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.
| Module | Type | Status | Taxon | PTNs | Concepts | Nodes | Annotons | Parts | Variant sets | Variants | Connections | Genes rev. | Leaf gaps | Module DR | Source |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
2-methylcitrate cycleMODULE:methylcitrate_cycle A reusable propionate-assimilation module that activates propionate to propionyl-CoA, condenses propionyl-CoA with oxaloacetate to form... [more...][less]A reusable propionate-assimilation module 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 module distinguishes the direct PrpD route from the two-component AcnD/PrpF route and represents the common aconitase-family hydration step separately. |
Metabolic Pathway | DRAFT | 0 | propionate catabolic process |
12 | 8 | 7 | 2 | 4 | 5 | 8/8 | 0 | ✓ | modules/methylcitrate_cycle.yaml | |
ADP-heptose precursor biosynthesisMODULE:adp_heptose_biosynthesisCONCRETE A bacterial nucleotide-sugar pathway that converts D-sedoheptulose 7-phosphate to ADP-D-glycero-beta-D-manno-heptose through GmhA, the kinase... [more...][less]A bacterial nucleotide-sugar pathway that converts D-sedoheptulose 7-phosphate to ADP-D-glycero-beta-D-manno-heptose through GmhA, the kinase activity of HldE, GmhB, and the adenylyltransferase activity of HldE. In lineages that use ADP-L-glycero-beta-D-manno-heptose, HldD performs a subsequent C-6 epimerization. Transfer of the activated heptose into the LPS core by heptosyltransferases is downstream of this module. |
Metabolic Pathway | DRAFT | 0 | phosphoheptose biosynthetic process ADP-L,D-heptose biosynthetic process |
6 | 5 | 5 | 0 | 0 | 4 | 3/7 | 0 | ✗ | modules/adp_heptose_biosynthesis.yaml | |
APS-dependent assimilatory sulfate reductionMODULE:aps_dependent_assimilatory_sulfate_reduction A reusable pathway that converts sulfate to sulfide through adenosine 5'-phosphosulfate (APS) and sulfite. The module contains sulfate activation... [more...][less]A reusable pathway that converts sulfate to sulfide through adenosine 5'-phosphosulfate (APS) and sulfite. The module contains sulfate activation by ATP sulfurylase, thioredoxin-dependent APS reduction, and assimilatory sulfite reduction. It represents the direct APS branch rather than the alternative APS-kinase/PAPS-reductase route. Sulfate import is upstream, whereas siroheme synthesis and incorporation of sulfide into cysteine are supporting or downstream biology outside the pathway boundary. |
Metabolic Pathway | DRAFT | 0 | sulfate assimilation |
6 | 5 | 3 | 1 | 2 | 2 | 5/10 | 0 | ✗ | modules/aps_dependent_assimilatory_sulfate_reduction.yaml | |
Activin receptor signaling pathway moduleMODULE:activin_receptor_signaling Activin ligands signal through ACVR type I and type II serine/threonine kinase receptors to activate SMAD2/3-SMAD4 transcriptional programs... [more...][less]Activin ligands signal through ACVR type I and type II serine/threonine kinase receptors to activate SMAD2/3-SMAD4 transcriptional programs controlling growth and differentiation. |
Signaling Pathway | DRAFT | metazoa |
1 | activin receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 1/6 | 0 | ✓ | modules/activin_receptor_signaling.yaml |
Adrenal steroidogenesis — cholesterol to corticosteroids and adrenal androgens; STAR/CYP11A1/HSD3B2/CYP17A1/CYP21A2/CYP11B1/CYP11B2MODULE:adrenal_steroidogenesis Adrenal steroidogenesis converts cholesterol into the three classes of steroid hormone — glucocorticoids (cortisol), mineralocorticoids... [more...][less]Adrenal steroidogenesis converts cholesterol into the three classes of steroid hormone — glucocorticoids (cortisol), mineralocorticoids (aldosterone) and adrenal androgens (DHEA, androstenedione) — through a branched network of mitochondrial and endoplasmic-reticulum enzymes. The acute, rate-limiting step is the delivery of cholesterol from the outer to the inner mitochondrial membrane by the steroidogenic acute regulatory protein STAR; there the side-chain-cleavage cytochrome P450 CYP11A1 (P450scc) makes pregnenolone, the common precursor of all steroid hormones. Pregnenolone is then routed by two ER enzymes whose order and combination select the branch: the 3beta-hydroxysteroid dehydrogenase/isomerase HSD3B2 (Delta5 -> Delta4, giving progesterone, 17-hydroxyprogesterone or androstenedione) and the bifunctional 17alpha-hydroxylase/17,20-lyase CYP17A1 (17-hydroxylation commits to cortisol; the 17,20-lyase reaction commits to androgens). 21-hydroxylase CYP21A2 then hydroxylates progesterone -> 11-deoxycorticosterone (mineralocorticoid branch) and 17-hydroxyprogesterone -> 11-deoxycortisol (glucocorticoid branch). The final oxidations return to the mitochondrion: CYP11B1 (11beta-hydroxylase) makes cortisol, while its close paralog CYP11B2 (aldosterone synthase), uniquely possessing 18-hydroxylase/18-oxidase activity, converts deoxycorticosterone through corticosterone and 18-hydroxycorticosterone to aldosterone in the zona glomerulosa. Inherited defects define the congenital adrenal hyperplasias and related disorders: STAR (congenital lipoid adrenal hyperplasia), CYP11A1 (adrenal insufficiency), HSD3B2 (3beta-HSD-deficiency CAH), CYP17A1 (combined 17alpha- hydroxylase/17,20-lyase deficiency), CYP21A2 (21-hydroxylase deficiency, >90% of CAH), CYP11B1 (11beta-hydroxylase-deficiency CAH) and CYP11B2 (aldosterone synthase / CMO deficiency; a CYP11B1/B2 chimera causes glucocorticoid-remediable aldosteronism). |
Metabolic Pathway | DRAFT | 0 | steroid hormone biosynthetic process C21-steroid hormone biosynthetic process |
8 | 7 | 7 | 0 | 0 | 8 | 7/7 | 0 | ✗ | modules/adrenal_steroidogenesis.yaml | |
Aerobic nicotinate degradation through 2,5-dihydroxypyridineMODULE:aerobic_nicotinate_degradationCONCRETE A reusable six-reaction bacterial pathway that converts nicotinate to fumarate through 6-hydroxynicotinate, 2,5-dihydroxypyridine,... [more...][less]A reusable six-reaction bacterial pathway that converts nicotinate to fumarate through 6-hydroxynicotinate, 2,5-dihydroxypyridine, N-formylmaleamate, maleamate, and maleate. NicAB performs the initial cytochrome-linked hydroxylation, NicC performs an oxygen- and NADH-dependent oxidative decarboxylation, NicX opens the pyridine ring, NicD removes the formyl group, NicF releases the amide nitrogen, and MaiA isomerizes maleate to fumarate. |
Metabolic Pathway | DRAFT | bacteria |
0 | nicotinate catabolic process |
7 | 6 | 6 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/aerobic_nicotinate_degradation.yaml |
Aerobic phenylacetate catabolismMODULE:phenylacetate_catabolism A reusable aerobic phenylacetyl-CoA pathway that activates phenylacetate, epoxidizes the aromatic ring with the multicomponent PaaABCE system,... [more...][less]A reusable aerobic phenylacetyl-CoA 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 | DRAFT | 0 | phenylacetate catabolic process |
11 | 9 | 10 | 0 | 0 | 8 | 10/10 | 0 | ✓ | modules/phenylacetate_catabolism.yaml | |
Alginate O-acetylationMODULE:alginate_o_acetylationCONCRETE A bacterial alginate-maturation module in which the inner-membrane AlgI component supplies acetyl groups to a periplasm-facing AlgJ-AlgF relay and... [more...][less]A bacterial alginate-maturation module in which the inner-membrane AlgI component supplies acetyl groups to a periplasm-facing AlgJ-AlgF relay and AlgX transfers acetyl groups to O-2 and O-3 positions of mannuronate residues in nascent alginate. Alginate precursor synthesis, polymerization, export, and mannuronate C5 epimerization are separate modules. |
Biological Process | DRAFT | 0 | alginic acid acetylation |
5 | 4 | 4 | 0 | 0 | 2 | 4/8 | 0 | ✗ | modules/alginate_o_acetylation.yaml | |
Alginate polymerization and exportMODULE:alginate_polymerization_exportCONCRETE A synthase-dependent bacterial exopolysaccharide module in which the inner-membrane Alg8-Alg44 complex polymerizes GDP-mannuronate, periplasmic... [more...][less]A synthase-dependent bacterial exopolysaccharide module in which the inner-membrane Alg8-Alg44 complex polymerizes GDP-mannuronate, periplasmic proteins guide and modify the nascent alginate chain, AlgL removes escaped polymer, and the AlgE outer-membrane channel exports the product. Precursor synthesis, O-acetylation chemistry, and transcriptional regulation are separate modules. |
Metabolic Pathway | DRAFT | 0 | alginic acid biosynthetic process |
6 | 6 | 5 | 0 | 0 | 5 | 6/11 | 0 | ✗ | modules/alginate_polymerization_export.yaml | |
Androgen receptor signaling pathway moduleMODULE:androgen_receptor_signaling Androgen receptor signaling couples steroid ligand binding, chaperone release, nuclear receptor dimerization, and co-regulator recruitment to... [more...][less]Androgen receptor signaling couples steroid ligand binding, chaperone release, nuclear receptor dimerization, and co-regulator recruitment to androgen-responsive transcriptional programs. |
Signaling Pathway | DRAFT | metazoa |
3 | androgen receptor signaling pathway |
4 | 8 | 3 | 0 | 0 | 2 | 1/6 | 0 | ✓ | modules/androgen_receptor_signaling.yaml |
B cell receptor signaling pathway moduleMODULE:b_cell_receptor_signaling Antigen-bound B cell receptor complexes signal through CD79 ITAM subunits, SYK, BLNK, BTK, PLC-gamma, and PI3K to drive calcium, NF-kappaB, MAPK,... [more...][less]Antigen-bound B cell receptor complexes signal through CD79 ITAM subunits, SYK, BLNK, BTK, PLC-gamma, and PI3K to drive calcium, NF-kappaB, MAPK, and transcriptional responses. |
Signaling Pathway | DRAFT | jawed vertebrates |
11 | B cell receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 1/7 | 0 | ✓ | modules/b_cell_receptor_signaling.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, especially, retrieval/export across the transition zone. LZTFL1/BBS17 and the accessory factor CCDC28B regulate BBSome ciliary trafficking. 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 | DRAFT | ciliated eukaryotes |
0 | BBSome intraciliary transport |
6 | 6 | 5 | 0 | 0 | 4 | 14/14 | 1 | ✗ | modules/bbsome.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 |
4 | 7 | 3 | 0 | 0 | 2 | 0/6 | 0 | ✓ | modules/bmp_signaling.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 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 | 4/4 | 0 | ✓ | modules/bacterial_rna_polymerase_core.yaml |
Bacterial NADPH-dependent GS-GOGAT ammonia assimilationMODULE:bacterial_ammonia_assimilationCONCRETE A reusable bacterial module for high-affinity assimilation of ammonium through the NADPH-dependent glutamine synthetase-glutamate synthase... [more...][less]A reusable bacterial module for high-affinity assimilation of ammonium through the NADPH-dependent glutamine synthetase-glutamate synthase (GS-GOGAT) cycle. Glutamine synthetase first ligates ammonium to L-glutamate, forming L-glutamine. The NADPH-dependent GltB/GltD glutamate synthase complex then transfers the glutamine amide nitrogen to 2-oxoglutarate, producing two molecules of L-glutamate and regenerating the substrate for glutamine synthetase. Direct reductive amination by NAD(P)-dependent glutamate dehydrogenase is a distinct, generally lower-affinity alternative and is not a required part of this module. |
Metabolic Pathway | DRAFT | bacteria |
1 | ammonia assimilation cycle |
3 | 2 | 2 | 0 | 0 | 2 | 3/6 | 0 | ✓ | modules/bacterial_ammonia_assimilation.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 | DRAFT | 1 | double-strand break repair via homologous recombination |
6 | 7 | 5 | 0 | 0 | 4 | 4/8 | 0 | ✗ | modules/bacterial_recbcd_end_resection.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 | DRAFT | 1 | recombinational repair |
5 | 4 | 4 | 0 | 0 | 3 | 2/6 | 2 | ✗ | modules/bacterial_ruvabc_holliday_junction_processing.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 |
0 | L-selenocysteine biosynthetic process selenocysteine incorporation |
13 | 9 | 8 | 2 | 4 | 5 | 9/10 | 0 | ✓ | modules/selenocysteine_biosynthesis_incorporation.yaml |
Bacterial cellulose biosynthesisMODULE:bacterial_cellulose_biosynthesis A species-neutral Gram-negative bacterial cellulose biosynthesis and export module covering BcsA cellulose polymerization, BcsB periplasmic... [more...][less]A species-neutral Gram-negative bacterial cellulose biosynthesis and export module covering BcsA cellulose polymerization, BcsB periplasmic accessory/regulatory support, BcsC outer-membrane export, and BcsQ/YhjQ-family accessory positioning where that P-loop NTPase is part of the local bcs locus. Pseudomonas putida KT2440 provides the current UniProt exemplars, but does not define the module boundary. |
Biological Process | DRAFT | 0 | cellulose biosynthetic process |
5 | 5 | 4 | 0 | 0 | 0 | 4/4 | 0 | ✓ | modules/bacterial_cellulose_biosynthesis.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 | 3/6 | 0 | ✗ | modules/fructose_pts_uptake_and_catabolism.yaml | |
Bacterial glutamate-to-P5C branch of proline biosynthesisMODULE:bacterial_glutamate_to_p5c_biosynthesisCONCRETE Species-neutral bacterial module for the two-enzyme conversion of L-glutamate to L-glutamate 5-semialdehyde, which cyclizes to... [more...][less]Species-neutral bacterial module for the two-enzyme conversion of L-glutamate to L-glutamate 5-semialdehyde, which cyclizes to 1-pyrroline-5-carboxylate (P5C), during proline biosynthesis. ProB phosphorylates L-glutamate to L-glutamyl 5-phosphate, and ProA reduces that acyl phosphate intermediate to L-glutamate 5-semialdehyde using NADPH. This module deliberately stops before the terminal P5C reductase step that makes L-proline. |
Metabolic Pathway | DRAFT | bacteria |
0 | L-proline biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✓ | modules/bacterial_glutamate_to_p5c_biosynthesis.yaml |
Bacterial glycerol uptake and catabolism through glycerol 3-phosphateMODULE:bacterial_glycerol_uptake_catabolismCONCRETE A reusable bacterial module for channel-mediated glycerol uptake followed by conversion to dihydroxyacetone phosphate. GlpF facilitates glycerol... [more...][less]A reusable bacterial module for channel-mediated glycerol uptake followed by conversion to dihydroxyacetone phosphate. GlpF facilitates glycerol movement across the cytoplasmic membrane, GlpK traps intracellular glycerol as sn-glycerol 3-phosphate, and FAD-dependent GlpD oxidizes that intermediate to dihydroxyacetone phosphate while reducing the respiratory quinone pool. |
Metabolic Pathway | DRAFT | bacteria |
2 | glycerol catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/6 | 0 | ✗ | modules/bacterial_glycerol_uptake_catabolism.yaml |
Bacterial glycolate and glyoxylate assimilationMODULE:glycolate_glyoxylate_assimilationCONCRETE A reusable bacterial central-carbon module for conversion of glycolate and glyoxylate into metabolites that can re-enter core carbon metabolism.... [more...][less]A reusable bacterial central-carbon module for conversion of glycolate and glyoxylate into metabolites that can re-enter core carbon metabolism. The core module starts at glycolate oxidation to glyoxylate and continues through the glyoxylate carboligase/tartronate-semialdehyde branch that converts glyoxylate-derived carbon toward glycerate. Optional glycolate-source routes, including phosphoglycolate salvage, can feed this core but are not required in every organism. Pseudomonas putida KT2440 provides local exemplars for GlcDEF glycolate dehydrogenase, Gcl, Hyi, and GlxR; PP_0416/PP_1907 remain housekeeping phosphoglycolate-salvage candidates rather than the physiological ppu00630 entry route. |
Metabolic Pathway | DRAFT | bacteria |
0 | glyoxylate metabolic process |
6 | 7 | 5 | 0 | 0 | 4 | 7/7 | 0 | ✓ | modules/glycolate_glyoxylate_assimilation.yaml |
Bacterial lipoprotein maturationMODULE:bacterial_lipoprotein_maturation A species-neutral bacterial envelope-biogenesis module for the ordered maturation of lipobox-containing prolipoproteins by Lgt diacylglyceryl... [more...][less]A species-neutral bacterial envelope-biogenesis module for the ordered maturation of lipobox-containing prolipoproteins by Lgt diacylglyceryl transfer, LspA signal peptide cleavage, and Lnt or lineage-equivalent N-acylation where triacylated lipoproteins are produced. Pseudomonas putida KT2440 provides the current UniProt exemplars for the canonical diderm Lgt-LspA-Lnt route; Lol sorting and substrate-specific lipoprotein functions are downstream context outside this module. |
Biological Process | DRAFT | bacteria |
0 | lipoprotein biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✓ | modules/bacterial_lipoprotein_maturation.yaml |
Bacterial non-homologous end joiningMODULE:bacterial_nonhomologous_end_joiningCONCRETE Species-neutral bacterial module for Ku/LigD-mediated repair of DNA double-strand breaks by non-homologous end joining. The module covers the... [more...][less]Species-neutral bacterial module for Ku/LigD-mediated repair of DNA double-strand breaks by non-homologous end joining. The module covers the compact prokaryotic system in which Ku binds broken double-stranded DNA ends, protects and aligns them, and recruits the multifunctional LigD enzyme for end processing and ATP-dependent ligation. It excludes homologous recombination, mismatch repair, nucleotide excision repair, and eukaryotic multi-protein NHEJ factors. |
Biological Process | DRAFT | bacteria |
0 | double-strand break repair via nonhomologous end joining |
3 | 2 | 2 | 0 | 0 | 1 | 2/2 | 0 | ✓ | modules/bacterial_nonhomologous_end_joining.yaml |
Bacterial phosphatidylethanolamine biosynthesis through phosphatidylserineMODULE:bacterial_phosphatidylethanolamine_biosynthesisCONCRETE A reusable two-reaction bacterial module for phosphatidylethanolamine biosynthesis from CDP-diacylglycerol. PssA transfers a phosphatidyl group to... [more...][less]A reusable two-reaction bacterial module for phosphatidylethanolamine biosynthesis from CDP-diacylglycerol. PssA transfers a phosphatidyl group to L-serine to form phosphatidylserine, and pyruvoyl-dependent Psd decarboxylates phosphatidylserine to phosphatidylethanolamine. |
Metabolic Pathway | DRAFT | bacteria |
1 | phosphatidylethanolamine biosynthetic process |
5 | 3 | 2 | 1 | 2 | 1 | 3/6 | 0 | ✗ | modules/bacterial_phosphatidylethanolamine_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 | DRAFT | bacteria |
0 | tRNA queuosine(34) biosynthetic process |
7 | 5 | 4 | 1 | 2 | 3 | 4/6 | 0 | ✓ | modules/bacterial_preq1_incorporation_queuosine_maturation.yaml |
Bacterial taurine uptake and desulfonationMODULE:taurine_uptake_and_desulfonation 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 | DRAFT | 0 | taurine transmembrane transport taurine catabolic process |
3 | 2 | 2 | 0 | 0 | 1 | 4/8 | 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, ThiO, 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 |
11 | 11 | 10 | 0 | 0 | 10 | 3/12 | 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 | |
Benzoate upper degradation pathwayMODULE:benzoate_upper_pathwayCONCRETE A reusable bacterial aromatic-catabolism module for the upper benzoate degradation route that converts benzoate to catechol. The pathway begins... [more...][less]A reusable bacterial aromatic-catabolism module for the upper benzoate degradation route that converts benzoate to catechol. The pathway begins with a multicomponent benzoate 1,2-dioxygenase system, represented here by BenA-like large oxygenase, BenB-like small oxygenase, and BenC-like reductase roles, and is followed by a BenD-like cis-diol dehydrogenase. Pseudomonas putida KT2440 benA/benB/benC/benD provide the local PSEPK exemplars for this module, but the module boundary is the conserved benzoate-to-catechol pathway segment rather than a PSEPK-specific locus definition. |
Metabolic Pathway | DRAFT | bacteria |
0 | benzoate catabolic process via hydroxylation |
3 | 4 | 2 | 0 | 0 | 1 | 4/4 | 0 | ✓ | modules/benzoate_upper_pathway.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 |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 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 | |
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 | 0/25 | 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 | |
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 | |
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 upstream branches - the Sln1 two-component phosphorelay (which derepresses the MAP3Ks Ssk2/Ssk22) and the Sho1 branch (which routes through Ste11) - both converging on the single MAP2K Pbs2, which 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 osmosensing input 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 |
10 | 7 | 9 | 0 | 0 | 6 | 0/6 | 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:0000750 (pheromone-dependent signal transduction involved in conjugation with cellular fusion). |
Signaling Pathway | DRAFT | Saccharomyces cerevisiae |
0 | pheromone-dependent signal transduction involved in conjugation with cellular fusion |
7 | 5 | 6 | 0 | 0 | 4 | 0/4 | 2 | ✗ | modules/scer_mating_fus3_cascade.yaml |
CMP-KDO biosynthesisMODULE:kdo_biosynthesisCONCRETE A four-reaction bacterial pathway that converts D-ribulose-5-phosphate to CMP-3-deoxy-D-manno-octulosonate (CMP-KDO). An arabinose-5-phosphate... [more...][less]A four-reaction bacterial pathway that converts D-ribulose-5-phosphate to CMP-3-deoxy-D-manno-octulosonate (CMP-KDO). An arabinose-5-phosphate isomerase supplies D-arabinose-5-phosphate, KdsA forms KDO-8-phosphate, KdsC removes the phosphate, and KdsB activates KDO with CTP. Alternative paralogs may implement the first two reactions. Transfer of CMP-KDO to lipid A by WaaA and the separate ADP-heptose pathway are outside the module boundary. |
Metabolic Pathway | DRAFT | 0 | KDO biosynthetic process CMP-KDO biosynthetic process |
9 | 6 | 4 | 2 | 4 | 3 | 6/9 | 0 | ✗ | modules/kdo_biosynthesis.yaml | |
Canonical Hedgehog/Smoothened signaling pathway moduleMODULE:hedgehog_signaling A compact vertebrate Hedgehog signaling module. Secreted Hedgehog ligand binds Patched, relieving Patched-mediated inhibition of Smoothened.... [more...][less]A compact vertebrate Hedgehog signaling module. Secreted Hedgehog ligand binds Patched, relieving Patched-mediated inhibition of Smoothened. Activated Smoothened accumulates in the primary cilium and shifts GLI transcription factors from repressor processing toward activator output. The module is grounded in GO:0007224, with curated UniProt exemplars for ligand, receptor, transducer, inhibitor, and GLI output; PTN ancestry is recorded only for Smoothened and SUFU, where the local PAINT cache has matching IBD seed rows. |
Signaling Pathway | DRAFT | metazoa |
2 | smoothened signaling pathway |
4 | 5 | 3 | 0 | 0 | 2 | 2/5 | 0 | ✗ | modules/hedgehog_signaling.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 | metazoans |
0 | cell surface receptor signaling pathway via JAK-STAT cytokine-mediated signaling pathway |
25 | 28 | 14 | 2 | 10 | 12 | 8/10 | 9 | ✗ | 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, IKK, IkappaB, and NF-kappaB exemplars, with PTN anchors where PAINT seed rows support the role. |
Signaling Pathway | DRAFT | metazoa |
4 | canonical NF-kappaB signal transduction |
4 | 5 | 3 | 0 | 0 | 2 | 1/7 | 0 | ✗ | modules/nfkb_canonical_signaling.yaml |
Canonical Notch signaling pathway moduleMODULE:notch_signaling A compact metazoan Notch signaling module. Notch is a contact-dependent juxtacrine pathway in which a Delta/Serrate/LAG-2 family ligand on one cell... [more...][less]A compact metazoan Notch signaling module. Notch is a contact-dependent juxtacrine pathway in which a Delta/Serrate/LAG-2 family ligand on one cell binds a Notch receptor on a neighboring cell, triggers ADAM/gamma-secretase proteolysis, releases the Notch intracellular domain, and converts CSL/RBPJ transcription complexes from repressors to activators of targets such as HES and HEY family genes. The trunk is grounded in GO:0007219 and annotated with curated UniProt exemplars plus PAINT ancestral nodes where the local PANTHER cache supports a function-by-descent claim. |
Signaling Pathway | DRAFT | metazoa |
3 | Notch signaling pathway |
4 | 4 | 3 | 0 | 0 | 2 | 2/3 | 1 | ✗ | modules/notch_signaling.yaml |
Carnitine shuttle (mitochondrial import of long-chain fatty acids)MODULE:carnitine_shuttle The carnitine shuttle is the system that imports long-chain fatty acids into the mitochondrial matrix for beta-oxidation. Long-chain acyl-CoA... [more...][less]The carnitine shuttle is the system that imports long-chain fatty acids into the mitochondrial matrix for beta-oxidation. Long-chain acyl-CoA cannot cross the inner mitochondrial membrane, so it is transiently converted to acylcarnitine, transported across the membrane, and converted back to acyl-CoA inside the matrix. First, the plasma-membrane sodium-dependent carnitine transporter SLC22A5 (OCTN2) imports L-carnitine into the cell (and mediates its renal reabsorption), supplying the carnitine pool. Carnitine palmitoyltransferase 1 (CPT1; the liver isoform is CPT1A), on the mitochondrial OUTER membrane, catalyses the committed, rate-limiting, malonyl-CoA-inhibited step: transfer of a long-chain acyl group from acyl-CoA to carnitine, giving long-chain acylcarnitine + CoA. The carnitine/acylcarnitine translocase SLC25A20 (CACT), an SLC25 carrier of the INNER membrane, then antiports acylcarnitine into the matrix in exchange for free carnitine. Finally carnitine palmitoyltransferase 2 (CPT2), on the matrix face of the inner membrane, reverses the CPT1 reaction — regenerating long-chain acyl-CoA (and releasing carnitine, which CACT recycles back out) so that beta-oxidation can proceed. Inherited defects of each component cause fatty-acid-oxidation disorders that typically present with hypoketotic hypoglycemia, cardiomyopathy/arrhythmia and/or myopathy: SLC22A5 → primary (systemic) carnitine deficiency; CPT1A → CPT1A deficiency; SLC25A20 → carnitine- acylcarnitine translocase deficiency; CPT2 → CPT2 deficiency (the myopathic form is a common cause of exercise-induced rhabdomyolysis). |
Metabolic Pathway | DRAFT | 0 | carnitine shuttle |
5 | 4 | 4 | 0 | 0 | 4 | 4/4 | 0 | ✗ | modules/carnitine_shuttle.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 that converts catechol to beta-ketoadipate enol-lactone. The... [more...][less]A reusable bacterial aromatic-catabolism module for the catechol ortho-cleavage branch that converts catechol to beta-ketoadipate enol-lactone. The branch begins with intradiol cleavage of catechol to cis,cis-muconate by a CatA-like catechol 1,2-dioxygenase, followed by CatB-like muconate cycloisomerase and CatC-like muconolactone delta-isomerase steps. In Pseudomonas putida KT2440, CatA-I/PP_3713 and CatA-II/PP_3166 provide paralogous catechol 1,2-dioxygenase exemplars, CatB/PP_3715 supplies the muconate cycloisomerase step, and CatC/PP_3714 supplies the isomerase step. The module starts at catechol, the output of upstream aromatic upper pathways such as BenABCD benzoate degradation, and stops before the shared lower beta-ketoadipate reactions that convert the enol-lactone toward central metabolism. |
Metabolic Pathway | DRAFT | bacteria |
0 | catechol catabolic process, ortho-cleavage |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 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 | |
Chemokine-mediated signaling pathway moduleMODULE:chemokine_signaling Chemokines activate seven-transmembrane chemokine receptors and heterotrimeric G proteins, coordinating PI3K, calcium, and Rho-family pathways that... [more...][less]Chemokines activate seven-transmembrane chemokine receptors and heterotrimeric G proteins, coordinating PI3K, calcium, and Rho-family pathways that direct leukocyte migration and positioning. |
Signaling Pathway | DRAFT | metazoa |
8 | chemokine-mediated signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 0/6 | 0 | ✓ | modules/chemokine_signaling.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; 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 (a 3-ketoreductase 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. 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 |
7 | 6 | 6 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/cholesterol_synthesis_post_lanosterol.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 hydroxylation by COQ6, C-methylation by the SAM-dependent methyltransferase COQ5, Zn-dependent C1 decarboxylation by COQ4, 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, 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 | 8 | 8 | 0 | 0 | 7 | 10/10 | 0 | ✗ | modules/coenzyme_q10_biosynthesis.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 |
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 | |
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 | 6/16 | 1 | ✗ | modules/cuproptosis.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 |
DXP-dependent de novo pyridoxal 5'-phosphate biosynthesisMODULE:pyridoxal_5_phosphate_biosynthesis 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 alternative DXP-independent PdxS/PdxT pathway and vitamin-B6 salvage are separate modules. |
Metabolic Pathway | DRAFT | 0 | 'de novo' pyridoxal 5'-phosphate biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/pyridoxal_5_phosphate_biosynthesis.yaml | |
De novo biotin biosynthesis via the BioC-BioH routeMODULE:biotin_biosynthesis Bacterial de novo biotin synthesis in which BioC methylates malonyl-ACP, shared fatty-acid-synthase reactions extend the masked intermediate to... [more...][less]Bacterial de novo biotin synthesis in which BioC methylates malonyl-ACP, shared fatty-acid-synthase reactions extend the masked intermediate to pimeloyl-ACP methyl ester, and BioH removes the methyl group. BioF, BioA, BioD, and BioB then assemble the two-ring biotin cofactor. The module models the six pathway-specific enzymes; generic fatty-acid elongation machinery is an explicit dependency rather than a biotin-specific member, and biotin attachment and BirA-mediated regulation are outside the biosynthesis boundary. |
Metabolic Pathway | DRAFT | 0 | biotin biosynthetic process |
7 | 6 | 6 | 0 | 0 | 5 | 6/6 | 0 | ✗ | modules/biotin_biosynthesis.yaml | |
De novo fatty acid synthesis / lipogenesis (ACLY -> ACACA/ACACB -> FASN -> OLAH)MODULE:fatty_acid_de_novo_synthesis De novo lipogenesis builds long-chain saturated fatty acids (chiefly palmitate, C16:0) from carbohydrate- derived carbon in the cytosol, supplying... [more...][less]De novo lipogenesis builds long-chain saturated fatty acids (chiefly palmitate, C16:0) from carbohydrate- derived carbon in the cytosol, supplying membrane lipids, storage triacylglycerol and signalling precursors. Citrate exported from mitochondria is cleaved by ATP-citrate lyase (ACLY) to regenerate cytosolic acetyl-CoA (plus oxaloacetate); this acetyl-CoA also feeds cholesterol synthesis and protein acetylation. Acetyl-CoA carboxylase then carboxylates acetyl-CoA to malonyl-CoA in the committed, rate- limiting step - a biotin-dependent reaction carried out by two isozymes with distinct roles: the cytosolic ACACA (ACC1) supplies malonyl-CoA for fatty acid synthesis, whereas ACACB (ACC2), anchored at the mitochondrial outer membrane, makes a malonyl-CoA pool that inhibits carnitine palmitoyltransferase 1 and thereby restrains fatty acid beta-oxidation. Fatty acid synthase (FASN), a homodimeric multifunctional megaenzyme, then condenses one acetyl-CoA primer with seven malonyl-CoA units in iterative NADPH-dependent cycles - using its ketoacyl-synthase, malonyl/acetyl-transacylase, ketoacyl-reductase, dehydratase, enoyl- reductase, acyl-carrier and thioesterase activities - to produce palmitate. The auxiliary thioesterase OLAH (thioesterase II) can release medium-chain fatty acids early from the FASN acyl-carrier, shifting the product spectrum (e.g. in lactating mammary gland). ACLY, ACACA and FASN are central to lipogenic tissues and are cancer and metabolic-disease drug targets. |
Metabolic Pathway | DRAFT | 0 | fatty acid biosynthetic process malonyl-CoA biosynthetic process acetyl-CoA biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/fatty_acid_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. 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 |
17 | 13 | 12 | 2 | 4 | 10 | 17/27 | 0 | ✓ | modules/de_novo_purine_synthesis.yaml | |
De novo pyrimidine synthesis (glutamine -> UMP); orotic aciduria, Miller syndrome, CAD-DEEMODULE:de_novo_pyrimidine_synthesis De novo pyrimidine biosynthesis is the six-step pathway that builds uridine monophosphate (UMP) — the parent pyrimidine ribonucleotide from which... [more...][less]De novo pyrimidine biosynthesis is the six-step pathway that builds uridine monophosphate (UMP) — the parent pyrimidine ribonucleotide from which CTP, UTP, dTTP and the other pyrimidines derive — from glutamine, bicarbonate, ATP, aspartate and PRPP. Unlike de novo purine synthesis, the ring is assembled first and only attached to ribose-phosphate at the fifth step. The large multifunctional cytosolic protein CAD performs the first three steps: carbamoyl-phosphate synthetase II (glutamine + 2 ATP + HCO3- -> carbamoyl phosphate; the cytosolic pyrimidine CPS, distinct from the mitochondrial urea-cycle CPS1), aspartate transcarbamylase (-> N-carbamoyl-aspartate) and dihydroorotase (-> dihydroorotate). Dihydroorotate dehydrogenase (DHODH) — the only membrane-bound, mitochondrial step — then oxidises dihydroorotate to orotate using FMN and ubiquinone, coupling pyrimidine synthesis to the respiratory chain. Finally the bifunctional UMP synthase (UMPS) attaches PRPP (orotate phosphoribosyltransferase -> OMP) and decarboxylates OMP to UMP. Inherited defects: UMPS deficiency causes hereditary orotic aciduria (megaloblastic anemia, uridine-responsive); DHODH deficiency causes Miller syndrome (postaxial acrofacial dysostosis); and CAD deficiency causes a uridine-responsive developmental and epileptic encephalopathy. DHODH is the target of the immunosuppressant leflunomide/teriflunomide. |
Metabolic Pathway | DRAFT | 0 | 'de novo' UMP biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/de_novo_pyrimidine_synthesis.yaml | |
De novo riboflavin biosynthesis and bacterial flavin cofactor activationMODULE:riboflavin_biosynthesis Species-neutral bacterial pathway for making the riboflavin ring de novo from GTP and ribulose 5-phosphate and then converting riboflavin to the... [more...][less]Species-neutral bacterial pathway for making the riboflavin ring de novo from GTP and ribulose 5-phosphate and then converting riboflavin to the active flavin cofactors FMN and FAD. The ring pathway has two converging branches: a GTP-derived pyrimidine branch made by GTP cyclohydrolase II, the RibD deaminase/reductase activities, and pyrimidine-intermediate dephosphorylation, and a ribulose-5-phosphate branch made by 3,4-dihydroxy-2-butanone 4-phosphate synthase. These branches converge at lumazine synthase, followed by riboflavin synthase. In bacteria, riboflavin kinase and FMN adenylyltransferase are frequently combined in a bifunctional RibF/RibC-family enzyme, connecting vitamin B2 synthesis to FMN and FAD supply. |
Metabolic Pathway | DRAFT | 0 | riboflavin biosynthetic process FMN biosynthetic process FAD biosynthetic process |
12 | 9 | 11 | 0 | 0 | 8 | 2/12 | 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 (ceramide) biosynthesis; SPTLC1/SPTLC2/SPTSSA/KDSR/CERS1-3/DEGS1MODULE: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 whose catalytic core is the SPTLC1-SPTLC2 heterodimer with the small regulatory subunit SPTSSA (which sets C16 acyl-CoA specificity): it condenses L-serine with palmitoyl-CoA to 3-ketodihydrosphingosine. 3-ketodihydrosphingosine reductase (KDSR) then reduces this, using NADPH, to dihydrosphingosine (sphinganine). A family of ceramide synthases (CERS1-6) N-acylates sphinganine with a fatty acyl-CoA to give dihydroceramide, each isoform preferring 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. Finally the dihydroceramide desaturase DEGS1 introduces the 4,5-trans double bond, an O2- and iron-dependent oxidation that converts dihydroceramide to ceramide. Inherited defects span the pathway: HSAN1 (SPTLC1/SPTLC2), spastic paraplegia (SPTSSA), erythrokeratodermia/thrombocytopenia (KDSR), progressive myoclonic epilepsy 8 (CERS1), congenital ichthyosis ARCI9 (CERS3) and hypomyelinating leukodystrophy 18 (DEGS1). |
Metabolic Pathway | DRAFT | 0 | sphingolipid biosynthetic process ceramide biosynthetic process |
5 | 6 | 4 | 0 | 0 | 3 | 8/8 | 0 | ✗ | modules/sphingolipid_de_novo_synthesis.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. |
Signaling Pathway | DRAFT | metazoa |
2 | extrinsic apoptotic signaling pathway via death domain receptors |
4 | 6 | 3 | 0 | 0 | 2 | 2/5 | 0 | ✓ | modules/death_receptor_apoptotic_signaling.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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 0 | aggregation involved in sorocarp development |
5 | 4 | 4 | 0 | 0 | 3 | 4/4 | 0 | ✗ | modules/dicty_starvation_initiation.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 -> DOLPP1 -> SRD5A3 -> 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 by the dolichyl-diphosphate phosphatase DOLPP1 (which also recycles the Dol-PP released after oligosaccharyltransferase moves the glycan onto protein), and the alpha-terminal isoprene unit is saturated by the polyprenol reductase SRD5A3 to give dolichol. Dolichol kinase DOLK then phosphorylates dolichol (CTP-dependent) to Dol-P, completing the carrier pool. All five enzymes reside in the endoplasmic reticulum membrane. Defects across this module cause congenital disorders of glycosylation (DHDDS-CDG/RP59, NUS1-CDG/epileptic encephalopathy, SRD5A3-CDG, DOLK-CDG) and inherited retinal dystrophy. |
Metabolic Pathway | DRAFT | 0 | dolichyl monophosphate biosynthetic process polyprenol biosynthetic process dolichol-linked oligosaccharide biosynthetic process |
5 | 5 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/dolichyl_phosphate_biosynthesis.yaml | |
Dolichol phosphate and lipid-linked sugar-donor supply for glycosylation; SRD5A3/DOLK/DPM1/DPM2/DPM3/ALG5/MPDU1MODULE:dolichol_phosphate_sugar_donor_supply Assembly of the dolichol-linked oligosaccharide (and of GPI anchors, O- and C-mannosylation) depends on a dolichyl-phosphate lipid carrier and on... [more...][less]Assembly of the dolichol-linked oligosaccharide (and of GPI anchors, O- and C-mannosylation) depends on a dolichyl-phosphate lipid carrier and on two lipid-linked monosaccharide donors, dolichyl-phosphate-mannose (Dol-P-Man) and dolichyl-phosphate-glucose (Dol-P-Glc). This module curates their supply at the endoplasmic-reticulum membrane. The polyprenol reductase SRD5A3 catalyses the last step of de novo dolichol synthesis, reducing the alpha-isoprene unit of polyprenol to dolichol; dolichol kinase DOLK then phosphorylates dolichol (using CTP) to dolichyl phosphate (Dol-P), the essential carrier. Dol-P is charged with sugars by two systems: the dolichol-phosphate-mannose (DPM) synthase, a three-subunit complex in which DPM1 is the GDP-mannose-utilising catalytic subunit and DPM2 (regulatory/stabilising) and DPM3 (membrane anchor for the TM-less DPM1) are non-catalytic, produces Dol-P-Man from GDP-mannose and Dol-P; and ALG5 (dolichyl-phosphate beta-glucosyltransferase) produces Dol-P-Glc from UDP-glucose and Dol-P. The utilisation factor MPDU1 (Lec35) is then required for these lipid-linked donors to be used by the lumenal glycosyltransferases. Because they feed the whole glycosylation system, defects in every gene here cause a congenital disorder of glycosylation: SRD5A3-CDG (CDG-Iq), DOLK-CDG (CDG-Im, dilated cardiomyopathy), DPM1-CDG (CDG-Ie), DPM2-CDG (CDG-Iu) and DPM3-CDG (CDG-Io) — the latter two dystroglycanopathies — MPDU1-CDG (CDG-If) and ALG5-CDG. |
Metabolic Pathway | DRAFT | 0 | dolichol-linked oligosaccharide biosynthetic process dolichyl monophosphate biosynthetic process |
6 | 7 | 5 | 0 | 0 | 5 | 7/7 | 0 | ✗ | modules/dolichol_phosphate_sugar_donor_supply.yaml | |
EF-P translation stall rescueMODULE:efp_translation_stall_rescue A species-neutral bacterial EF-P-family module for elongation factor P-dependent stimulation of peptide-bond formation and rescue of stalled... [more...][less]A species-neutral bacterial EF-P-family module for elongation factor P-dependent stimulation of peptide-bond formation and rescue of stalled cytosolic ribosomes. Pseudomonas putida KT2440 efp/PP_1858 (UniProtKB:Q88LS0) is the local UPA00345 exemplar, not the defining scope of the module. Lineage-specific EF-P activation chemistry, including pseudomonad EarP-dependent Arg32 rhamnosylation and enterobacterial beta-lysylation, is adjacent context rather than a member of the EF-P step itself. |
Biological Process | DRAFT | bacteria |
1 | translational elongation rescue of stalled cytosolic ribosome |
3 | 2 | 2 | 0 | 0 | 0 | 1/2 | 1 | ✓ | modules/efp_translation_stall_rescue.yaml |
EGFR signaling pathway moduleMODULE:egfr_signaling EGF-family ligand binding activates EGFR/ERBB1 receptor tyrosine kinase dimers, creating phosphotyrosine docking sites that recruit GRB2/SOS, PI3K,... [more...][less]EGF-family ligand binding activates EGFR/ERBB1 receptor tyrosine kinase dimers, creating phosphotyrosine docking sites that recruit GRB2/SOS, PI3K, PLCG, and STAT branches for proliferation and differentiation outputs. |
Signaling Pathway | DRAFT | metazoa |
4 | epidermal growth factor receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 1/6 | 0 | ✓ | modules/egfr_signaling.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 | 0/5 | 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: (1) recruitment of SH2/SH3 adaptors (GRB2, SHC) to a receptor phosphotyrosine; (2) GRB2-mediated recruitment of the Ras guanine nucleotide exchange factor SOS; (3) the Ras nucleotide switch (SOS GEF -> Ras GTPase -> RasGAP), declared as an inner bundle that `conforms_to` gtpase_switch; (4) 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; (5) ERK action on nuclear (ELK1/Ets, RSK, MSK) and cytoplasmic substrates to drive transcription, proliferation, and differentiation; and (6) DUSP/MKP negative feedback on ERK. Grounded in GO:0000165 (MAPK cascade) / GO:0070371 (ERK1 and ERK2 cascade). |
Signaling Pathway | DRAFT | eukaryotes |
0 | MAPK cascade ERK1 and ERK2 cascade |
12 | 9 | 11 | 0 | 0 | 8 | 6/6 | 5 | ✗ | 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 | 0 | ERK5 cascade |
7 | 5 | 6 | 0 | 0 | 4 | 0/4 | 2 | ✗ | modules/erk5_cascade.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 | 0/4 | 6 | ✗ | modules/early_metazoan_development.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 | |
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 | 0/8 | 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. 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 | 0 | protein lipoylation |
12 | 8 | 8 | 1 | 3 | 5 | 3/10 | 0 | ✓ | modules/endogenous_protein_lipoylation.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 | |
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 |
6 | ephrin receptor signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 0/5 | 0 | ✓ | modules/ephrin_receptor_signaling.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 | 0/5 | 0 | ✓ | modules/estrogen_receptor_signaling.yaml |
Ether lipid / plasmalogen biosynthesis (FAR1/2 -> GNPAT -> AGPS -> ... -> 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 |
5 | 4 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/ether_lipid_plasmalogen_biosynthesis.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. A GlcNAc-kinase salvage branch enters at the N-acetylglucosamine 6-phosphate intermediate. Feedback inhibition of GFAT by UDP-GlcNAc couples pathway flux to nutrient availability and glycosylation demand. The product supplies protein and lipid glycosylation, proteoglycan and GPI-anchor synthesis, O-GlcNAcylation, and the GNE-dependent sialic-acid route. |
Metabolic Pathway | DRAFT | eukaryotes |
0 | UDP-N-acetylglucosamine biosynthetic process UDP-N-acetylglucosamine metabolic process |
6 | 5 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/hexosamine_biosynthesis.yaml |
FGFR signaling pathway moduleMODULE:fgfr_signaling FGF ligands and heparan sulfate cofactor activate FGFR receptor tyrosine kinases, recruiting FRS2/GRB2/SOS, PI3K, PLCG, and MAPK outputs for... [more...][less]FGF ligands and heparan sulfate cofactor activate FGFR receptor tyrosine kinases, recruiting FRS2/GRB2/SOS, PI3K, PLCG, and MAPK outputs for development, angiogenesis, and tissue repair. |
Signaling Pathway | DRAFT | metazoa |
4 | fibroblast growth factor receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 0/6 | 0 | ✓ | modules/fgfr_signaling.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 | 1/7 | 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 | 1/7 | 0 | ✓ | modules/fc_gamma_receptor_signaling.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 | 21/24 | 1 | ✗ | modules/ferroptosis.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. 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 | 3 | tetrahydrofolate interconversion |
14 | 10 | 4 | 3 | 9 | 2 | 8/13 | 3 | ✓ | 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 | |
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 | 2/6 | 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 | |
Galactose catabolism (Leloir pathway)MODULE:galactose_leloir_pathway The Leloir pathway, the main route by which dietary D-galactose (chiefly from the milk sugar lactose) is converted to glucose-1-phosphate and... [more...][less]The Leloir pathway, the main route by which dietary D-galactose (chiefly from the milk sugar lactose) is converted to glucose-1-phosphate and thereby fed into glycolysis and general carbohydrate metabolism. It is a short cytosolic pathway of four enzymes. Galactose mutarotase (GALM/aldose 1-epimerase) first equilibrates the β- and α-anomers of D-galactose, supplying the α-anomer; galactokinase (GALK1) then phosphorylates α-D-galactose with ATP to α-D-galactose 1-phosphate; galactose-1-phosphate uridylyltransferase (GALT) transfers a UMP group from UDP-glucose to galactose-1-phosphate, producing glucose-1-phosphate (which enters glycolysis/glycogen metabolism via phosphoglucomutase) and UDP-galactose; and UDP-galactose-4-epimerase (GALE) interconverts UDP-galactose and UDP-glucose, regenerating the UDP-glucose that GALT consumes and balancing the UDP-galactose pool used for glycoconjugate synthesis. Because GALT both consumes UDP-glucose and (via GALE) regenerates it, the pathway is catalytic in UDP-sugars: only a trace pool is needed to turn over large amounts of galactose. Each enzyme has a corresponding inherited galactosemia: GALT deficiency causes classic galactosemia (type I, severe neonatal toxicity); GALK1 deficiency causes type II (predominantly cataracts, from galactitol); GALE deficiency causes type III (epimerase deficiency, peripheral to generalized); and GALM deficiency causes type IV. The shared toxic intermediates are galactose-1-phosphate and, via aldose reductase, galactitol. |
Metabolic Pathway | DRAFT | 0 | galactose catabolic process via UDP-galactose, Leloir pathway galactose metabolic process |
5 | 4 | 4 | 0 | 0 | 4 | 4/4 | 0 | ✗ | modules/galactose_leloir_pathway.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 | |
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 GTPase nucleotide switch motif (GEF / GTP / GAP)MODULE:gtpase_switch 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 | 3 | ✗ | 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 | eukaryotes |
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 | 2/13 | 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_gluconeogenesis A generic, taxon-neutral decomposition of gluconeogenesis as a module. The module is intentionally phrased as a set of functions and pathway... [more...][less]A generic, taxon-neutral decomposition of gluconeogenesis as a module. The module is intentionally phrased as a set of functions and pathway segments rather than as a fixed list of genes, so it can represent bacterial, fungal, plant, and animal implementations. |
Metabolic Pathway | DRAFT | 0 | gluconeogenesis |
11 | 6 | 5 | 2 | 5 | 4 | 0/0 | 8 | ✗ | 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 | 1/9 | 0 | ✗ | modules/germ_layer_specification.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 | 1/6 | 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 | 6/13 | 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 | 3/7 | 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_biosynthesis 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 | DRAFT | 0 | glutathione biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 4/7 | 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). |
Metabolic Pathway | DRAFT | 0 | glutathione biosynthetic process glutathione catabolic process |
8 | 8 | 7 | 0 | 0 | 8 | 8/8 | 0 | ✗ | modules/glutathione_synthesis_gamma_glutamyl_cycle.yaml | |
Glutathione-dependent methylglyoxal detoxificationMODULE:methylglyoxal_detoxificationCONCRETE A two-reaction detoxification module in which glyoxalase I converts the spontaneously formed methylglyoxal-glutathione hemithioacetal to... [more...][less]A two-reaction detoxification module 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. Glutathione biosynthesis, methylglyoxal generation, alternative glutathione-independent routes, and downstream D-lactate oxidation are separate modules. |
Metabolic Pathway | DRAFT | 0 | methylglyoxal catabolic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/4 | 0 | ✗ | modules/methylglyoxal_detoxification.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-phosphate pathway) (GPAM -> AGPAT2 -> LPIN1 -> DGAT1/2)MODULE:triacylglycerol_biosynthesis Triacylglycerol (TAG) is the principal energy-storage lipid, assembled from glycerol-3-phosphate and fatty acyl-CoAs by the glycerol-phosphate... [more...][less]Triacylglycerol (TAG) is the principal energy-storage lipid, assembled from glycerol-3-phosphate and fatty acyl-CoAs by the glycerol-phosphate pathway, whose intermediate diacylglycerol is also the branch point to the major glycerophospholipids. Glycerol-3-phosphate acyltransferase (GPAM/GPAT1, at the mitochondrial outer membrane) performs the first, committed and rate-limiting acylation of sn-glycerol-3-phosphate at sn-1 to lysophosphatidic acid (LPA). 1-Acylglycerol-3-phosphate O-acyltransferase (AGPAT2/LPAAT-beta, at the ER) acylates LPA at sn-2 to phosphatidic acid (PA). The Mg2+-dependent phosphatidate phosphatase lipin-1 (LPIN1) dephosphorylates PA to diacylglycerol (DAG); LPIN1 additionally moonlights in the nucleus as a transcriptional coregulator of lipid-metabolism genes. Finally the diacylglycerol O-acyltransferases DGAT1 (an ER MBOAT-family enzyme with broad acyl-acceptor specificity) and DGAT2 (the ER/lipid-droplet DGAT2- family enzyme that is the quantitatively major TAG synthase) esterify DAG at sn-3 with a fatty acyl-CoA to form TAG - the final, dedicated step, which packages TAG into cytoplasmic lipid droplets. Defects cause metabolic disease: AGPAT2 and (via the pathway) other steps cause congenital generalized lipodystrophy, LPIN1 causes recurrent childhood rhabdomyolysis, and DGAT1 causes a congenital diarrhoea / protein-losing enteropathy. |
Metabolic Pathway | DRAFT | 0 | triglyceride biosynthetic process phosphatidic acid biosynthetic process diacylglycerol biosynthetic process |
5 | 5 | 4 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/triacylglycerol_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. |
Protein Complex | DRAFT | 2 | glycine decarboxylation via glycine cleavage system |
5 | 4 | 4 | 0 | 0 | 4 | 13/13 | 0 | ✗ | modules/glycine_cleavage_system.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 GLB1, GM2 via beta-hexosaminidase A + the GM2-activator, globosides via GLA/HEXA-HEXB — reviewed in the ganglioside/GAG modules), ultimately yielding 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 |
7 | 7 | 6 | 0 | 0 | 5 | 7/7 | 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 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 | 3 | 5/5 | 0 | ✗ | modules/glyoxylate_oxalate_metabolism.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 | 10/18 | 0 | ✗ | modules/bacterial_sec_posttranslational_protein_export.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 | 0/5 | 0 | ✓ | modules/hgf_met_signaling.yaml |
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 are alternative routes to... [more...][less]A reusable cross-taxon model of protoporphyrin-dependent heme B biosynthesis. C5 glutamyl-tRNA and C4/Shemin reactions are alternative routes to 5-aminolevulinate (ALA). 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. |
Metabolic Pathway | DRAFT | 0 | heme B biosynthetic process |
18 | 13 | 10 | 3 | 7 | 8 | 19/35 | 0 | ✓ | modules/heme_biosynthesis.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 | |
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 | |
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 | 0/5 | 0 | ✗ | modules/hippo_signaling.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. One bacterial route uses HutF and HutG to release ammonium and formate; a second bacterial 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 | 9/11 | 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_catabolism A reusable three-reaction pathway that opens the aromatic ring of homogentisate to form maleylacetoacetate, isomerizes maleylacetoacetate to... [more...][less]A reusable three-reaction pathway that opens the aromatic ring of homogentisate to form maleylacetoacetate, isomerizes maleylacetoacetate to fumarylacetoacetate, and hydrolyzes fumarylacetoacetate to fumarate and acetoacetate. This lower pathway accepts homogentisate from multiple upstream aromatic-substrate routes and ends at metabolites that can enter central carbon metabolism. |
Metabolic Pathway | DRAFT | 0 | homogentisate catabolic process |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✓ | modules/homogentisate_catabolism.yaml | |
Hydroxycinnamate and vanillate catabolism to protocatechuateMODULE:hydroxycinnamate_vanillate_catabolismCONCRETE A four-part bacterial peripheral aromatic-catabolism module in which Fcs activates ferulate to feruloyl-CoA, Ech cleaves the thioester to vanillin,... [more...][less]A four-part bacterial peripheral aromatic-catabolism module in which Fcs activates ferulate to feruloyl-CoA, Ech cleaves the thioester to vanillin, Vdh oxidizes vanillin to vanillate, and the two-component VanAB enzyme O-demethylates vanillate to protocatechuate. Aromatic-acid uptake, formaldehyde detoxification, gallate catabolism, and the downstream protocatechuate beta-ketoadipate pathway are separate modules. |
Metabolic Pathway | DRAFT | 0 | ferulate catabolic process aerobic phenol-containing compound catabolic process |
5 | 5 | 4 | 0 | 0 | 3 | 3/5 | 4 | ✗ | modules/hydroxycinnamate_vanillate_catabolism.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 | 1/6 | 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 | 2/6 | 0 | ✓ | modules/il6_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 | 1/5 | 0 | ✗ | modules/insulin_receptor_signaling.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 | 0/5 | 0 | ✗ | modules/integrin_fak_src_signaling.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 | 3/5 | 0 | ✓ | modules/intrinsic_apoptotic_signaling.yaml |
Isoprenoid (prenyl) diphosphate biosynthesis (IPP/DMAPP -> GPP -> FPP -> GGPP)MODULE:isoprenoid_diphosphate_biosynthesis The isoprenoid-diphosphate trunk converts the universal five-carbon isoprene units produced by the mevalonate pathway into the linear prenyl... [more...][less]The isoprenoid-diphosphate trunk converts the universal five-carbon isoprene units produced by the mevalonate pathway into the linear prenyl diphosphates that seed every downstream isoprenoid class. The mevalonate pathway (HMGCS1/HMGCR/MVK/PMVK/MVD, curated separately) delivers isopentenyl diphosphate (IPP). Isopentenyl-diphosphate delta-isomerase (IDI1, ubiquitous; IDI2, muscle-enriched paralog) reversibly interconverts IPP and its allylic isomer dimethylallyl diphosphate (DMAPP), balancing the two pools. Farnesyl diphosphate synthase (FDPS) 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/cholesterol synthesis (via squalene, SQLE/ FDFT1), heme A, ubiquinone/CoQ side chains, dolichol (cis-prenyltransferase DHDDS/NUS1), and protein farnesylation (FTase). Geranylgeranyl diphosphate synthase (GGPS1) adds one more IPP to FPP giving geranylgeranyl diphosphate (GGPP, C20), the C20 donor for protein geranylgeranylation (GGTase-I and RabGGTase). All three enzymes are cytosolic Mg2+-dependent prenyltransferases/isomerases (IDI1/IDI2 also peroxisomal). The pathway is the pharmacological target of nitrogen bisphosphonates (FDPS); GGPS1 loss-of-function causes a muscular dystrophy / sensorineural hearing loss / ovarian insufficiency syndrome. |
Metabolic Pathway | DRAFT | 0 | isoprenoid biosynthetic process farnesyl diphosphate biosynthetic process geranylgeranyl diphosphate biosynthetic process |
4 | 3 | 3 | 0 | 0 | 2 | 4/4 | 0 | ✗ | modules/isoprenoid_diphosphate_biosynthesis.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 | 0 | JNK cascade stress-activated MAPK cascade |
8 | 6 | 7 | 0 | 0 | 5 | 0/4 | 3 | ✗ | modules/jnk_cascade.yaml | |
Kennedy pathway (CDP-choline / CDP-ethanolamine synthesis of PC and PE)MODULE:kennedy_pathway_phospholipid_synthesis 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. |
Metabolic Pathway | DRAFT | 0 | phosphatidylcholine biosynthetic process phosphatidylethanolamine biosynthetic process |
8 | 7 | 7 | 0 | 0 | 5 | 11/11 | 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 oxidation (ketolysis)MODULE:ketone_body_oxidation Mitochondrial oxidation of the ketone bodies D-3-hydroxybutyrate and acetoacetate to acetyl-CoA for entry into the TCA cycle, the route by which... [more...][less]Mitochondrial oxidation of the ketone bodies D-3-hydroxybutyrate and acetoacetate to acetyl-CoA for entry into the TCA cycle, the route by which extrahepatic tissues (heart, brain, skeletal muscle, renal cortex) use ketone bodies as fuel during fasting. The pathway is three obligate steps: D-3-hydroxybutyrate dehydrogenase (BDH1) oxidises 3-hydroxybutyrate to acetoacetate; succinyl-CoA:3-oxoacid CoA-transferase (OXCT1/SCOT) activates acetoacetate to acetoacetyl-CoA; and acetyl-CoA acetyltransferase (ACAT1, mitochondrial thiolase) thiolytically cleaves acetoacetyl-CoA to two acetyl-CoA. The SCOT step is the committed, irreversible activation step and the metabolic switch that distinguishes ketone-consuming tissues from the liver: the liver produces ketone bodies but does not express OXCT1, so it cannot re-oxidise them and instead exports them. This module is built to be evaluated against tissue expression so that the tissues capable of ketone-body oxidation, and the basis of the liver's inability, can be resolved directly. |
Metabolic Pathway | DRAFT | 0 | ketolysis |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/ketone_body_oxidation.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 ornithine (microbial)MODULE:arginine_biosynthesis De novo microbial L-arginine biosynthesis from L-glutamate through N-acetylated intermediates and L-ornithine. The module includes the linear... [more...][less]De novo microbial L-arginine biosynthesis from L-glutamate through N-acetylated intermediates and L-ornithine. The module includes the linear route, in which ArgA initiates acetylation and ArgE hydrolyses N-acetyl-L-ornithine, and the cyclic route, in which bifunctional ArgJ can initiate the pathway and recycle the acetyl group from N-acetyl-L-ornithine. After ornithine formation, ArgF, ArgG, and ArgH convert it through L-citrulline and argininosuccinate to L-arginine. Carbamoyl-phosphate production is shared with pyrimidine metabolism and is intentionally outside the module boundary. Succinylated-intermediate, N-acetylcitrulline, and LysW-dependent arginine pathways are distinct implementations not expanded in this module. |
Metabolic Pathway | DRAFT | 1 | L-arginine biosynthetic process |
15 | 11 | 8 | 3 | 6 | 7 | 10/13 | 0 | ✗ | modules/arginine_biosynthesis.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 | 10/18 | 1 | ✓ | modules/nad_biosynthesis_salvage.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 biosynthesis (microbial)MODULE:histidine_biosynthesis De novo biosynthesis of L-histidine from PRPP and ATP through the conserved microbial His pathway. The module begins at the first committed ATP... [more...][less]De novo biosynthesis of L-histidine from PRPP and ATP through the conserved microbial His pathway. 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 HisF-HisH imidazole-glycerol-phosphate synthase reaction. Its enzyme architecture varies across lineages: short-form HisG uses a separate HisZ regulatory subunit, the phosphoribosyl-ATP diphosphatase and phosphoribosyl-AMP cyclohydrolase can be separate or fused, and histidinol-phosphate phosphatase activity has arisen in several unrelated families. The terminal HisD enzyme performs two successive NAD+-dependent oxidations through histidinal to produce L-histidine. |
Metabolic Pathway | DRAFT | 0 | L-histidine biosynthetic process |
12 | 12 | 9 | 1 | 2 | 8 | 12/13 | 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 | 0 | L-lysine biosynthetic process |
8 | 7 | 7 | 0 | 0 | 6 | 10/10 | 0 | ✗ | modules/lysine_biosynthesis.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, modelled as a species-agnostic pathway template with alternative routes at three steps, so... [more...][less]De novo biosynthesis of L-methionine from L-homoserine, modelled as a species-agnostic pathway template with alternative routes at three steps, so the same logic can be evaluated across genomes (a eukaryote-to-prokaryote test of the module satisfiability engine). Homoserine is first activated by acylation, for which bacteria use either an O-succinyltransferase (metA) or an O-acetyltransferase (metX). Sulfur is then incorporated to give homocysteine by one of two routes: trans-sulfuration (cystathionine gamma-synthase metB plus cystathionine beta-lyase metC, drawing sulfur from cysteine) or direct sulfhydrylation (an O-acyl-homoserine sulfhydrylase, metY/metZ, using free sulfide in a single step). Finally homocysteine is methylated to methionine by either the cobalamin-independent synthase (metE) or the cobalamin-dependent synthase (metH). Because every step has alternatives, no single enzyme is universally required; an organism makes methionine if it encodes at least one option at each of the three steps. This mirrors GapMind-style pathway reconstruction: the template defines steps and route alternatives, and a per-genome oracle decides which candidates are present. |
Metabolic Pathway | DRAFT | 0 | methionine biosynthesis |
13 | 8 | 5 | 3 | 7 | 2 | 0/0 | 0 | ✓ | modules/methionine_biosynthesis.yaml | |
L-tryptophan biosynthesis (microbial)MODULE:tryptophan_biosynthesis De novo biosynthesis of L-tryptophan from chorismate, the branch-point precursor of the aromatic amino acids. Five enzymatic activities convert... [more...][less]De novo biosynthesis of L-tryptophan from chorismate, the branch-point precursor of the aromatic amino acids. Five enzymatic activities 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 pathway is the classic textbook microbial operon (the trp operon) and is notable for extensive enzyme fusion and channeling: anthranilate synthase is a glutamine amidotransferase built from a synthase component (TrpE) and a glutaminase component (TrpD/TrpG), the latter frequently fused to anthranilate phosphoribosyltransferase in enteric bacteria; phosphoribosylanthranilate isomerase (TrpF) is often fused to indole-3-glycerol-phosphate synthase (TrpC); and the terminal tryptophan synthase is an alpha-2-beta-2 complex in which indole produced at the TrpA (alpha) active site is channeled through an intramolecular tunnel to the TrpB (beta) active site, where it condenses with L-serine, so free indole is not released. The pathway is feedback-regulated by L-tryptophan, classically at anthranilate synthase and, in many bacteria, also transcriptionally via attenuation and the TrpR repressor. |
Metabolic Pathway | DRAFT | 0 | L-tryptophan biosynthetic process |
8 | 8 | 5 | 1 | 2 | 4 | 7/8 | 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 Microbial biosynthesis of the three branched-chain amino acids. L-isoleucine synthesis begins with threonine deamination to 2-oxobutanoate. The... [more...][less]Microbial biosynthesis of the three branched-chain amino acids. L-isoleucine synthesis begins with threonine deamination to 2-oxobutanoate. The IlvI-IlvH acetohydroxy-acid synthase, IlvC ketol-acid reductoisomerase, and IlvD 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 LeuA/LeuC-LeuD/LeuB extension branch. IlvE performs the terminal transamination for all three products. The module requires each biochemical step but allows any validated member of the biosynthetic threonine-deaminase family to satisfy the entry reaction. |
Metabolic Pathway | DRAFT | 0 | branched-chain amino acid biosynthetic process |
10 | 10 | 9 | 0 | 0 | 8 | 11/11 | 0 | ✗ | modules/branched_chain_amino_acid_biosynthesis.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 | |
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 | |
MEP isoprenoid precursor biosynthesisMODULE:mep_isoprenoid_precursor_biosynthesis The bacterial methylerythritol phosphate (MEP/DOXP) route converts pyruvate and glyceraldehyde 3-phosphate through seven reactions into isopentenyl... [more...][less]The bacterial 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 |
10 | 8 | 7 | 1 | 2 | 6 | 7/15 | 0 | ✓ | modules/mep_isoprenoid_precursor_biosynthesis.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 GABA shunt (glutamate to GABA to succinate)MODULE:gaba_shuntCONCRETE The mammalian GABA shunt couples cytosolic neurotransmitter synthesis to mitochondrial catabolism. PLP-dependent GAD1/2 decarboxylate L-glutamate... [more...][less]The mammalian GABA shunt couples cytosolic neurotransmitter synthesis to mitochondrial catabolism. PLP-dependent GAD1/2 decarboxylate L-glutamate to GABA and carbon dioxide in the cytosol. After GABA enters the mitochondrial matrix, PLP-dependent ABAT transfers its amino group to 2-oxoglutarate, producing succinate semialdehyde and regenerating L-glutamate; ALDH5A1 then uses NAD+ to oxidize the semialdehyde to succinate and NADH. The shunt feeds the TCA cycle while bypassing its 2-oxoglutarate-to-succinate segment. GAD1, ABAT, and ALDH5A1 deficiencies cause inherited neurological or metabolic disorders, including GABA-transaminase and succinate-semialdehyde-dehydrogenase deficiencies. |
Metabolic Pathway | DRAFT | 0 | GABA shunt |
4 | 3 | 3 | 0 | 0 | 2 | 3/4 | 0 | ✗ | modules/gaba_shunt.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 proline-P5C biosynthesis and catabolismMODULE:proline_metabolismCONCRETE Mammalian proline metabolism interconverts L-glutamate, L-ornithine, delta-1-pyrroline-5-carboxylate (P5C), and L-proline in mitochondria.... [more...][less]Mammalian proline metabolism interconverts L-glutamate, L-ornithine, delta-1-pyrroline-5-carboxylate (P5C), and L-proline in mitochondria. Bifunctional P5C synthase first phosphorylates and then reduces glutamate to glutamate 5-semialdehyde/P5C. Ornithine aminotransferase reversibly connects the same intermediate pool to ornithine, supporting either proline synthesis or arginine/ornithine degradation. Pyrroline-5-carboxylate reductases produce proline, whereas proline dehydrogenase and P5C dehydrogenase return proline carbon to glutamate. ALDH4A1 also provides a shared downstream oxidation step in trans-4-hydroxy-L-proline degradation. |
Metabolic Pathway | DRAFT | Mammalia |
0 | L-proline biosynthetic process L-proline catabolic process |
7 | 6 | 6 | 0 | 0 | 6 | 6/6 | 0 | ✗ | modules/proline_metabolism.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 |
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. |
Metabolic Pathway | DRAFT | 0 | methionine cycle |
17 | 9 | 11 | 2 | 5 | 20 | 0/0 | 11 | ✗ | modules/methionine_cycle.yaml | |
Mevalonate pathway (acetyl-CoA -> isopentenyl diphosphate); statin target, mevalonate kinase deficiencyMODULE:mevalonate_pathway The mevalonate pathway is the cytosolic/ER route that converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl... [more...][less]The mevalonate pathway is the cytosolic/ER route that converts acetyl-CoA into the universal five-carbon isoprenoid building block isopentenyl diphosphate (IPP), the precursor of cholesterol, dolichol, ubiquinone (CoQ), heme A, and the farnesyl/ geranylgeranyl groups used for protein prenylation. Cytosolic HMG-CoA synthase (HMGCS1) condenses acetoacetyl-CoA with acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA); HMG-CoA reductase (HMGCR), the rate-limiting, committed, sterol-feedback-regulated enzyme and target of the statin drugs, reduces HMG-CoA to mevalonate using 2 NADPH on the endoplasmic-reticulum membrane; mevalonate kinase (MVK) and phosphomevalonate kinase (PMVK) then doubly phosphorylate mevalonate to mevalonate-5-diphosphate; and diphosphomevalonate decarboxylase (MVD) decarboxylates it to IPP. Inherited defects cause: mevalonate kinase deficiency (MVK) — spanning hyper-IgD/periodic fever syndrome to mevalonic aciduria; porokeratosis (MVD and MVK); and HMGCR/HMGCS1 are pharmacologic/ autoimmune (statin) and rare-myopathy loci rather than classic enzymopathies. |
Metabolic Pathway | DRAFT | 0 | isopentenyl diphosphate biosynthetic process, mevalonate pathway |
6 | 5 | 5 | 0 | 0 | 4 | 5/5 | 0 | ✗ | modules/mevalonate_pathway.yaml | |
Microsomal fatty-acid elongation cycle (ELOVL -> HSD17B12 -> HACD1/2 -> TECR)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. |
Metabolic Pathway | DRAFT | 0 | fatty acid elongation very long-chain fatty acid biosynthetic process |
5 | 4 | 4 | 0 | 0 | 4 | 10/10 | 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 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 FOXRED1 acts on a mid/late Q-module intermediate. 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/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 | 10 | 5 | 0 | 0 | 4 | 10/10 | 0 | ✗ | modules/complex_iv_assembly_factors.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 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 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 pyruvate fates — pyruvate dehydrogenase complex and pyruvate carboxylaseMODULE:pyruvate_metabolism The two committed mitochondrial fates of pyruvate (imported from glycolysis via the mitochondrial pyruvate carrier). (1) Oxidative decarboxylation... [more...][less]The two committed mitochondrial fates of pyruvate (imported from glycolysis via the mitochondrial pyruvate carrier). (1) Oxidative decarboxylation by the pyruvate dehydrogenase complex (PDC) links glycolysis to the TCA cycle: pyruvate + CoA + NAD+ -> acetyl-CoA + CO2 + NADH. The PDC is a giant mitochondrial-matrix multienzyme machine built on a 60-mer E2 (DLAT) core, with the thiamine-pyrophosphate-dependent E1 decarboxylase (an alpha2-beta2 heterotetramer of PDHA1 and PDHB), the E3-binding structural subunit PDHX (component X) that anchors the shared E3 dihydrolipoyl dehydrogenase (DLD), and DLD itself which reoxidises the lipoyl arms (passing electrons to NAD+). PDC flux is switched off by phosphorylation of E1alpha (by the pyruvate dehydrogenase kinases PDK1-4) and on by dephosphorylation (by the phosphatases PDP1/2). (2) Carboxylation by the biotin-dependent pyruvate carboxylase (PC): pyruvate + HCO3- + ATP -> oxaloacetate, the principal anaplerotic reaction replenishing TCA-cycle oxaloacetate and the committed first step of gluconeogenesis from pyruvate/lactate; PC is allosterically activated by acetyl-CoA (the PDC product), coordinating the two fates. 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), and PC deficiency causes lactic acidosis with hypoglycemia; DLD deficiency (the shared E3) gives a combined phenotype (see the BCAA and homocysteine/cobalamin contexts). |
Metabolic Pathway | DRAFT | 0 | pyruvate metabolic process |
3 | 6 | 2 | 0 | 0 | 1 | 6/6 | 0 | ✗ | modules/pyruvate_metabolism.yaml | |
Mitochondrial respiratory Complex I core (NADH:ubiquinone oxidoreductase) — catalytic N and Q modules; NDUFV1/NDUFV2/NDUFS1-3/NDUFS6-8/NDUFA9MODULE: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 — organised into two 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. 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 |
4 | 10 | 3 | 0 | 0 | 2 | 10/10 | 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 | 6 | 2 | 0 | 0 | 1 | 6/6 | 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 promotes assembly and dimerisation of the whole complex. 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 | |
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 | 7/22 | 0 | ✗ | modules/muth_independent_mismatch_repair.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 | 0 | dolichol-linked oligosaccharide biosynthetic process protein N-linked glycosylation |
6 | 6 | 5 | 0 | 0 | 4 | 6/6 | 0 | ✗ | modules/n_glycan_llo_assembly_cytoplasmic.yaml | |
N-glycan LLO assembly II — ER-lumenal face + glucosylation (to Glc3Man9GlcNAc2-PP-dolichol); 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 | 0 | dolichol-linked oligosaccharide biosynthetic process protein N-linked glycosylation |
8 | 7 | 7 | 0 | 0 | 6 | 6/6 | 0 | ✗ | modules/n_glycan_llo_assembly_lumenal.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 | |
NLR signaling pathway moduleMODULE:nlr_signaling Nucleotide-binding leucine-rich-repeat receptors detect intracellular perturbations and assemble RIPK-, ASC-, or caspase-containing signaling... [more...][less]Nucleotide-binding leucine-rich-repeat receptors detect intracellular perturbations and assemble RIPK-, ASC-, or caspase-containing signaling platforms for inflammatory and antimicrobial responses. |
Signaling Pathway | DRAFT | metazoa |
7 | nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 0/5 | 0 | ✓ | modules/nlr_signaling.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 | 0/6 | 0 | ✓ | modules/neurotrophin_trk_signaling.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 |
4 | 7 | 3 | 0 | 0 | 2 | 1/7 | 0 | ✓ | modules/nodal_signaling.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 | |
Osmoregulated periplasmic glucan biosynthesisMODULE:osmoregulated_periplasmic_glucan_biosynthesis A species-neutral Gram-negative bacterial module for osmoregulated periplasmic glucan backbone biosynthesis by an OpgH inner-membrane... [more...][less]A species-neutral Gram-negative bacterial module for osmoregulated periplasmic glucan backbone biosynthesis by an OpgH inner-membrane glucosyltransferase and an OpgG/OpgD-family periplasmic glucan-processing partner. Pseudomonas putida KT2440 provides the current UniProt exemplars, but accessory OPG decoration and unrelated cyclic-glucan routes remain outside the module boundary. |
Biological Process | DRAFT | 0 | osmoregulated periplasmic glucan biosynthetic process |
3 | 2 | 2 | 0 | 0 | 0 | 2/2 | 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 | 23 | 18 | 2 | 5 | 9 | 0/0 | 19 | ✗ | modules/oxphos.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. |
Biological Process | DRAFT | cyanobacteria eukaryotic algae land plants |
0 | oxygenic photosynthesis |
25 | 22 | 17 | 3 | 7 | 9 | 3/6 | 14 | ✓ | modules/photosynthesis.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 | 1/5 | 0 | ✓ | modules/pdgfr_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. Beta-alanine supply is an upstream dependency because organisms use different routes, including PanD-dependent aspartate decarboxylation, pyrimidine degradation, and uptake. 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 |
21 | 14 | 11 | 4 | 9 | 8 | 13/24 | 0 | ✓ | modules/coenzyme_a_biosynthesis.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 and the non-oxidative interconversion of pentose phosphates with fructose 6-phosphate and glyceraldehyde 3-phosphate. The oxidative branch generates NADPH through glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, with 6-phosphogluconolactonase hydrolyzing the intermediate lactone. The 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. Pseudomonas putida KT2440 proteins are used as concrete exemplars, but the boundary is the conserved PPP chemistry rather than a KT2440-specific KEGG map. |
Metabolic Pathway | DRAFT | 2 | pentose-phosphate shunt |
11 | 8 | 10 | 0 | 0 | 9 | 9/11 | 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_biosynthesis 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 | 10/12 | 0 | ✓ | modules/peptidoglycan_precursor_biosynthesis.yaml | |
Peroxisomal fatty-acid beta-oxidation (VLCFA, branched-chain, bile-acid intermediates)MODULE:peroxisomal_beta_oxidation Peroxisomal beta-oxidation chain-shortens the fatty acids that mitochondria cannot handle: very-long-chain fatty acids (VLCFAs, >=C22),... [more...][less]Peroxisomal beta-oxidation chain-shortens the fatty acids that mitochondria cannot handle: very-long-chain fatty acids (VLCFAs, >=C22), 2-methyl-branched fatty acids (pristanic acid, from phytanic-acid alpha-oxidation), the C27 bile-acid intermediates di- and tri-hydroxycholestanoyl-CoA (DHCA/THCA, en route to cholic/chenodeoxycholic acid), and dicarboxylic acids from omega-oxidation. Each cycle removes two carbons as acetyl-CoA through the same four reactions, but with peroxisome-specific enzymes. Step 1 is an FAD-dependent acyl-CoA OXIDASE that passes electrons directly to O2 (making H2O2, not feeding the respiratory chain): ACOX1 acts on straight-chain (VLC) acyl-CoAs, and ACOX3 on 2-methyl-branched (pristanoyl) acyl-CoAs. Steps 2-3 (hydration then NAD+-dependent dehydrogenation) are performed by multifunctional proteins of opposite stereochemistry: the D-bifunctional protein HSD17B4 (the main enzyme for VLCFA, pristanic acid and bile-acid intermediates) and the L-bifunctional protein EHHADH (more important for medium-chain and dicarboxylic-acid substrates). Step 4, thiolytic cleavage to acetyl-CoA (or propionyl-CoA for branched substrates) plus a shortened acyl-CoA, is carried out by ACAA1 (straight-chain thiolase) and by the SCPx thiolase (encoded by SCP2, which also yields the sterol-carrier protein SCP2) for branched-chain and bile-acid substrates. The chain-shortened acyl-CoA re-enters the spiral. Inherited single-enzyme defects — ACOX1 deficiency (pseudo-neonatal adrenoleukodystrophy), D-bifunctional protein (HSD17B4) deficiency, EHHADH (renal Fanconi), and SCP2 deficiency — as well as the peroxisome-biogenesis Zellweger spectrum, cause VLCFA/pristanic-acid/bile-acid accumulation with severe neurological disease. |
Metabolic Pathway | DRAFT | 0 | fatty acid beta-oxidation fatty acid beta-oxidation using acyl-CoA oxidase |
4 | 5 | 3 | 0 | 0 | 3 | 6/6 | 0 | ✗ | modules/peroxisomal_beta_oxidation.yaml | |
Peroxisome lifecycle and matrix protein import moduleMODULE:peroxisome_lifecycle Peroxisomes are maintained by coordinated membrane-protein delivery, matrix cargo recognition, receptor docking and translocation at the... [more...][less]Peroxisomes are maintained by coordinated membrane-protein delivery, matrix cargo recognition, receptor docking and translocation at the importomer, ubiquitin-dependent receptor recycling, membrane growth and division, and import of resident metabolic enzymes. This module captures the conserved peroxin roles and the major route variants that support peroxisome assembly, inheritance, and function across eukaryotes. |
Organelle Lifecycle | DRAFT | Eukaryota fungi with Pex15-dependent extraction human and metazoan cells where RRBP1 is retained metazoan lineages metazoan lineages and some fungi |
17 | peroxisome organization peroxisome |
20 | 14 | 9 | 5 | 10 | 8 | 16/18 | 5 | ✓ | modules/peroxisome-lifecycle.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 | |
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. The module represents the conserved SerA, SerC, and SerB reaction roles independently of their genomic arrangement. Additional activities of individual enzymes, including 2-hydroxyglutarate oxidation 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 | 3/6 | 0 | ✓ | modules/phosphorylated_serine_biosynthesis.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 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 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 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 |
8 | 8 | 7 | 0 | 0 | 5 | 0/10 | 0 | ✗ | modules/xylan_biosynthesis.yaml |
Polyamine metabolism (biosynthesis, back-conversion catabolism, and antizyme regulation)MODULE:polyamine_metabolism The polyamines putrescine, spermidine and spermine are small polycationic metabolites essential for cell growth, chromatin and nucleic-acid... [more...][less]The polyamines putrescine, spermidine and spermine are small polycationic metabolites essential for cell growth, chromatin and nucleic-acid stabilisation, ion-channel regulation and translation (spermidine is also the precursor of the eIF5A hypusine modification). Their intracellular levels are held under exceptionally tight homeostatic control by a biosynthetic arm, a catabolic/back-conversion arm and a dedicated feedback regulatory system. Biosynthesis begins with ornithine decarboxylase (ODC1), the rate-limiting, PLP-dependent enzyme that decarboxylates L-ornithine to putrescine. In parallel, the pyruvoyl-dependent S-adenosylmethionine decarboxylase (AMD1) produces decarboxylated SAM (dcSAM), the aminopropyl-group donor. Spermidine synthase (SRM) then transfers an aminopropyl group from dcSAM to putrescine to make spermidine, and spermine synthase (SMS) adds a further aminopropyl group to make spermine (each step releasing 5'-methylthioadenosine). Catabolism proceeds mainly by back-conversion: spermidine/spermine N1-acetyltransferase (SAT1) N1-acetylates spermine and spermidine using acetyl-CoA, and the peroxisomal FAD oxidase PAOX oxidises these N1-acetyl polyamines back to spermidine and putrescine (releasing H2O2 and 3-acetamidopropanal); spermine oxidase (SMOX) provides a parallel, acetylation- independent route that oxidises free spermine directly to spermidine. Overlaying all of this is the antizyme feedback loop: ornithine decarboxylase antizyme (OAZ1) — itself translated via a polyamine- stimulated +1 ribosomal frameshift — binds ODC1, inhibits it and targets it for ubiquitin-independent 26S proteasomal degradation while also suppressing polyamine uptake; antizyme inhibitor (AZIN1), a catalytically dead ODC homolog, binds and sequesters antizyme to release active ODC1. Dysregulated polyamine metabolism drives cancer and several inherited disorders (ODC1 gain-of-function Bachmann-Bupp syndrome; SMS-deficiency Snyder-Robinson syndrome; SAT1 overactivity). |
Metabolic Pathway | DRAFT | 0 | polyamine biosynthetic process polyamine catabolic process |
10 | 9 | 9 | 0 | 0 | 9 | 9/9 | 0 | ✗ | modules/polyamine_metabolism.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 | 1/7 | 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 | DRAFT | 0 | Mo-molybdopterin cofactor biosynthetic process |
15 | 10 | 10 | 2 | 4 | 6 | 9/16 | 3 | ✓ | modules/molybdenum_cofactor_biosynthesis.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 | |
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 | |
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 | 4 | peptidoglycan turnover |
9 | 8 | 8 | 0 | 0 | 9 | 8/13 | 0 | ✗ | modules/peptidoglycan_recycling.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 nucleotide interconversion (IMP -> AMP/GMP; purine nucleotide cycle) — ADSS1/IMPDH/AMPD disordersMODULE:purine_nucleotide_interconversion Inosine monophosphate (IMP), the first complete purine nucleotide made by de novo synthesis (and by salvage), sits at the branch point from which... [more...][less]Inosine monophosphate (IMP), the first complete purine nucleotide made by de novo synthesis (and by salvage), sits at the branch point from which the adenine and guanine ribonucleotides are made, and it is the hub of the purine nucleotide cycle. Toward AMP, adenylosuccinate synthetase (ADSS1 muscle / ADSS2 liver) condenses IMP with L-aspartate using GTP to form adenylosuccinate (S-AMP), which adenylosuccinate lyase (ADSL) then cleaves to AMP + fumarate. Toward GMP, IMP dehydrogenase (IMPDH1/IMPDH2) oxidises IMP to xanthosine monophosphate (XMP) with NAD+ — the committed, rate-limiting step of guanine- nucleotide synthesis — and GMP synthase (GMPS) then aminates XMP to GMP using the amide nitrogen of glutamine. Completing the cycle, AMP deaminase (AMPD1 muscle / AMPD2 broad- neuronal / AMPD3 erythrocyte) hydrolytically deaminates AMP back to IMP + ammonia; in exercising muscle the AMPD1 -> ADSS1 -> ADSL loop (the purine nucleotide cycle) buffers the adenylate energy charge and supplies fumarate (anaplerosis) and ammonia. Because GTP is required to make AMP and ATP to make GMP, these reactions also cross-regulate the two nucleotide pools. Inherited defects: ADSS1 deficiency causes a distal myopathy; IMPDH1 mutations cause retinitis pigmentosa (RP10) and IMPDH2 a neurodevelopmental dystonia (IMPDH2 is the mycophenolate/ribavirin target); AMPD1 deficiency is myoadenylate deaminase deficiency (common, often benign) and AMPD2 deficiency causes pontocerebellar hypoplasia type 9 / spastic paraplegia (SPG63). |
Metabolic Pathway | DRAFT | 0 | purine nucleotide biosynthetic process |
5 | 4 | 4 | 0 | 0 | 3 | 7/7 | 0 | ✗ | modules/purine_nucleotide_interconversion.yaml | |
Purine salvage and catabolism (to uric acid) — Lesch-Nyhan, ADA/PNP-SCID, xanthinuriaMODULE:purine_salvage_and_catabolism The cytosolic handling of purine bases and nucleosides after nucleic-acid/nucleotide turnover, comprising a salvage arm (which recycles free bases... [more...][less]The cytosolic handling of purine bases and nucleosides after nucleic-acid/nucleotide turnover, comprising a salvage arm (which recycles free bases into nucleotides, sparing costly de novo synthesis) and a catabolic arm (which degrades purine nucleosides to the excretory end-product uric acid). Salvage: hypoxanthine-guanine phosphoribosyltransferase (HPRT1) transfers the phosphoribosyl group of PRPP onto hypoxanthine and guanine to regenerate IMP and GMP, and adenine phosphoribosyltransferase (APRT) does the same for adenine to regenerate AMP. Catabolism: adenosine deaminase (ADA) deaminates (deoxy)adenosine to (deoxy)inosine; purine nucleoside phosphorylase (PNP) phosphorolyses inosine, guanosine and their deoxy forms to the free bases hypoxanthine/guanine (which can then re-enter salvage via HPRT1 or continue to catabolism); and xanthine oxidoreductase (XDH) oxidises hypoxanthine to xanthine and xanthine to urate (uric acid), the final human purine catabolite (humans lack uricase). Inherited defects define classic disorders: HPRT1 deficiency causes Lesch-Nyhan syndrome (complete) or Kelley-Seegmiller gout/hyperuricemia (partial); APRT deficiency causes 2,8-dihydroxyadenine nephrolithiasis; ADA deficiency causes ADA-SCID and PNP deficiency a T-cell immunodeficiency (both from lymphotoxic deoxynucleotide accumulation); and XDH deficiency causes xanthinuria type I (XDH is the target of the gout drugs allopurinol/febuxostat). |
Metabolic Pathway | DRAFT | 0 | purine nucleobase metabolic process |
6 | 5 | 5 | 0 | 0 | 3 | 5/5 | 0 | ✗ | modules/purine_salvage_and_catabolism.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 | 0 | pyrroloquinoline quinone biosynthetic process |
9 | 8 | 5 | 1 | 3 | 5 | 7/10 | 2 | ✓ | modules/pqq_biosynthesis.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 | 2/5 | 0 | ✓ | modules/rig_i_signaling.yaml |
Reductive pyrimidine degradationMODULE:pyrimidine_degradationCONCRETE A reusable three-reaction pathway for reductive degradation of uracil and thymine. Dihydropyrimidine dehydrogenase first reduces the pyrimidine... [more...][less]A reusable three-reaction pathway for reductive degradation of uracil and thymine. Dihydropyrimidine dehydrogenase first reduces the pyrimidine ring, dihydropyrimidinase opens the saturated ring, and beta-ureidopropionase releases beta-alanine or beta-aminoisobutyrate, carbon dioxide, and ammonium. The pathway chemistry is conserved, but the first and third enzymes have distinct taxonomic implementations. |
Metabolic Pathway | DRAFT | bacteria eukaryotes |
0 | pyrimidine nucleobase catabolic process |
8 | 5 | 3 | 2 | 4 | 2 | 6/6 | 1 | ✗ | modules/pyrimidine_degradation.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 | 1/5 | 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 | |
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 | 0/4 | 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 | |
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 | |
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 | |
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 | |
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, 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) and an NPL-related myopathy — several of which are amenable to ManNAc / sialic-acid supplementation. |
Metabolic Pathway | DRAFT | 0 | N-acetylneuraminate biosynthetic process N-acetylneuraminate catabolic process |
8 | 7 | 7 | 0 | 0 | 6 | 7/7 | 0 | ✗ | modules/sialic_acid_metabolism.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 | |
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 |
T cell receptor signaling pathway moduleMODULE:t_cell_receptor_signaling A compact T cell receptor (TCR) signaling module. Antigen-bound TCR/CD3 complexes are phosphorylated by Src-family kinases such as LCK, recruit and... [more...][less]A compact T cell receptor (TCR) signaling module. Antigen-bound TCR/CD3 complexes are phosphorylated by Src-family kinases such as LCK, recruit and activate ZAP70, phosphorylate LAT/SLP76 adaptor scaffolds, and split into PLC gamma/calcium/NFAT, Ras-MAPK/AP-1, and PKC/NF-kappaB outputs. The module is grounded in GO:0050852 and uses PAINT PTN anchors for the LCK/ZAP70 non-receptor tyrosine kinase tier where the local cache supports them. |
Signaling Pathway | DRAFT | jawed vertebrates |
2 | T cell receptor signaling pathway |
4 | 6 | 3 | 0 | 0 | 2 | 0/7 | 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 |
4 | 4 | 3 | 0 | 0 | 2 | 1/6 | 0 | ✗ | modules/tgfb_smad_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 |
9 | tumor necrosis factor-mediated signaling pathway |
4 | 7 | 3 | 0 | 0 | 2 | 1/5 | 0 | ✓ | modules/tnf_signaling.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 | |
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 | |
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 |
4 | 3 | 3 | 0 | 0 | 2 | 3/3 | 0 | ✗ | modules/thymidylate_synthesis.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 | 1/5 | 0 | ✗ | modules/toll_like_receptor_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 |
1 | 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 pathway in which TreY converts the reducing end of an alpha-1,4-glucan to a trehalose-containing alpha,alpha-1,1 linkage... [more...][less]A reusable two-reaction pathway in which TreY converts the reducing end of an alpha-1,4-glucan to a trehalose-containing alpha,alpha-1,1 linkage and TreZ hydrolyzes the resulting maltooligosyltrehalose to release trehalose. Alpha-glucan synthesis and remodeling, alternative OtsA/OtsB or TreS trehalose routes, and trehalose degradation are outside the boundary. |
Metabolic Pathway | DRAFT | 0 | trehalose biosynthetic process |
3 | 2 | 2 | 0 | 0 | 1 | 2/4 | 0 | ✗ | modules/trey_trez_trehalose_biosynthesis.yaml | |
Tricarboxylic acid cycleMODULE:tca_cycle 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, oxidative decarboxylation to succinyl-CoA, succinate-level phosphorylation, succinate oxidation through respiratory complex II, fumarate hydration, and malate oxidation to regenerate oxaloacetate. The module also records common bacterial alternatives at the malate/oxaloacetate node and pyruvate carboxylase as an anaplerotic input to oxaloacetate. |
Metabolic Pathway | DRAFT | 0 | tricarboxylic acid cycle |
13 | 12 | 12 | 0 | 0 | 0 | 0/0 | 11 | ✓ | modules/tca_cycle.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 | 3/8 | 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 | 2/6 | 0 | ✓ | modules/type_ii_interferon_signaling.yaml |
Type-II fatty-acid synthesisMODULE:type_ii_fatty_acid_synthesis A reusable dissociated bacterial fatty-acid synthase pathway that forms malonyl-CoA with acetyl-CoA carboxylase, loads malonate onto acyl carrier... [more...][less]A reusable dissociated bacterial fatty-acid synthase pathway that forms malonyl-CoA with acetyl-CoA carboxylase, loads malonate onto acyl carrier protein, initiates an acyl-ACP chain, and iteratively elongates that chain through condensation, beta-keto reduction, dehydration, and enoyl reduction. An optional FabA/FabB branch introduces and extends cis unsaturation. Enzyme-family and cofactor variants are represented explicitly rather than collapsed into a type-I fatty-acid synthase. |
Metabolic Pathway | DRAFT | 1 | fatty acid biosynthetic process |
27 | 18 | 14 | 5 | 12 | 11 | 15/18 | 0 | ✓ | modules/type_ii_fatty_acid_synthesis.yaml | |
Ubiquinone biosynthesis from chorismate-derived 4-hydroxybenzoateMODULE:ubiquinone_biosynthesis Reusable bacterial pathway for de novo aerobic biosynthesis of ubiquinone (coenzyme Q) from chorismate-derived 4-hydroxybenzoate and a supplied... [more...][less]Reusable bacterial pathway for de novo aerobic biosynthesis of ubiquinone (coenzyme Q) from chorismate-derived 4-hydroxybenzoate and a supplied polyprenyl diphosphate side chain. UbiC forms the aromatic head group, UbiA attaches the side chain, and UbiD decarboxylates the prenylated intermediate using prenylated FMN supplied by UbiX. Three complementary ring hydroxylations and three methylations then generate mature ubiquinone. The identities of the aerobic hydroxylases vary by lineage; Coq7-family enzymes can replace the UbiF-type late hydroxylase. UbiJ, UbiK, and UbiB are modeled as optional bacterial assembly/ATP-dependent accessory context rather than reaction chemistry. Oxygen-independent UbiT/UbiU/UbiV implementations are a distinct conditional variant and are outside this aerobic module. |
Metabolic Pathway | DRAFT | 7 | ubiquinone biosynthetic process |
7 | 13 | 6 | 0 | 0 | 7 | 12/24 | 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 | 9/11 | 0 | ✗ | modules/urea_cycle.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 | 1/6 | 0 | ✓ | modules/vegfr_signaling.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 | |
Vitamin B6 (pyridoxal 5'-phosphate) salvage and homeostasis (PDXK/PNPO/PDXP)MODULE:vitamin_b6_plp_metabolism Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the obligatory cofactor of ~140 human enzymes — transaminases, decarboxylases,... [more...][less]Pyridoxal 5'-phosphate (PLP) is the active form of vitamin B6 and the obligatory cofactor of ~140 human enzymes — transaminases, decarboxylases, racemases and others across amino-acid, one-carbon, heme and neurotransmitter metabolism. Because humans cannot synthesise the vitamin de novo, PLP is produced and homeostatically balanced by a small salvage pathway that interconverts the dietary B6 vitamers and their phosphorylated forms. Pyridoxal kinase (PDXK) phosphorylates the three unphosphorylated vitamers — pyridoxal, pyridoxine and pyridoxamine — with ATP (and a divalent metal) to pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PNP) and pyridoxamine 5'-phosphate (PMP). The FMN-dependent pyridoxine 5'-phosphate oxidase (PNPO) then carries out the terminal, rate-limiting step, oxidising PNP and PMP to the active PLP cofactor. Balancing this, the magnesium-dependent pyridoxal phosphatase PDXP (chronophin) dephosphorylates PLP back to pyridoxal, tuning intracellular PLP levels; PDXP also has a well-documented moonlighting role dephosphorylating the actin-regulatory protein cofilin (phospho-Ser3) to promote actin depolymerisation. Inherited PNPO deficiency causes a severe pyridoxal-5'-phosphate-responsive neonatal epileptic encephalopathy, underscoring how tightly neuronal PLP supply depends on this pathway. |
Metabolic Pathway | DRAFT | 0 | pyridoxal 5'-phosphate salvage vitamin B6 metabolic process |
3 | 3 | 2 | 0 | 0 | 1 | 3/3 | 0 | ✗ | modules/vitamin_b6_plp_metabolism.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 | DRAFT | bacteria |
0 | dTDP-rhamnose biosynthetic process |
5 | 6 | 4 | 0 | 0 | 3 | 6/6 | 0 | ✓ | modules/dtdp_l_rhamnose_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 | 0 | p38MAPK cascade stress-activated MAPK cascade |
8 | 6 | 7 | 0 | 0 | 5 | 1/4 | 3 | ✗ | modules/p38_cascade.yaml |