Ser and L-Pro in Variovorax sp. H002 variochelins in PMID:38590537, with Ser/Thr combinatorialization and amino-acid substitutions noted in V. paradoxus P4B variobactin A/B in PMID:26412281); and the terminal bimodular NRPS-thioesterase Var7 incorporates two C-terminal modified N-hydroxyornithine hydroxamate chelators (established as N-delta-acetyl-N-delta-hydroxy-L-ornithine in H002 variochelins and combinatorialized across N-formyl/N-acetyl/unmodified N-hydroxyornithine in P4B variobactin) and cleaves the mature lipopeptide siderophore. The inner-membrane SyrD-family type I ABC half-transporter Var14 exports the apo-siderophore across the cytoplasmic membrane. After extracellular Fe(III) chelation (and optional light-driven Fe(III)-to-Fe(II) photolysis), the outer-membrane TonB-dependent receptor Var8 imports ferric-variobactin/variochelin across the outer membrane, and following uptake into the cytoplasm, the FhuF-family ferric-siderophore reductase Var13 reduces complexed Fe(III) to release bioavailable Fe(II). |
Metabolic Pathway | DRAFT | 0 | siderophore biosynthetic process siderophore-iron import into cell |
7 | 9 | 6 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/variochelin_siderophore_biosynthesis_and_uptake.yaml | ||
Variovorax periplasmic D-gluconate production, intracellular iron trafficking, metalloregulatory repression, polyphosphate turnover, and heavy-metal cation efflux and signalingMODULE:variovorax_metallophore_metal_homeostasis A functional grouping of six metabolic, polyphosphate, and metal-homeostasis subsystems across the cell envelope and cytoplasm of Variovorax... [more...][less]A functional grouping of six metabolic, polyphosphate, and metal-homeostasis subsystems across the cell envelope and cytoplasm of Variovorax paradoxus: (1) periplasmic PQQ-dependent glucose dehydrogenase (Gcd) oxidation of D-glucose to D-glucono-1,5-lactone coupled to membrane ubiquinone reduction in the D-gluconate pathway; (2) cytosolic YggX-family Fe(2+)-trafficking protein (FetP) binding of ferrous iron for intracellular iron transactions and Fe-S cluster assembly/repair; (3) Fe(2+)- and Zn(2+)-responsive transcriptional repression of iron- and zinc-uptake operons under metal sufficiency by the Fur-family metalloregulators Fur1 and Zur; (4) cytoplasmic inorganic polyphosphate (polyP) polymerization by polyphosphate kinase 1 (Ppk) and hydrolytic depolymerization to orthophosphate by exopolyphosphatase (Ppx); (5) transmembrane export of heavy-metal cations by the tripartite CzcCBA HME-RND trans-envelope efflux complex (CzcA3 inner-membrane RND antiporter, CzcB periplasmic membrane-fusion adaptor, and CzcC outer-membrane factor channel), the inner-membrane CzcD cation diffusion facilitator (CDF) antiporter, and the inner-membrane P1B-type Zn(2+)/Cd(2+) and Cu(+) efflux ATPases CadA2 and CopA2; and (6) periplasmic heavy-metal modulation by CzcI and His-Asp phosphorelay transcriptional regulation of heavy-metal efflux by the CusS-CzcR two-component signaling system. |
Biological Process | DRAFT | 0 | intracellular iron ion homeostasis monoatomic cation transmembrane transport |
10 | 15 | 9 | 0 | 0 | 1 | 15/15 | 0 | ✗ | modules/variovorax_metallophore_metal_homeostasis.yaml | ||
Vasopressin receptor signaling — V1a/V1b Gq/11-phospholipase C coupling and the renal V2 Gs/ADCY6/cAMP/AKAP-anchored PKA pathway driving aquaporin-2 exocytosis and water reabsorptionMODULE:vasopressin_receptor_signalingCONCRETE Arginine vasopressin (AVP), a neurohypophyseal nonapeptide hormone, acts through three G protein-coupled receptors that fall into two signalling... [more...][less]Arginine vasopressin (AVP), a neurohypophyseal nonapeptide hormone, acts through three G protein-coupled receptors that fall into two signalling classes. The V1a receptor (AVPR1A; vascular smooth muscle, liver, platelets, brain) and the V1b receptor (AVPR1B; anterior pituitary corticotrophs) couple to the Gq/11 alpha subunits GNAQ and GNA11, stimulating phospholipase C beta, inositol trisphosphate-driven calcium release and diacylglycerol/PKC signalling, which underlie vasoconstriction and pituitary ACTH release. The V2 receptor (AVPR2), on the basolateral membrane of renal collecting-duct principal cells, couples to the stimulatory G alpha subunit GNAS, which activates adenylyl cyclase type 6 (ADCY6), the dominant inner-medullary cyclase. cAMP activates protein kinase A, which is tethered to intracellular aquaporin-2 (AQP2)-bearing vesicles by the A-kinase anchoring protein AKAP18 (AKAP7) together with the cAMP phosphodiesterase PDE4D. PKA phosphorylates AQP2 at serine 256, which is required for the regulated exocytosis of AQP2 vesicles. The vesicles move through a RAB11A-positive recycling compartment with the motor myosin Vb (MYO5B) and its Rab11 adaptor RAB11FIP2, the Rap1 GTPase-activating protein SPA-1 (SIPA1) binds AQP2 and is required for its apical delivery, and the R-SNARE VAMP2 on the vesicle fuses with the apical Q-SNAREs SNAP23 and syntaxin-3 (or syntaxin-4). AQP2 water channels in the apical membrane then let water follow the osmotic gradient out of the tubular lumen, concentrating the urine. PKA also phosphorylates and activates PDE4D on the same vesicles, providing local negative feedback, and PKA-phosphorylated CREB drives AQP2 transcription. Loss-of-function mutations in AVPR2 or AQP2 cause nephrogenic diabetes insipidus. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cellular response to vasopressin |
19 | 20 | 12 | 3 | 6 | 10 | 6/21 | 0 | ✗ | modules/vasopressin_receptor_signaling.yaml | |
Vertebrate Wnt/planar cell polarity (PCP) signalling - Wnt5a/Wnt11, ROR2/PTK7, core PCP complexes and Rho/Rac effector armsMODULE:wnt_planar_cell_polarityCONCRETE Planar cell polarity (PCP) orients cells within the plane of a tissue. It is needed for convergent extension during gastrulation, neural tube... [more...][less]Planar cell polarity (PCP) orients cells within the plane of a tissue. It is needed for convergent extension during gastrulation, neural tube closure, orientation of inner-ear hair-cell bundles and hair follicles, and limb elongation. In vertebrates the system is set up by Wnt ligands, chiefly Wnt5a and Wnt11, which do not stabilize beta-catenin in most contexts. They act through Frizzled receptors with the ROR2 and PTK7 co-receptors and induce dose-dependent phosphorylation of the four-pass membrane protein VANGL2. The core PCP proteins form two mutually exclusive membrane complexes at opposite sides of each cell. One is Frizzled with Dishevelled, recruited through its DEP domain to the Frizzled tail. The other is VANGL with Prickle, which binds Dishevelled and antagonizes its recruitment by Frizzled. The atypical cadherin CELSR1 forms homophilic bridges between neighbouring cells and recruits both sides to the junction. Dishevelled drives two effector arms: the formin DAAM1 links it to RhoA and Rho kinase for actomyosin contractility, and Rac1 activates JNK. Together they turn polarity cues into oriented cytoskeletal behaviour and cell movement. The pathway works independently of the beta-catenin destruction complex and TCF/LEF transcription. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | establishment of planar polarity non-canonical Wnt signaling pathway |
14 | 13 | 9 | 2 | 4 | 10 | 5/16 | 0 | ✗ | modules/wnt_planar_cell_polarity.yaml | |
Viral factory (virus-induced replication microcompartment)MODULE:viral_factoryABSTRACT A viral factory (VF) is a virus-induced intracellular microcompartment that concentrates the viral genome, the replication and transcription... [more...][less]A viral factory (VF) is a virus-induced intracellular microcompartment that concentrates the viral genome, the replication and transcription machinery, and the structural proteins of the progeny virion into one place, raising the local concentration of every reactant in the replication cycle while screening replication intermediates from host nucleic-acid sensors and nucleases. The module is deliberately mechanism-neutral at its core and taxon-spanning: what makes a VF a VF is the compartment boundary plus the co-localised replication, transcription, and assembly programme, not any one way of drawing the boundary. Three boundary mechanisms are modelled as variants along a single axis - a host-membrane-derived boundary (spherules, tubes, double-membrane vesicles, convoluted ER), a membraneless biomolecular condensate formed by liquid-liquid phase separation, and a self-assembled proteinaceous shell - because the same downstream programme runs inside all three. Around that core the module places the recruitment of host systems the factory depends on (cytoskeleton, mitochondria, donor membranes, host lipid kinases, in some lineages host transcription machinery), the shielding of replication intermediates from host defences, non-lytic egress, and the antagonists that act on the factory itself. |
Organelle Lifecycle | DRAFT | Viruses |
0 | viral factory viral replication complex formation and maintenance viral replication complex |
26 | 32 | 8 | 6 | 17 | 7 | 2/26 | 0 | ✗ | modules/viral_factory.yaml | |
Visual phototransduction — opsin, transducin, PDE6 and CNG-channel activation cascade in rods and cones, with GRK/arrestin, RGS9 and GCAP/retGC recovery; RHO/OPN1SW/OPN1MW/OPN1LW/GNAT1/GNAT2/PDE6/CNGA1/CNGA3/SLC24A1/GRK1/SAG/RGS9/GUCY2DMODULE:visual_phototransductionCONCRETE Vertebrate visual phototransduction converts the absorption of a photon by a visual pigment in the outer segment of a rod or cone photoreceptor... [more...][less]Vertebrate visual phototransduction converts the absorption of a photon by a visual pigment in the outer segment of a rod or cone photoreceptor into a hyperpolarisation of the photoreceptor plasma membrane. The visual pigment is an opsin, a G protein-coupled receptor that carries covalently bound 11-cis-retinal: rhodopsin (RHO) in rods, and the short-, medium- and long-wavelength cone opsins (OPN1SW, OPN1MW, OPN1LW) in the three classes of human cone. Photoisomerisation of the chromophore to all-trans-retinal activates the opsin, which catalyses GDP/GTP exchange on many molecules of the photoreceptor G protein transducin (rod GNAT1 with GNB1 and GNGT1; cone GNAT2 with GNB3 and GNGT2). GTP-bound transducin alpha binds the inhibitory gamma subunits of the cGMP phosphodiesterase PDE6 (rod PDE6A/PDE6B catalytic heterodimer with PDE6G; cone PDE6C homodimer with PDE6H) and relieves their inhibition. Activated PDE6 hydrolyses cGMP. The fall in cytoplasmic cGMP closes the cGMP-gated cation (CNG) channels of the outer-segment plasma membrane (rod CNGA1/CNGB1; cone CNGA3/CNGB3) that carry the inward dark current, and the cell hyperpolarises. Because the potassium-dependent sodium/calcium exchanger of the outer segment (rod SLC24A1, cone SLC24A2) continues to extrude Ca2+ while the channels are closed, cytoplasmic Ca2+ falls. Recovery has three arms. The opsin is phosphorylated by rhodopsin kinase (GRK1 in rods; GRK1 and GRK7 in human cones) and then capped by arrestin (rod arrestin SAG, cone arrestin ARR3), which blocks further transducin activation; Ca2+-bound recoverin (RCVRN) inhibits rhodopsin kinase in darkness, so the fall in Ca2+ speeds opsin shut-off. Transducin is switched off by its own GTPase, accelerated by a GTPase-activating complex of RGS9-1, the long isoform of GNB5 and the membrane anchor RGS9BP (R9AP). cGMP is resynthesised by the membrane retinal guanylate cyclases (GUCY2D/RetGC1 and GUCY2F/RetGC2), which are stimulated by the Ca2+-free form of the guanylate cyclase-activating proteins GCAP1 (GUCA1A) and GCAP2 (GUCA1B); the light-induced fall in Ca2+ thus drives cGMP resynthesis and channel reopening. The chromophore released by bleaching is regenerated by the separate retinoid visual cycle. Loss-of-function variants across the cascade cause inherited retinal disease, including achromatopsia (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H), retinitis pigmentosa (RHO, PDE6A, PDE6B, CNGA1, CNGB1), congenital stationary night blindness (RHO, GNAT1, SAG and GRK1 in Oguchi disease, SLC24A1), bradyopsia (RGS9, RGS9BP) and GUCY2D Leber congenital amaurosis. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | transducin-mediated opsin signaling pathway |
29 | 22 | 11 | 8 | 17 | 15 | 8/33 | 0 | ✗ | modules/visual_phototransduction.yaml | |
Vitamin B6 (pyridoxal 5'-phosphate) supply by PdxS/PdxT synthesis or vitamer salvage, and PLP homeostasisMODULE:vitamin_b6_plp_metabolism Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the cofactor of a large set of enzymes, including transaminases, decarboxylases... [more...][less]Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the cofactor of a large set of enzymes, including transaminases, decarboxylases and racemases of amino-acid, one-carbon, heme and neurotransmitter metabolism. Cells obtain PLP in two ways. Fungi, plants, archaea and many bacteria can make PLP de novo with the two-subunit PLP synthase: the PdxT (SNO) subunit hydrolyses glutamine and passes the ammonia to the PdxS (SNZ/PDX1) subunit, which builds PLP directly from ribose 5-phosphate and glyceraldehyde 3-phosphate. This route does not use deoxyxylulose 5-phosphate; the separate DXP-dependent route of some bacteria is described in modules/pyridoxal_5_phosphate_biosynthesis.yaml. All cells can also salvage the B6 vitamers. Pyridoxal kinase (PDXK; BUD16 in budding yeast) phosphorylates pyridoxal, pyridoxine and pyridoxamine with ATP to PLP, pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP), and the FMN-dependent PNP/PMP oxidase (PNPO; PDX3 in yeast) oxidises PNP and PMP to PLP. Animals cannot make PLP de novo and depend on salvage of dietary vitamers. In mammals, PLP levels are also tuned by the magnesium-dependent pyridoxal phosphatase PDXP (chronophin), which dephosphorylates PLP back to pyridoxal and also dephosphorylates the actin regulator cofilin. Inherited PNPO deficiency causes a PLP-responsive neonatal epileptic encephalopathy. |
Metabolic Pathway | DRAFT | 2 | pyridoxal 5'-phosphate biosynthetic process pyridoxal 5'-phosphate salvage vitamin B6 metabolic process |
7 | 5 | 4 | 1 | 2 | 2 | 12/14 | 0 | ✗ | modules/vitamin_b6_plp_metabolism.yaml | ||
Vitamin D activation and VDR signalling — CYP2R1 25-hydroxylation, CYP27B1 1-alpha-hydroxylation, VDR/RXR genomic actionMODULE:vitamin_d_activation_signaling Vitamin D (cholecalciferol from skin or diet, or ergocalciferol) is a prohormone that must be hydroxylated twice before it can act. A microsomal... [more...][less]Vitamin D (cholecalciferol from skin or diet, or ergocalciferol) is a prohormone that must be hydroxylated twice before it can act. A microsomal cytochrome P450 25-hydroxylase, principally CYP2R1 in the liver, converts vitamin D to 25-hydroxyvitamin D (calcidiol), the abundant circulating storage form. The mitochondrial cytochrome P450 CYP27B1, whose renal proximal-tubule expression is induced by PTH and suppressed by calcitriol and FGF23, then performs the rate-limiting 1-alpha-hydroxylation to 1-alpha,25-dihydroxyvitamin D (calcitriol). Calcitriol binds the nuclear vitamin D receptor (VDR), which heterodimerises with RXR on vitamin D response elements and recruits coactivators to regulate target genes driving intestinal calcium and phosphate absorption, skeletal mineralization and feedback on vitamin D metabolism: liganded VDR represses CYP27B1 and induces the 24-hydroxylase CYP24A1, which inactivates both calcidiol and calcitriol. Loss of each step causes a vitamin D-dependent rickets: CYP2R1 (VDDR1B, low 25-hydroxyvitamin D), CYP27B1 (VDDR1A, low calcitriol) and VDR (VDDR2A, hereditary 1,25-dihydroxyvitamin D-resistant rickets with high calcitriol). |
Biological Process | DRAFT | 0 | vitamin D3 biosynthetic process vitamin D receptor signaling pathway |
4 | 3 | 3 | 0 | 0 | 3 | 3/3 | 0 | ✗ | modules/vitamin_d_activation_signaling.yaml | ||
WASH complex in Drosophila melanogasterMODULE:dmel_wash_complexCONCRETE The WASH complex is a five-subunit regulatory complex on endosomes that activates the Arp2/3 complex to build branched actin patches on endosomal... [more...][less]The WASH complex is a five-subunit regulatory complex on endosomes that activates the Arp2/3 complex to build branched actin patches on endosomal membranes. These patches help sort cargo into recycling tubules in cooperation with retromer. The subunits are WASH (wash), FAM21, CCDC53, SWIP and Strumpellin (Strump). WASH carries the C-terminal VCA domain that activates Arp2/3, and FAM21 links the complex to retromer and to capping protein. Drosophila wash mutant hemocytes are defective in lysosomal neutralization. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | WASH complex Arp2/3 complex-mediated actin nucleation |
6 | 5 | 5 | 0 | 0 | 0 | 5/5 | 0 | ✗ | modules/dmel_wash_complex.yaml | |
WAVE regulatory complex (SCAR complex) in Drosophila melanogasterMODULE:dmel_wave_regulatory_complexCONCRETE The WAVE regulatory complex (WRC) is a five-subunit complex that holds the Arp2/3 activator SCAR (WAVE) in an inactive state until it is recruited... [more...][less]The WAVE regulatory complex (WRC) is a five-subunit complex that holds the Arp2/3 activator SCAR (WAVE) in an inactive state until it is recruited and activated at the plasma membrane, mainly by the small GTPase Rac. It is built from two subcomplexes: a Cyfip (Sra1)-Hem (Nap1) dimer and a trimer of SCAR, Abi and HSPC300. Once activated, the C-terminal VCA region of SCAR binds actin and the Arp2/3 complex and stimulates branched actin nucleation. In Drosophila the WRC is needed for lamellipodia formation, axon growth, myoblast fusion and egg chamber development, and loss of one subunit destabilizes the others. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | SCAR complex |
3 | 2 | 2 | 0 | 0 | 1 | 5/5 | 0 | ✗ | modules/dmel_wave_regulatory_complex.yaml | |
Wnt-TCF (canonical Wingless) signaling in Drosophila melanogasterMODULE:dmel_wnt_tcf_signalingCONCRETE In canonical Wnt signaling, secreted Wnt proteins, chiefly Wingless, bind Frizzled receptors and the LRP5/6 co-receptor Arrow. Wnt secretion... [more...][less]In canonical Wnt signaling, secreted Wnt proteins, chiefly Wingless, bind Frizzled receptors and the LRP5/6 co-receptor Arrow. Wnt secretion requires palmitoleoylation by Porcupine and transport by Wntless. In the absence of ligand, a destruction complex of Axin, Adenomatous polyposis coli (Apc or Apc2), Casein kinase I alpha and Shaggy (GSK3) phosphorylates Armadillo (beta-catenin) and targets it for degradation. Ligand engagement recruits Dishevelled and Axin to the receptor, inhibiting the destruction complex, so that Armadillo accumulates, enters the nucleus and joins Pangolin (TCF), Legless (BCL9), Pygopus, Chip and Ssdp in a Wnt enhanceosome that activates Wingless target genes. The pathway patterns the embryonic segments, the wing, and many other tissues. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | canonical Wnt signaling pathway |
9 | 13 | 6 | 1 | 2 | 5 | 2/21 | 0 | ✗ | modules/dmel_wnt_tcf_signaling.yaml | |
Wood-Ljungdahl (reductive acetyl-CoA) pathwayMODULE:wood_ljungdahl_pathwayABSTRACT The reductive acetyl-CoA pathway, by which acetogenic bacteria and methanogenic and acetoclastic archaea fix two molecules of CO2 into the two... [more...][less]The reductive acetyl-CoA pathway, by which acetogenic bacteria and methanogenic and acetoclastic archaea fix two molecules of CO2 into the two carbons of acetyl-CoA. It is the only carbon-fixation route that is linear rather than cyclic, and the only one that conserves energy as it fixes carbon. Two branches converge on one active site: the methyl branch reduces CO2 to formate and carries it through tetrahydrofolate-bound C1 intermediates down to a methyl group, which is handed to a corrinoid iron-sulfur protein; the carbonyl branch reduces a second CO2 to enzyme-bound carbon monoxide. Acetyl-CoA synthase then condenses the methyl group, the carbonyl and coenzyme A. The pathway runs on low-potential ferredoxin, is irreversibly oxygen-sensitive at the nickel-iron-sulfur A-cluster, and is widely held to be among the most ancient metabolisms. It is a sibling of the other non-Calvin fixation routes (MODULE:reductive_tca_cycle, MODULE:hydroxypropionate_bicycle) and of MODULE:calvin_benson_bassham_cycle; unlike those, it references none of them, because its product is acetyl-CoA directly. |
Metabolic Pathway | DRAFT | 0 | carbon fixation by acetyl-CoA pathway carbon fixation |
6 | 8 | 5 | 0 | 0 | 4 | 1/9 | 0 | ✗ | modules/wood_ljungdahl_pathway.yaml | ||
Wzy-dependent O-antigen chain-length controlMODULE:wzy_dependent_o_antigen_chain_length_controlCONCRETE A structural regulation module for Wzy-dependent O-antigen biosynthesis in which the inner-membrane Wzz-family polysaccharide co-polymerase FepE... [more...][less]A structural regulation module for Wzy-dependent O-antigen biosynthesis in which the inner-membrane Wzz-family polysaccharide co-polymerase FepE controls very-long modal O-antigen chain length. FepE is a PCP-1 family scaffold/regulator of Wzy polymerase processivity and is not a protein kinase or ferric enterobactin transporter. |
Biological Process | DRAFT | bacteria |
0 | O antigen biosynthetic process |
1 | 1 | 0 | 0 | 0 | 0 | 1/1 | 0 | ✗ | modules/wzy_dependent_o_antigen_chain_length_control.yaml | |
YrhB ATP-independent chaperone-like refoldingMODULE:yrhb_chaperone_like_refoldingCONCRETE A draft single-protein module for the small E. coli YrhB protein, which has been reported to prevent heat-induced PurK aggregation and support... [more...][less]A draft single-protein module for the small E. coli YrhB protein, which has been reported to prevent heat-induced PurK aggregation and support refolding of a model client without ATP. The purified K-12 and BL21(DE3) proteins are identical, but the physiological client set and whether this is a native chaperone function rather than an overexpression-associated moonlighting behavior remain unresolved. |
Biological Process | DRAFT | Escherichia coli |
0 | protein folding chaperone |
1 | 1 | 0 | 0 | 0 | 0 | 1/1 | 0 | ✗ | modules/yrhb_chaperone_like_refolding.yaml | |
ZIP-2/CEBP-2 translation-surveillance immunity in Caenorhabditis elegansMODULE:c_elegans_translation_surveillance_immunityCONCRETE Caenorhabditis elegans can detect a pathogen by the damage it does to a core host process instead of by recognizing a microbial molecule. The best... [more...][less]Caenorhabditis elegans can detect a pathogen by the damage it does to a core host process instead of by recognizing a microbial molecule. The best defined case is translation surveillance in the intestine. Pseudomonas aeruginosa Exotoxin A (ToxA) is endocytosed and ADP-ribosylates elongation factor 2, which inhibits host mRNA translation. Chemical translation inhibitors such as cycloheximide, and loss of other core host functions, trigger the same response. Enzymatically inactive ToxA does not. So the host senses the block in translation, not the toxin itself. Translation inhibition raises the level of the bZIP transcription factor ZIP-2 through a conserved upstream open reading frame (uORF) in the zip-2 mRNA. This fits a model in which a general fall in translation derepresses ZIP-2 synthesis. ZIP-2 acts with the C/EBP-gamma ortholog CEBP-2, a bZIP partner that binds it, to induce a set of intestinal infection-response genes. These include irg-1 and irg-2, which are induced independently of the PMK-1 p38 MAPK, DBL-1 TGF-beta and KGB-1 JNK pathways. zip-2 and cebp-2 mutants are more susceptible to P. aeruginosa and to ToxA. The molecular functions of the IRG-1 and IRG-2 proteins are unknown. Mitochondrial surveillance through ATFS-1 and the mitochondrial UPR is a parallel, separately regulated surveillance pathway. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | antibacterial innate immune response defense response to Gram-negative bacterium |
4 | 5 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/c_elegans_translation_surveillance_immunity.yaml | |
cAMP/PKA signal transduction — adenylyl cyclase cAMP production, PKA holoenzyme activation, AKAP anchoring and PDE termination; ADCY1-10, PRKAR1A/1B/2A/2B, PRKACA/B/G, AKAP1/5/6/7/10/12, EZR, PDE1-4/7/8/10/11MODULE:camp_pka_signal_transductionCONCRETE The cAMP/PKA cassette is the intracellular core shared by every Gs-coupled receptor and by bicarbonate/calcium sensing through soluble adenylyl... [more...][less]The cAMP/PKA cassette is the intracellular core shared by every Gs-coupled receptor and by bicarbonate/calcium sensing through soluble adenylyl cyclase. Cyclic AMP is made from ATP by ten mammalian adenylyl cyclases. Nine (ADCY1-9) are polytopic plasma-membrane enzymes whose two cytoplasmic catalytic domains form the active site; they are stimulated by GTP-bound G alpha s and are grouped by how other inputs regulate them: calcium/calmodulin stimulates ADCY1, ADCY3 and ADCY8; G beta gamma conditionally stimulates ADCY2, ADCY4 and ADCY7; G alpha i and calcium inhibit ADCY5 and ADCY6; ADCY9 is insensitive to forskolin. The tenth, ADCY10 (soluble adenylyl cyclase), has no membrane spans, is not regulated by heterotrimeric G proteins and is activated by bicarbonate and calcium. cAMP acts mainly through cAMP-dependent protein kinase (PKA). The inactive PKA holoenzyme is a tetramer of a regulatory-subunit dimer (type I, RIalpha/RIbeta, PRKAR1A/PRKAR1B; or type II, RIIalpha/RIIbeta, PRKAR2A/PRKAR2B) holding two catalytic subunits (Calpha, Cbeta, Cgamma; PRKACA, PRKACB, PRKACG) with a pseudosubstrate or substrate-like inhibitory segment in each active site. Each regulatory subunit has two cAMP-binding domains, and type I binds cAMP with higher affinity than type II. Binding of four cAMP molecules releases the catalytic subunits, which phosphorylate serine and threonine residues in R-R-X-S/T motifs of cytoplasmic and nuclear substrates. Where in the cell this happens is set by A-kinase anchoring proteins (AKAPs), which bind the docking/dimerisation domain of the regulatory dimer through an amphipathic helix, mostly that of type II PKA, and assemble PKA with substrates, phosphatases, phosphodiesterases and sometimes adenylyl cyclases at the plasma membrane, mitochondria, the perinuclear membrane and other sites. The signal is ended by cyclic-nucleotide phosphodiesterases (PDEs), the only enzymes that hydrolyse cAMP to 5'-AMP. PDE4, PDE7 and PDE8 are cAMP-specific, whereas PDE1, PDE2, PDE3, PDE10 and PDE11 hydrolyse both cAMP and cGMP and are regulated by calcium/calmodulin (PDE1) or by cGMP (stimulation of PDE2, inhibition of PDE3). PDEs tethered to AKAP complexes shape local cAMP microdomains, and PKA phosphorylation of some PDE4 isoforms provides negative feedback. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | cAMP/PKA signal transduction |
23 | 25 | 6 | 5 | 16 | 6 | 3/40 | 0 | ✗ | modules/camp_pka_signal_transduction.yaml | |
cGAS-STING nucleic-acid sensing signaling pathway moduleMODULE:cgas_sting_signaling A cGAS or cGAS-like receptor detects cytosolic nucleic acid and synthesises a cyclic-dinucleotide second messenger that activates the ER adaptor... [more...][less]A cGAS or cGAS-like receptor detects cytosolic nucleic acid and synthesises a cyclic-dinucleotide second messenger that activates the ER adaptor STING; activated STING traffics to the ERGIC/Golgi and engages TBK1-family kinase signalling, which drives an innate immune transcriptional output. In vertebrates cGAS senses double-stranded DNA and the output is IRF3-dependent type I interferon; in Drosophila cGLR1 senses double-stranded RNA and the output is the NF-kappaB factor Relish. |
Signaling Pathway | DRAFT | Drosophila melanogaster metazoa vertebrates |
2 | cGAS/STING signaling pathway |
9 | 8 | 4 | 2 | 4 | 3 | 10/15 | 0 | ✗ | modules/cgas_sting_signaling.yaml | |
cGAS-STING signaling pathway in Drosophila melanogasterMODULE:dmel_cgas_sting_signalingCONCRETE Drosophila has two cGAS-like receptors, cGlr1 and cGlr2, that sense infection-associated nucleic acids and synthesize cyclic GMP-AMP dinucleotides.... [more...][less]Drosophila has two cGAS-like receptors, cGlr1 and cGlr2, that sense infection-associated nucleic acids and synthesize cyclic GMP-AMP dinucleotides. cGlr1 is activated by double-stranded RNA and produces 3',2'-cGAMP. The cyclic dinucleotides bind Sting, which signals through the IKK kinases to activate the NF-kappa-B family transcription factor Relish. Relish then induces Sting-regulated genes that restrict RNA virus infection. |
Signaling Pathway | DRAFT | Drosophila melanogaster |
0 | cGAS/STING signaling pathway |
5 | 6 | 4 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/dmel_cgas_sting_signaling.yaml | |
cGMP-dependent sensory transduction in Caenorhabditis elegans ciliated neuronsMODULE:c_elegans_cgmp_sensory_transductionCONCRETE Many Caenorhabditis elegans sensory neurons turn an environmental stimulus into an electrical signal through the second messenger cGMP. A guanylyl... [more...][less]Many Caenorhabditis elegans sensory neurons turn an environmental stimulus into an electrical signal through the second messenger cGMP. A guanylyl cyclase in or near the sensory cilium makes cGMP. The cGMP then opens a cyclic nucleotide-gated (CNG) cation channel made of the pore-forming alpha subunit TAX-4 and the modulatory beta subunit TAX-2. The resulting cation and Ca2+ influx changes the activity of the neuron. The channel is the same in different neurons, but the cyclase differs with the stimulus. In the AWC olfactory neurons, odorant receptors act through the stimulatory Galpha ODR-3, and the transmembrane guanylyl cyclases ODR-1 and DAF-11 act downstream and are required for responses to AWC-sensed odors. In the AFD thermosensory neurons, the receptor guanylyl cyclases GCY-8, GCY-18 and GCY-23 sit in the microvilli of the sensory ending and together are required for temperature-evoked currents. GCY-8 is the one needed to carry out isothermal tracking, GCY-18 is the main cyclase at 20-25 C, and GCY-23 is modulatory; all three help set the temperature range of tracking. In the URX and BAG gas-sensing neurons, heme-containing soluble guanylyl cyclases are both the cyclase and the O2 sensor: GCY-35/GCY-36 respond to rises in O2 and GCY-31/GCY-33 to falls. tax-4 and tax-2 are expressed in the thermosensory, gustatory and olfactory neurons. tax-4 mutants fail to respond to temperature and to soluble or volatile attractants, and they are defective in oxygen responses. A separate set of C. elegans sensory neurons, including AWA and ASH, uses OSM-9/OCR-2 TRPV channels instead of this cGMP-CNG pathway. |
Signaling Pathway | DRAFT | Caenorhabditis elegans |
0 | detection of stimulus involved in sensory perception |
6 | 12 | 2 | 1 | 3 | 3 | 12/12 | 0 | ✗ | modules/c_elegans_cgmp_sensory_transduction.yaml | |
dTDP-L-rhamnose biosynthesisMODULE:dtdp_l_rhamnose_biosynthesisCONCRETE Species-neutral bacterial module for synthesis of the activated sugar dTDP-L-rhamnose from alpha-D-glucose 1-phosphate. The pathway proceeds... [more...][less]Species-neutral bacterial module for synthesis of the activated sugar dTDP-L-rhamnose from alpha-D-glucose 1-phosphate. The pathway proceeds through dTDP-glucose formation, dTDP-glucose 4,6-dehydration, dTDP-4-dehydrorhamnose 3,5-epimerization, and final NADPH-dependent reduction to dTDP-L-rhamnose. The module represents the soluble nucleotide-sugar supply pathway and treats downstream O-antigen, LPS, and specialized-polysaccharide assembly reactions as consumers, not as part of the biosynthetic module itself. |
Metabolic Pathway | COMPLETE | bacteria |
4 | dTDP-rhamnose biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 9/9 | 0 | ✓ | modules/dtdp_l_rhamnose_biosynthesis.yaml | |
eIF4E-Cup translational repressor complex in Drosophila melanogasterMODULE:dmel_eif4e_cup_complexCONCRETE Cup is an ovary-enriched eIF4E-binding protein that represses translation of specific maternal mRNAs during oogenesis. Cup binds the cap-binding... [more...][less]Cup is an ovary-enriched eIF4E-binding protein that represses translation of specific maternal mRNAs during oogenesis. Cup binds the cap-binding factor eIF4E1 through a motif resembling that of eIF4G, so that eIF4E1 bound to the mRNA cap cannot recruit eIF4G and the ribosome. Cup is recruited to target mRNAs such as oskar and nanos by sequence-specific RNA-binding repressors (Bruno and Smaug), so that these mRNAs stay silent until they are localized in the oocyte. Cup is also required for eIF4E localization to the oocyte. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | eif4e-cup complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_eif4e_cup_complex.yaml | |
eRF1-eRF3 translation termination complex in Drosophila melanogasterMODULE:dmel_erf1_erf3_termination_complexCONCRETE Eukaryotic translation termination is carried out by the release factors eRF1 and eRF3. eRF1 recognizes all three stop codons in the ribosomal A... [more...][less]Eukaryotic translation termination is carried out by the release factors eRF1 and eRF3. eRF1 recognizes all three stop codons in the ribosomal A site and triggers hydrolysis of the peptidyl-tRNA bond through its conserved GGQ motif. eRF3 is a translational GTPase that delivers eRF1 to the ribosome as a ternary complex with GTP; GTP hydrolysis by eRF3 accommodates eRF1 and accelerates peptide release. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | translation release factor complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_erf1_erf3_termination_complex.yaml | |
mRNA 3' end cleavage and polyadenylation machinery in Drosophila melanogasterMODULE:dmel_cleavage_polyadenylationCONCRETE Most eukaryotic mRNAs acquire their 3' end by endonucleolytic cleavage of the pre-mRNA followed by addition of a poly(A) tail. The cleavage and... [more...][less]Most eukaryotic mRNAs acquire their 3' end by endonucleolytic cleavage of the pre-mRNA followed by addition of a poly(A) tail. The cleavage and polyadenylation specificity factor (CPSF) recognizes the AAUAAA polyadenylation signal through Cpsf160, Wdr33 and Clp (CPSF30), and Fip1 recruits poly(A) polymerase. The cleavage stimulation factor (CstF; CstF50, CstF64 and Su(f), the CstF77 homolog) binds GU-rich sequences downstream of the cleavage site. The core cleavage complex of Cpsf73, Cpsf100 and the scaffold Symplekin (Sym) carries out cleavage, with Cpsf73 as the endonuclease. Cpsf73, Cpsf100 and Sym are shared with the histone pre-mRNA processing machinery. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | mRNA cleavage and polyadenylation specificity factor complex |
4 | 3 | 3 | 0 | 0 | 0 | 0/10 | 0 | ✗ | modules/dmel_cleavage_polyadenylation.yaml | |
mRNA m6A methyltransferase complex in Drosophila melanogasterMODULE:dmel_m6a_methyltransferase_complexCONCRETE N6-methyladenosine (m6A) is deposited on mRNA co-transcriptionally by a methyltransferase complex. Its catalytic core is the Mettl3-Mettl14... [more...][less]N6-methyladenosine (m6A) is deposited on mRNA co-transcriptionally by a methyltransferase complex. Its catalytic core is the Mettl3-Mettl14 heterodimer, in which Mettl3 is the active methyltransferase and Mettl14 an inactive partner that supports RNA binding. A regulatory subcomplex (MACOM) of Fl(2)d, Virilizer (vir), the E3 ligase Hakai, Flacc and the RNA-binding protein Spenito (nito) is required for m6A deposition and specificity. In Drosophila, m6A modification by this complex regulates Sex-lethal pre-mRNA splicing in sex determination and contributes to neuronal function. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | RNA N6-methyladenosine methyltransferase complex |
3 | 2 | 2 | 0 | 0 | 0 | 0/7 | 0 | ✗ | modules/dmel_m6a_methyltransferase_complex.yaml | |
mRNA nuclear export machinery in Drosophila melanogasterMODULE:dmel_mrna_nuclear_exportCONCRETE Bulk export of mRNA from the nucleus is coupled to transcription and processing. The TREX complex, consisting of the THO subcomplex with the... [more...][less]Bulk export of mRNA from the nucleus is coupled to transcription and processing. The TREX complex, consisting of the THO subcomplex with the DEAD-box helicase Hel25E (UAP56) and the adaptor Ref1 (ALY), is loaded onto nascent mRNA and hands it to the export receptor heterodimer formed by sbr (NXF1) and Nxt1, which carries the mRNP through the nuclear pore complex by interacting with FG-repeat nucleoporins. TREX-2 (xmas, PCID2 and e(y)2) associates with the nuclear pore and couples transcription with export; in Drosophila it links actively transcribed genes to the nuclear periphery and shares e(y)2 with the SAGA deubiquitinase module. |
Biological Process | DRAFT | Drosophila melanogaster |
0 | mRNA export from nucleus |
4 | 3 | 3 | 0 | 0 | 1 | 0/13 | 0 | ✗ | modules/dmel_mrna_nuclear_export.yaml | |
myo-Inositol and inositol (pyro)phosphate biosynthesis (MIPS/IMPase and the PLC-IPMK-IPK1-IP6K-PPIP5K route)MODULE:myo_inositol_and_inositol_phosphate_biosynthesisCONCRETE myo-Inositol is made de novo from glucose 6-phosphate in two cytosolic steps: myo-inositol-3-phosphate synthase (MIPS), an NAD+-dependent... [more...][less]myo-Inositol is made de novo from glucose 6-phosphate in two cytosolic steps: myo-inositol-3-phosphate synthase (MIPS), an NAD+-dependent isomerase, cyclises glucose 6-phosphate to 1D-myo-inositol 3-phosphate, and a lithium-sensitive inositol monophosphatase (IMPase) removes the phosphate to release free myo-inositol. Free inositol is used to make phosphatidylinositol and, through the phosphoinositides, the higher soluble inositol phosphates. In the lipid-dependent route, phospholipase C cleaves phosphatidylinositol 4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate (IP3). An inositol polyphosphate multikinase (IPMK; yeast Arg82/Ipk2) phosphorylates IP3 to inositol 1,4,5,6-tetrakisphosphate and then to inositol 1,3,4,5,6-pentakisphosphate (IP5), and inositol-pentakisphosphate 2-kinase (IPK1) completes inositol hexakisphosphate (IP6, phytate). IP6 is further pyrophosphorylated to the high-energy inositol pyrophosphates by two unrelated kinase families: IP6 kinases (yeast Kcs1, mammalian IP6K) make 5-diphosphoinositol pentakisphosphate (IP7), and the PPIP5K/Vip1/Asp1 kinases add a further diphosphate to make IP8. IP6 and the inositol pyrophosphates act in mRNA export, phosphate homeostasis, vacuole biogenesis and stress responses. Some fungi, including fission yeast, lack the de novo branch and rely on imported inositol. |
Metabolic Pathway | DRAFT | Eukaryota |
0 | inositol biosynthetic process inositol phosphate biosynthetic process myo-inositol hexakisphosphate biosynthetic process |
11 | 8 | 10 | 0 | 0 | 7 | 13/19 | 0 | ✗ | modules/myo_inositol_and_inositol_phosphate_biosynthesis.yaml | |
p38 stress-activated MAPK cascade moduleMODULE:p38_cascade A taxon-neutral decomposition of the p38 mitogen-activated protein kinase cascade, the stress- and cytokine-activated concrete realization of the... [more...][less]A taxon-neutral decomposition of the p38 mitogen-activated protein kinase cascade, the stress- and cytokine-activated concrete realization of the generic three-tier MAP kinase relay (MODULE:mapk_relay). Environmental stresses (UV, osmotic and oxidative stress) and inflammatory cytokines (TNF, IL-1) signal through upstream MAP3Ks (ASK1/MAP3K5, TAK1/MAP3K7, MLK family) to the dual-specificity MAP2Ks MKK3 (MAP2K3) and MKK6 (MAP2K6), which dually phosphorylate the p38 MAPKs (p38 alpha/beta/gamma/delta) on their TGY activation-loop motif. Active p38 phosphorylates substrate kinases (MK2/MAPKAPK2) and transcription factors (ATF2, MEF2), driving stress-response and inflammatory gene programs. The RAF-analogous kinase relay - MAP3K -> MKK3/6 -> p38 - is declared as an inner bundle that `conforms_to` mapk_relay, while the stress/cytokine input and the p38 effector output and DUSP-mediated feedback are this cascade's free extensions around the conforming core. Grounded in GO:0038066 (p38MAPK cascade) / GO:0051403 (stress-activated MAPK cascade). |
Signaling Pathway | DRAFT | 3 | p38MAPK cascade stress-activated MAPK cascade |
8 | 6 | 7 | 0 | 0 | 6 | 4/4 | 3 | ✗ | Boolean | modules/p38_cascade.yaml | |
p53 signaling — stress-kinase stabilisation of p53 (ATM/ATR, CHK2/CHK1), MDM2-MDM4 ubiquitin-ligase negative feedback, ARF inhibition of MDM2, acetylation control, and p53 tetramer transactivation of target genes; TP53/MDM2/MDM4/CDKN2A(ARF)/ATM/ATR/CHEK2/CHEK1/EP300/CREBBP/KAT5/SIRT1MODULE:p53_signalingCONCRETE The tumour suppressor p53 (TP53) is a sequence-specific transcription factor that is kept at low levels in unstressed cells by the RING E3... [more...][less]The tumour suppressor p53 (TP53) is a sequence-specific transcription factor that is kept at low levels in unstressed cells by the RING E3 ubiquitin ligase MDM2. MDM2 binds the N-terminal transactivation domain of p53, which both conceals the domain from the transcription machinery and positions p53 for polyubiquitylation and proteasomal degradation. The MDM2 paralog MDM4 (MDMX) has no ligase activity of its own toward p53 but heterodimerises with MDM2 through the RING domain, stimulating MDM2 E3 activity, and also binds and inhibits the p53 transactivation domain. Because the MDM2 gene is itself a p53 target, the circuit is a negative feedback loop. Stress releases p53 from this loop in two main ways. DNA damage activates the PI3K-like kinases ATM (double-strand breaks) and ATR (replication stress and UV damage), which phosphorylate p53 on Ser15 and MDM2, and activate the effector kinases CHK2 and CHK1, which phosphorylate p53 on Ser20 in the MDM2-binding region; these modifications weaken the p53-MDM2 interaction and stabilise p53. Oncogenic signalling induces the ARF product of the CDKN2A locus, which binds MDM2, inhibits its E3 activity and sequesters it in the nucleolus. Stabilised p53 binds its response elements as a tetramer and recruits the coactivator acetyltransferases p300 and CBP, which acetylate the p53 C-terminal domain as well as promoter histones; KAT5 (TIP60) acetylates p53 Lys120 in the DNA-binding domain, a mark needed for induction of pro-apoptotic targets, and the NAD-dependent deacetylase SIRT1 removes p53 acetylation and dampens its activity. The transcriptional outputs, such as CDKN1A (p21), BBC3 (PUMA), PMAIP1 (NOXA) and BAX, then execute cell-cycle arrest, apoptosis or senescence through modules downstream of this circuit. |
Signaling Pathway | DRAFT | Homo sapiens |
0 | signal transduction by p53 class mediator |
10 | 11 | 9 | 0 | 0 | 10 | 8/12 | 0 | ✗ | modules/p53_signaling.yaml | |
piRNA-mediated germline silencingMODULE:pirna_mediated_germline_silencingCONCRETE Animal germ cells use PIWI-clade Argonautes loaded with PIWI-interacting RNAs (piRNAs) to recognize transposon transcripts and other foreign or... [more...][less]Animal germ cells use PIWI-clade Argonautes loaded with PIWI-interacting RNAs (piRNAs) to recognize transposon transcripts and other foreign or unwanted RNAs and to silence them. The module has three conserved steps. First, a cytoplasmic PIWI-piRNA complex in perinuclear nuage recognizes a target RNA by base pairing. Second, recognition is converted into an amplified pool of secondary small RNAs. Third, a nuclear Argonaute carries small RNAs into the nucleus and silences complementary loci co-transcriptionally. How the second and third steps are carried out differs between lineages. In insects and vertebrates, amplification is the ping-pong cycle: piRNA-guided slicing by cytoplasmic PIWI proteins (fly Aubergine and Ago3, mammalian PIWIL2/MILI) cuts target and precursor transcripts, and the cleavage products become new piRNAs. Nematodes lack ping-pong. In Caenorhabditis elegans the PIWI protein PRG-1 does not need to slice; its targets are instead used as templates by RNA-dependent RNA polymerase to make secondary 22G-RNAs, which are loaded into nematode-specific WAGO Argonautes. The nuclear step is also carried out by different, non-slicing effectors: fly Piwi directs H3K9me3 heterochromatin, mammalian PIWIL4/MIWI2 directs de novo DNA methylation of transposons, and in nematodes the WAGO HRDE-1 recruits the nuclear RNAi factor NRDE-2 and directs H3K9me3. In C. elegans the silenced state can be inherited for many generations without the piRNA trigger, through the nuclear HRDE-1 loop and a cytoplasmic loop in which the helicase ZNFX-1 and WAGO-4 form Z granules. Loss of the core PIWI proteins causes transposon derepression and sterility in flies and mice, and progressive loss of fertility in nematodes. |
Biological Process | DRAFT | Caenorhabditis elegans Metazoa |
1 | regulatory ncRNA-mediated gene silencing transposable element silencing |
10 | 12 | 4 | 2 | 5 | 9 | 13/13 | 0 | ✗ | modules/pirna_mediated_germline_silencing.yaml | |
tRNA-guanine transglycosylase (queuine insertase) in Drosophila melanogasterMODULE:dmel_trna_guanine_transglycosylaseCONCRETE Eukaryotic tRNA-guanine transglycosylase exchanges guanine 34 in the anticodon of tRNA-Asp, tRNA-Asn, tRNA-His and tRNA-Tyr for queuine, forming... [more...][less]Eukaryotic tRNA-guanine transglycosylase exchanges guanine 34 in the anticodon of tRNA-Asp, tRNA-Asn, tRNA-His and tRNA-Tyr for queuine, forming queuosine. Animals cannot synthesize queuine and obtain it from diet and gut microbes. The enzyme is a heterodimer of a catalytic subunit (QTRT1 ortholog, Tgt) and a catalytically inactive paralogous accessory subunit (QTRT2 ortholog, CG3434) required for activity. |
Protein Complex | DRAFT | Drosophila melanogaster |
0 | tRNA-guanine transglycosylase complex |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 0 | ✗ | modules/dmel_trna_guanine_transglycosylase.yaml |