# Generated by audit_activator_convergence.py; do not edit by hand. summary: ALTERNATIVE_VARIANTS: 40 DECLARED: 8 UNDECIDED: 226 steps: - module: adrenal_steroidogenesis step: cyp17a1_step step_label: 17alpha-hydroxylation and 17,20-lyase (to 17OH-steroids and DHEA/androstenedione) classification: UNDECIDED default_rule: (cyp11a1_step | hsd3b2_step) rule: (cyp11a1_step | hsd3b2_step) activators: - id: cyp11a1_step label: cholesterol to pregnenolone connection: 'PROVIDES_INPUT_FOR: Pregnenolone can also be 17-hydroxylated first by CYP17A1 (Delta5 pathway).' - id: hsd3b2_step label: pregnenolone to progesterone (and 17OH-pregnenolone to 17OH-progesterone; DHEA to androstenedione) connection: 'PROVIDES_INPUT_FOR: Progesterone from HSD3B2 is 17-hydroxylated by CYP17A1 toward the cortisol branch.' - module: adrenal_steroidogenesis step: cyp21a2_step step_label: 21-hydroxylation (progesterone to DOC; 17OH-progesterone to 11-deoxycortisol) classification: UNDECIDED default_rule: (cyp17a1_step | hsd3b2_step) rule: (cyp17a1_step | hsd3b2_step) activators: - id: cyp17a1_step label: 17alpha-hydroxylation and 17,20-lyase (to 17OH-steroids and DHEA/androstenedione) connection: 'PROVIDES_INPUT_FOR: 17-hydroxyprogesterone from CYP17A1 is 21-hydroxylated by CYP21A2 to 11-deoxycortisol.' - id: hsd3b2_step label: pregnenolone to progesterone (and 17OH-pregnenolone to 17OH-progesterone; DHEA to androstenedione) connection: 'PROVIDES_INPUT_FOR: Progesterone from HSD3B2 is 21-hydroxylated by CYP21A2 to DOC (mineralocorticoid branch).' - module: alginate_polymerization_export step: algK_scaffold step_label: AlgK secretion scaffold classification: UNDECIDED default_rule: (alg8_alg44_synthase | algG_maturation) rule: (alg8_alg44_synthase | algG_maturation) activators: - id: alg8_alg44_synthase label: Alg8-Alg44 alginate synthase complex connection: 'PRECEDES: ' - id: algG_maturation label: AlgG periplasmic epimerization connection: 'PRECEDES: ' - module: aliphatic_glucosinolate_myrosinase_defense step: mam_condensation step_label: Methylthioalkylmalate synthase (MAM) classification: UNDECIDED default_rule: (ipmdh_decarboxylation | met_deamination) rule: (ipmdh_decarboxylation | met_deamination) activators: - id: ipmdh_decarboxylation label: Isopropylmalate dehydrogenase (IPMDH1) connection: 'PROVIDES_INPUT_FOR: The elongated 2-oxo acid can re-enter MAM for a further turn.' - id: met_deamination label: Methionine deamination (BCAT4) connection: 'PROVIDES_INPUT_FOR: 4-methylthio-2-oxobutanoate made in the cytosol is imported into the chloroplast (the transport step is outside this module) and is the MAM acceptor.' - module: aliphatic_glucosinolate_myrosinase_defense step: myrosinase_hydrolysis step_label: Myrosinase (thioglucosidase) hydrolysis classification: UNDECIDED default_rule: (alkenylation | sulfation) rule: (alkenylation | sulfation) activators: - id: alkenylation label: AOP2 alkenyl glucosinolate formation connection: via a container - id: sulfation label: Desulfoglucosinolate sulfotransferase (SOT17/SOT18) connection: via a container - module: aps_dependent_assimilatory_sulfate_reduction step: sulfite_reduction_step step_label: Assimilatory reduction of sulfite to sulfide classification: ALTERNATIVE_VARIANTS default_rule: (direct_aps_reduction_route | paps_reductase_activity) rule: (direct_aps_reduction_route | paps_reductase_activity) activators: - id: direct_aps_reduction_route label: Direct APS reduction connection: via a container - id: paps_reductase_activity label: PAPS reductase connection: via a container - module: arginine_biosynthesis step: acetylglutamate_kinase_step step_label: N-acetyl-L-glutamate to N-acetyl-L-glutamyl 5-phosphate classification: UNDECIDED default_rule: (argJ_transacetylation_variant | glutamate_acetylation_step) rule: (argJ_transacetylation_variant | glutamate_acetylation_step) activators: - id: argJ_transacetylation_variant label: Cyclic ArgJ transacetylation connection: 'PROVIDES_INPUT_FOR: The cyclic ArgJ release reaction regenerates N-acetyl-L-glutamate for the kinase step; this feedback does not replace the forward eight-step chain or make ArgJ mandatory for the linear ArgA/ArgE route.' - id: glutamate_acetylation_step label: L-glutamate to N-acetyl-L-glutamate connection: 'PRECEDES: ' - module: arginine_biosynthesis step: ornithine_carbamoyltransferase_step step_label: L-ornithine to L-citrulline classification: UNDECIDED default_rule: (argE_deacetylation_variant | argJ_transacetylation_variant | carbamoyl_phosphate_synthetase_a_step) rule: (argE_deacetylation_variant | argJ_transacetylation_variant | carbamoyl_phosphate_synthetase_a_step) activators: - id: argE_deacetylation_variant label: Hydrolytic ArgE deacetylation connection: via a container - id: argJ_transacetylation_variant label: Cyclic ArgJ transacetylation connection: via a container - id: carbamoyl_phosphate_synthetase_a_step label: L-glutamine + hydrogencarbonate + 2 ATP to carbamoyl phosphate connection: 'PROVIDES_INPUT_FOR: Where present, the pathway-dedicated CPS-A supplies the carbamoyl phosphate co-substrate of ornithine carbamoyltransferase; it is a side input, not a step in the glutamate-to-arginine carbon chain.' - module: auxin_polar_transport step: pin_polar_efflux step_label: PIN-mediated polar auxin efflux classification: UNDECIDED default_rule: (abcb_auxin_export | auxin_influx | pin_kinase_regulation) rule: (abcb_auxin_export | auxin_influx | pin_kinase_regulation) activators: - id: abcb_auxin_export label: ABCB19-mediated auxin export connection: 'POSITIVELY_REGULATES: ABCB19 interacts with PIN1 and stabilizes it in sterol-enriched plasma membrane domains, enhancing coordinated auxin efflux.' - id: auxin_influx label: AUX1/LAX auxin influx connection: 'PROVIDES_INPUT_FOR: Auxin imported by AUX1 is the cellular pool exported by polar PINs (e.g. AUX1 and PIN2 together drive the root-tip shootward stream in gravitropism).' - id: pin_kinase_regulation label: PIN phosphorylation by PID and D6PK connection: 'POSITIVELY_REGULATES: PID and D6PK phosphorylate the PIN hydrophilic loop, activating efflux and (for PID) directing apical PIN polarity.' - module: bacterial_alkanesulfonate_uptake_desulfonation step: ssud_desulfonation step_label: SsuD alkanesulfonate monooxygenation classification: DECLARED default_rule: (ssuabc_import | ssue_fmn_reduction) rule: ssuabc_import & ssue_fmn_reduction activators: - id: ssuabc_import label: SsuABC alkanesulfonate import connection: 'PROVIDES_INPUT_FOR: SsuABC supplies cytoplasmic alkanesulfonate to SsuD.' - id: ssue_fmn_reduction label: SsuE NADPH-dependent FMN reduction connection: 'PROVIDES_INPUT_FOR: SsuE supplies reduced FMN to the SsuD monooxygenase cycle.' - module: bacterial_c_di_amp_signaling step: c_di_amp_hydrolysis step_label: Phosphodiesterase hydrolysis of c-di-AMP to pApA classification: UNDECIDED default_rule: (c_di_amp_synthesis | papa_clearance) rule: (c_di_amp_synthesis | papa_clearance) activators: - id: c_di_amp_synthesis label: Diadenylate cyclase synthesis of c-di-AMP connection: 'PRECEDES: Cyclase-made c-di-AMP is the substrate of GdpP and PgpH. Cyclase and phosphodiesterase act on the same pool in opposition, and the steady-state level, which must stay within a narrow window, is set by their relative activities; that opposition is a shared-pool effect, not a regulation of one enzyme by the other, and is not encoded as a regulatory edge.' - id: papa_clearance label: Pde2/NrnA-class hydrolysis of pApA to AMP connection: 'POSITIVELY_REGULATES: By keeping pApA low, the clearance step relieves pApA feedback inhibition of GdpP and so sustains c-di-AMP hydrolysis.' - module: bacterial_chemotaxis_signal_transduction step: flagellar_motor_rotation_output step_label: Flagellum-dependent motility output classification: UNDECIDED default_rule: (c_ring_motor_switch | flagellar_stator_conductance) rule: (c_ring_motor_switch | flagellar_stator_conductance) activators: - id: c_ring_motor_switch label: FliG/FliM/FliN C-ring switch connection: 'CAUSES: C-ring conformation sets rotational direction and switching bias.' - id: flagellar_stator_conductance label: Flagellar stator proton conductance connection: 'CAUSES: Proton conductance through occupied stators supplies torque for rotation.' - module: bacterial_chromosomal_dna_replication step: poliii_core_synthesis step_label: DNA polymerase III alpha-epsilon core classification: UNDECIDED default_rule: (beta_clamp_processivity | dnag_priming) rule: (beta_clamp_processivity | dnag_priming) activators: - id: beta_clamp_processivity label: DnaN beta sliding clamp connection: 'PROVIDES_INPUT_FOR: ' - id: dnag_priming label: DnaG primer synthesis connection: 'PROVIDES_INPUT_FOR: ' - module: bacterial_cytochrome_c_maturation_system_i step: ccme_heme_chaperone step_label: CcmE heme chaperone classification: UNDECIDED default_rule: (ccmc_heme_handling_subunit | ccmd_accessory_subunit) rule: (ccmc_heme_handling_subunit | ccmd_accessory_subunit) activators: - id: ccmc_heme_handling_subunit label: CcmC heme-handling subunit connection: 'PROVIDES_INPUT_FOR: ' - id: ccmd_accessory_subunit label: CcmD accessory subunit connection: 'PROVIDES_INPUT_FOR: ' - module: bacterial_cytochrome_c_maturation_system_i step: ccmfh_heme_ligation step_label: CcmF/CcmH heme-ligation machinery classification: UNDECIDED default_rule: (ccmab_energy_coupling | ccmh_redox_component) rule: (ccmab_energy_coupling | ccmh_redox_component) activators: - id: ccmab_energy_coupling label: CcmAB energy-coupling subcomplex connection: via a container - id: ccmh_redox_component label: CcmH redox component connection: via a container - module: bacterial_flagellar_assembly_export step: filament_completion step_label: Hook-filament junction, flagellin filament, and cap classification: UNDECIDED default_rule: (flagellar_late_transcription | rod_hook_assembly) rule: (flagellar_late_transcription | rod_hook_assembly) activators: - id: flagellar_late_transcription label: FliA and FlgM transcriptional checkpoint connection: 'POSITIVELY_REGULATES: ' - id: rod_hook_assembly label: Distal rod, hook, and hook-length checkpoint connection: 'PRECEDES: ' - module: bacterial_isc_iron_sulfur_cluster_assembly step: iscu_scaffold_assembly step_label: IscU scaffold assembly classification: DECLARED default_rule: (fdx_electron_delivery | isc_sulfur_mobilization) rule: isc_sulfur_mobilization & fdx_electron_delivery activators: - id: fdx_electron_delivery label: Isc ferredoxin electron delivery connection: 'PROVIDES_INPUT_FOR: ' - id: isc_sulfur_mobilization label: IscS sulfur mobilization connection: 'PROVIDES_INPUT_FOR: ' - module: bacterial_methionine_cycle step: homocysteine_remethylation step_label: Folate-dependent methionine regeneration classification: ALTERNATIVE_VARIANTS default_rule: (ahcy_route | luxs_step) rule: (ahcy_route | luxs_step) activators: - id: ahcy_route label: Direct AhcY hydrolysis connection: via a container - id: luxs_step label: S-ribosylhomocysteine cleavage connection: via a container - module: bacterial_nonhomologous_end_joining step: ligd_end_ligation step_label: LigD-mediated DNA-end sealing classification: DECLARED default_rule: (ku_end_recognition | ligd_end_processing) rule: ku_end_recognition activators: - id: ku_end_recognition label: Ku-dependent double-strand-break end recognition connection: 'PROVIDES_INPUT_FOR: Ku-bound compatible ends can be sealed without an obligatory processing reaction.' - id: ligd_end_processing label: LigD-dependent DNA-end remodeling connection: 'PRECEDES: When remodeling is required, polymerase or phosphatase activity generates a ligatable substrate before sealing.' - module: bacterial_pst_phosphate_uptake step: pstsacb_phosphate_translocation step_label: PstSACB phosphate translocation classification: DECLARED default_rule: (pstb_energy_coupling | psts_phosphate_capture) rule: psts_phosphate_capture & pstb_energy_coupling activators: - id: pstb_energy_coupling label: PstB ATP hydrolysis connection: 'CAUSES: PstB ATP hydrolysis drives phosphate passage through PstA/PstC.' - id: psts_phosphate_capture label: PstS phosphate capture connection: 'PROVIDES_INPUT_FOR: Phosphate-loaded PstS presents substrate to PstCAB.' - module: bacterial_purine_base_oxidation_to_urate step: xanthine_oxidation_to_urate step_label: XdhAB-dependent xanthine oxidation to urate classification: ALTERNATIVE_VARIANTS default_rule: (guanine_deamination_route | hypoxanthine_oxidation_route) rule: (guanine_deamination_route | hypoxanthine_oxidation_route) activators: - id: guanine_deamination_route label: Guanine deamination to xanthine connection: 'PRECEDES: The guanine branch converges on the terminal xanthine oxidation step.' - id: hypoxanthine_oxidation_route label: Hypoxanthine oxidation to xanthine connection: 'PRECEDES: The hypoxanthine branch proceeds through xanthine to urate.' - module: bacterial_rna_degradation step: rna_exonucleolysis step_label: Processive 3'-to-5' RNA degradation classification: UNDECIDED default_rule: (degradosome_helicase_assistance | rne_endonucleolytic_cleavage) rule: (degradosome_helicase_assistance | rne_endonucleolytic_cleavage) activators: - id: degradosome_helicase_assistance label: DEAD-box-helicase-assisted RNA unwinding connection: 'PROVIDES_INPUT_FOR: Helicase-assisted unwinding makes structured substrates accessible to exonucleases.' - id: rne_endonucleolytic_cleavage label: RNase E cleavage of RNA connection: 'PROVIDES_INPUT_FOR: RNase E cleavage generates substrates for processive 3''-to-5'' degradation.' - module: bacterial_rna_polymerase_core step: rpob_rpoc_catalytic_cleft step_label: RpoB/RpoC catalytic cleft classification: UNDECIDED default_rule: (rpoa_alpha_dimer_platform | rpoz_omega_assembly_subunit) rule: (rpoa_alpha_dimer_platform | rpoz_omega_assembly_subunit) activators: - id: rpoa_alpha_dimer_platform label: RpoA alpha dimer platform connection: 'PROVIDES_INPUT_FOR: The alpha dimer provides the assembly platform for recruitment of the beta and beta-prime subunits into the core enzyme.' - id: rpoz_omega_assembly_subunit label: RpoZ omega assembly/stability subunit connection: 'PROVIDES_INPUT_FOR: The omega subunit supports proper assembly and stability of the beta/beta-prime-containing core enzyme.' - module: bacterial_ruvabc_holliday_junction_processing step: ruvc_junction_resolution step_label: RuvC cleavage and resolution of the Holliday junction classification: UNDECIDED default_rule: (recg_branch_migration | ruvb_branch_migration) rule: (recg_branch_migration | ruvb_branch_migration) activators: - id: recg_branch_migration label: RecG-dependent alternative branch migration connection: 'PROVIDES_INPUT_FOR: ' - id: ruvb_branch_migration label: RuvB-driven Holliday-junction branch migration connection: 'PROVIDES_INPUT_FOR: ' - module: bacterial_sec_posttranslational_protein_export step: secyeg_channel step_label: SecYEG protein-conducting channel classification: DECLARED default_rule: (seca_atpase_motor | secdf_yajc_accessory_complex) rule: seca_atpase_motor activators: - id: seca_atpase_motor label: SecA ATP-driven protein-export motor connection: 'PROVIDES_INPUT_FOR: ' - id: secdf_yajc_accessory_complex label: SecDF-YajC accessory translocation complex connection: 'POSITIVELY_REGULATES: SecDF uses proton motive force to improve late-stage translocation through SecYEG; this accessory route is not obligatory for every substrate.' - module: bacterial_shikimate_chorismate_biosynthesis step: chorismate_formation step_label: EPSP to chorismate classification: ALTERNATIVE_VARIANTS default_rule: (arom_epsps_step | discrete_epsps_step) rule: (arom_epsps_step | discrete_epsps_step) activators: - id: arom_epsps_step label: shikimate 3-phosphate to EPSP connection: via a container - id: discrete_epsps_step label: shikimate 3-phosphate to EPSP connection: via a container - module: bacterial_twin_arginine_translocation step: tata_translocation_assembly step_label: Active Tat translocon assembly classification: UNDECIDED default_rule: (tatb_receptor_organization | tatc_substrate_recognition) rule: (tatb_receptor_organization | tatc_substrate_recognition) activators: - id: tatb_receptor_organization label: TatB receptor-complex organization connection: 'PRECEDES: ' - id: tatc_substrate_recognition label: TatC substrate recognition connection: 'PRECEDES: ' - module: bacterial_type_ii_secretion step: pseudopilus step_label: Type II secretion pseudopilus classification: UNDECIDED default_rule: (inner_membrane_platform | secretion_atpase) rule: (inner_membrane_platform | secretion_atpase) activators: - id: inner_membrane_platform label: Type II secretion inner-membrane platform connection: 'PROVIDES_INPUT_FOR: ' - id: secretion_atpase label: Type II secretion ATPase connection: 'CAUSES: ' - module: bacterial_type_iv_secretion_apparatus step: conjugative_pilus step_label: Type IV secretion pilus classification: DECLARED default_rule: (envelope_core_complex | mating_pair_stabilization | virb4_family_atpase) rule: envelope_core_complex & virb4_family_atpase activators: - id: envelope_core_complex label: Type IV secretion envelope core complex connection: 'PROVIDES_INPUT_FOR: The core complex provides the outer-membrane platform from which the filament extends.' - id: mating_pair_stabilization label: Mating-pair stabilization connection: 'POSITIVELY_REGULATES: Stabilizing the mating pair converts transient pilus-mediated contact into a junction that persists for the duration of transfer.' - id: virb4_family_atpase label: VirB4-family translocation ATPase connection: 'CAUSES: VirB4-family activity is required for polymerization of mature pilin subunits into an extended pilus.' - module: bile_acid_biosynthesis step: hsd3b7_step step_label: 3-beta-hydroxy-Delta5-C27-steroid dehydrogenase (HSD3B7) classification: UNDECIDED default_rule: (cholesterol_7a_hydroxylation | oxysterol_7a_hydroxylation) rule: (cholesterol_7a_hydroxylation | oxysterol_7a_hydroxylation) activators: - id: cholesterol_7a_hydroxylation label: Cholesterol 7-alpha-hydroxylase (CYP7A1) connection: 'PROVIDES_INPUT_FOR: The 7-alpha-hydroxycholesterol made by CYP7A1 is oxidised/isomerised by HSD3B7.' - id: oxysterol_7a_hydroxylation label: Oxysterol 7-alpha-hydroxylases (CYP7B1 / CYP39A1) connection: 'PROVIDES_INPUT_FOR: The 7-alpha-hydroxylated oxysterols converge on the shared HSD3B7 3-oxo-Delta4 step.' - module: bile_acid_synthesis_ring_modification step: hsd3b7_step step_label: 7-alpha-hydroxycholesterol to 7-alpha-hydroxy-4-cholesten-3-one classification: UNDECIDED default_rule: (cyp7a1_step | cyp7b1_step) rule: (cyp7a1_step | cyp7b1_step) activators: - id: cyp7a1_step label: cholesterol to 7-alpha-hydroxycholesterol connection: 'PROVIDES_INPUT_FOR: 7-alpha-hydroxycholesterol (classic pathway) is oxidised/isomerised by HSD3B7.' - id: cyp7b1_step label: 25-/27-hydroxycholesterol to 7-alpha,X-dihydroxycholesterol connection: 'PROVIDES_INPUT_FOR: 7-alpha-hydroxy-oxysterols (acidic pathway) are also processed by HSD3B7.' - module: bile_acid_synthesis_sidechain_conjugation step: baat_step step_label: choloyl-CoA + glycine/taurine to glyco-/tauro-cholate classification: UNDECIDED default_rule: (acox2_step | slc27a5_step) rule: (acox2_step | slc27a5_step) activators: - id: acox2_step label: (25S)-THCA-CoA to 24-ene-THCA-CoA (leading to choloyl-CoA) connection: 'PROVIDES_INPUT_FOR: Peroxisomal beta-oxidation (ACOX2 + MFP2/SCPx) shortens the side chain to the C24 choloyl-CoA that BAAT conjugates.' - id: slc27a5_step label: cholate + CoA + ATP to choloyl-CoA connection: 'PROVIDES_INPUT_FOR: SLC27A5 re-activates free bile acids to choloyl-CoA, supplying BAAT for re-conjugation during enterohepatic recycling.' - module: biotin_biosynthesis step: bioF_step step_label: Pimelate thioester to 8-amino-7-oxononanoate (KAPA) classification: ALTERNATIVE_VARIANTS default_rule: (bioH_step | fungal_peroxisomal_beta_oxidation_variant | saccharomyces_bio1_variant) rule: (bioH_step | fungal_peroxisomal_beta_oxidation_variant | saccharomyces_bio1_variant) activators: - id: bioH_step label: Pimeloyl-ACP methyl ester to pimeloyl-ACP connection: via a container - id: fungal_peroxisomal_beta_oxidation_variant label: Peroxisomal beta-oxidation route to pimeloyl-CoA (filamentous fungi) connection: via a container - id: saccharomyces_bio1_variant label: BIO1-dependent, oxygen-requiring route (Saccharomyces yeasts) connection: via a container - module: branched_chain_amino_acid_biosynthesis step: leuCD_step step_label: 2-Isopropylmalate to 3-isopropylmalate classification: UNDECIDED default_rule: (ipm_export_step | leuA_step) rule: (ipm_export_step | leuA_step) activators: - id: ipm_export_step label: Mitochondrial 2-isopropylmalate export connection: 'PRECEDES: ' - id: leuA_step label: 2-Oxoisovalerate to 2-isopropylmalate connection: 'PRECEDES: Single-compartment route (prokaryotes; cytosolic LEU4 short form).' - module: branched_chain_amino_acid_biosynthesis step: ilvE_step step_label: Branched-chain 2-oxoacids to L-valine, L-leucine, and L-isoleucine classification: UNDECIDED default_rule: (ilvD_step | leuB_step) rule: (ilvD_step | leuB_step) activators: - id: ilvD_step label: Dihydroxy acids to branched-chain 2-oxoacids connection: 'PRECEDES: ' - id: leuB_step label: 3-Isopropylmalate to 2-oxoisocaproate connection: via a container - module: c_elegans_cgmp_sensory_transduction step: tax4_tax2_cng step_label: TAX-4/TAX-2 heteromeric cyclic nucleotide-gated channel classification: UNDECIDED default_rule: (afd_thermosensory_rgc | daf11_gc | o2_sensing_sgc | odr1_gc) rule: (afd_thermosensory_rgc | daf11_gc | o2_sensing_sgc | odr1_gc) activators: - id: afd_thermosensory_rgc label: AFD thermosensory receptor guanylyl cyclases GCY-8, GCY-18 and GCY-23 connection: via a container - id: daf11_gc label: DAF-11 transmembrane guanylyl cyclase connection: via a container - id: o2_sensing_sgc label: URX/BAG oxygen-sensing soluble guanylyl cyclases connection: via a container - id: odr1_gc label: ODR-1 transmembrane guanylyl cyclase connection: via a container - module: c_elegans_dbl1_body_size_signaling step: receptor_pair step_label: SMA-6/DAF-4 receptor activation classification: DECLARED default_rule: (dbl1_ligand | sma10_lrig) rule: dbl1_ligand activators: - id: dbl1_ligand label: DBL-1 ligand secretion connection: 'POSITIVELY_REGULATES: ' - id: sma10_lrig label: SMA-10 positive regulation at the receptors connection: 'POSITIVELY_REGULATES: SMA-10 binds SMA-6 and DAF-4 and enhances signaling.' - module: c_elegans_lysosomal_lipid_signaling step: lbp8_lipid_shuttle step_label: LBP-8 lipid chaperone shuttle classification: UNDECIDED default_rule: (lipl4_lysosomal_lipolysis | nhr_reception) rule: (lipl4_lysosomal_lipolysis | nhr_reception) activators: - id: lipl4_lysosomal_lipolysis label: LIPL-4 lysosomal acid lipolysis connection: 'PROVIDES_INPUT_FOR: LIPL-4 activity raises the lipid ligands, OEA most of all, that LBP-8 binds. It also induces lbp-8 and its nuclear entry.' - id: nhr_reception label: NHR-80/NHR-49 nuclear receptor output connection: 'POSITIVELY_REGULATES: Positive feedback: NHR-49 and NHR-80 are needed for the rise in lbp-8 transcription caused by LIPL-4 overexpression or OEA.' - module: c_elegans_mutator_22g_rna_amplification step: pug_tailing step_label: RDE-3/MUT-2 poly(UG) tailing of target RNA classification: UNDECIDED default_rule: (mut14_helicase | mutator_scaffold | rde8_endonuclease) rule: (mut14_helicase | mutator_scaffold | rde8_endonuclease) activators: - id: mut14_helicase label: MUT-14 DEAD-box RNA helicase connection: via a container - id: mutator_scaffold label: MUT-16 scaffolding of Mutator foci connection: 'POSITIVELY_REGULATES: MUT-16 is required for MUT-2/RDE-3 localization to the foci.' - id: rde8_endonuclease label: RDE-8 target mRNA endoribonuclease connection: via a container - module: c_elegans_mutator_22g_rna_amplification step: rdrp_synthesis step_label: RRF-1 RNA-dependent RNA polymerase synthesis of 22G-RNAs classification: UNDECIDED default_rule: (mutator_scaffold | pug_tailing) rule: (mutator_scaffold | pug_tailing) activators: - id: mutator_scaffold label: MUT-16 scaffolding of Mutator foci connection: 'POSITIVELY_REGULATES: MUT-16 region F recruits RRF-1. RRF-1 localization depends on MUT-16.' - id: pug_tailing label: RDE-3/MUT-2 poly(UG) tailing of target RNA connection: 'PROVIDES_INPUT_FOR: pUG-tailed target RNA fragments are templates for RdRP synthesis of 22G-RNAs.' - module: c_elegans_mutator_22g_rna_amplification step: wago_silencing_branch step_label: Mutator-dependent WAGO silencing branch classification: UNDECIDED default_rule: (ego1_rdrp | rdrp_synthesis) rule: (ego1_rdrp | rdrp_synthesis) activators: - id: ego1_rdrp label: EGO-1 RNA-dependent RNA polymerase connection: 'PROVIDES_INPUT_FOR: EGO-1 also contributes, redundantly with RRF-1, to WAGO-class 22G-RNAs; the two RdRP systems are not fully separate.' - id: rdrp_synthesis label: RRF-1 RNA-dependent RNA polymerase synthesis of 22G-RNAs connection: 'PROVIDES_INPUT_FOR: RRF-1-synthesized 22G-RNAs are the guides loaded into WAGO-1 and other WAGOs.' - module: c_elegans_p_granule_assembly_segregation step: pgl_core step_label: PGL self-associating RNA-binding scaffold core classification: UNDECIDED default_rule: (glh_perinuclear_layer | meg_embryonic_shell) & !mex_gradient rule: (glh_perinuclear_layer | meg_embryonic_shell) & !mex_gradient activators: - id: glh_perinuclear_layer label: GLH Vasa helicases and DEPS-1 at the nuclear periphery connection: 'POSITIVELY_REGULATES: GLH-1/GLH-4 are needed for PGL proteins to associate with perinuclear P granules. DEPS-1 is needed for PGL-1 localization.' - id: meg_embryonic_shell label: MEG-3/MEG-4 RNA-condensing shell on PGL droplets connection: 'POSITIVELY_REGULATES: MEG-3 binds PGL-3 through its HMGL motif, coats PGL droplets and stabilizes them so that they co-segregate to the germline.' - module: camalexin_biosynthesis step: ian_formation step_label: Indole cyanohydrin / dehydro-IAN formation classification: UNDECIDED default_rule: (iaox_formation | wrky33_activity) rule: (iaox_formation | wrky33_activity) activators: - id: iaox_formation label: IAOx formation connection: 'PROVIDES_INPUT_FOR: IAOx is the CYP71A13 substrate (channelled within the P450 metabolon).' - id: wrky33_activity label: 'WRKY33: W-box-binding activator of CYP71A13 and PAD3' connection: via a container - module: camalexin_biosynthesis step: pad3_dhca_synthase step_label: 'CYP71B15/PAD3: dihydrocamalexate synthase (no GO term yet)' classification: UNDECIDED default_rule: (ggp_step | wrky33_activity) rule: (ggp_step | wrky33_activity) activators: - id: ggp_step label: Gamma-glutamyl removal (GGP1/GGP3) connection: via a container - id: wrky33_activity label: 'WRKY33: W-box-binding activator of CYP71A13 and PAD3' connection: via a container - module: cardiac_specification_network step: gata_factor step_label: Cardiogenic GATA factor classification: UNDECIDED default_rule: (nk2_factor | tbox_factor) rule: (nk2_factor | tbox_factor) activators: - id: nk2_factor label: NK-2 homeodomain cardiac factor connection: 'POSITIVELY_REGULATES: pannier is a direct transcriptional target of Tinman in the heart-forming region; the two proteins then cooperate.' - id: tbox_factor label: Cardiac T-box factor connection: 'POSITIVELY_REGULATES: Dorsocross acts in parallel with tinman to activate pannier.' - module: cardiac_specification_network step: hand_factor step_label: Hand bHLH factor classification: UNDECIDED default_rule: (gata_factor | nk2_factor) rule: (gata_factor | nk2_factor) activators: - id: gata_factor label: Cardiogenic GATA factor connection: 'POSITIVELY_REGULATES: Pannier directly activates Hand through the same enhancer.' - id: nk2_factor label: NK-2 homeodomain cardiac factor connection: 'POSITIVELY_REGULATES: Tinman directly activates Hand through a minimal cardiac enhancer.' - module: cardiac_specification_network step: mef2_effector step_label: MEF2 myocardial differentiation factor classification: UNDECIDED default_rule: (gata_factor | nk2_factor) rule: (gata_factor | nk2_factor) activators: - id: gata_factor label: Cardiogenic GATA factor connection: 'POSITIVELY_REGULATES: Tinman and Pannier synergistically activate the D-mef2 cardiac enhancer.' - id: nk2_factor label: NK-2 homeodomain cardiac factor connection: 'POSITIVELY_REGULATES: D-mef2 cardiac expression requires an enhancer with two essential Tinman binding sites.' - module: carnitine_shuttle step: slc25a20_step step_label: acylcarnitine (cytosolic side) / carnitine (matrix) antiport classification: UNDECIDED default_rule: (cpt1_step | cpt2_step) rule: (cpt1_step | cpt2_step) activators: - id: cpt1_step label: acyl-CoA + L-carnitine to acylcarnitine + CoA connection: 'PROVIDES_INPUT_FOR: Acylcarnitine (or acetylcarnitine) is imported into the matrix by the translocase.' - id: cpt2_step label: acylcarnitine + CoA to acyl-CoA + L-carnitine (matrix) connection: 'PROVIDES_INPUT_FOR: Free carnitine released in the matrix is exported by the translocase (the antiport counter-substrate), recycling carnitine and closing the shuttle.' - module: carotene_backbone_biosynthesis step: epsilon_ring_cyclization step_label: Epsilon cyclization (lycopene -> delta-carotene) classification: ALTERNATIVE_VARIANTS default_rule: (crti_type_desaturation | crtiso_step) rule: (crti_type_desaturation | crtiso_step) activators: - id: crti_type_desaturation label: CrtI-type single-enzyme desaturation connection: via a container - id: crtiso_step label: CRTISO step (7,7',9,9'-tetra-cis-lycopene -> all-trans-lycopene) connection: via a container - module: cdp_dag_phospholipid_synthesis step: cardiolipin_synthesis step_label: CDP-DAG-dependent cardiolipin synthase (CRD1) classification: UNDECIDED default_rule: (cdp_dag_synthesis | pgp_dephosphorylation) rule: (cdp_dag_synthesis | pgp_dephosphorylation) activators: - id: cdp_dag_synthesis label: Phosphatidate cytidylyltransferase (ER CDS1-type and mitochondrial Tam41-type) connection: 'PROVIDES_INPUT_FOR: The second CDP-DAG used by cardiolipin synthase is also supplied by Tam41.' - id: pgp_dephosphorylation label: Mitochondrial PGP phosphatase (GEP4) connection: 'PRECEDES: ' - module: cellulose_biosynthesis step: glucan_polymerization step_label: (1->4)-beta-D-glucan polymerization by the CSC classification: UNDECIDED default_rule: (accessory_factors | microtubule_guidance | udp_glucose_supply) rule: (accessory_factors | microtubule_guidance | udp_glucose_supply) activators: - id: accessory_factors label: KORRIGAN endoglucanase and COBRA connection: 'POSITIVELY_REGULATES: KORRIGAN and COBRA are required for productive, well-ordered synthesis; their loss reduces cellulose amount and microfibril quality.' - id: microtubule_guidance label: CSC guidance by the cortical microtubule cytoskeleton connection: 'POSITIVELY_REGULATES: Cortical microtubules (via CSI1) guide the trajectory of active CSCs, directing where microfibrils are deposited.' - id: udp_glucose_supply label: UDP-glucose provision to the cellulose synthase complex connection: 'PROVIDES_INPUT_FOR: UDP-glucose supply provides the donor substrate consumed by the CSC.' - module: cerebellum_development step: gcp_smoothened_transducer step_label: SMO transducer in granule-cell precursors classification: UNDECIDED default_rule: (early_purkinje_plate_formation | germinal_zone_lineage_specification | purkinje_shh_signal) rule: (early_purkinje_plate_formation | germinal_zone_lineage_specification | purkinje_shh_signal) activators: - id: early_purkinje_plate_formation label: Reelin-dependent reorientation during early Purkinje-plate formation connection: via a container - id: germinal_zone_lineage_specification label: Rhombic-lip and ventricular-zone lineage specification connection: via a container - id: purkinje_shh_signal label: Purkinje-derived SHH mitogenic signal connection: 'POSITIVELY_REGULATES: Purkinje-derived SHH activates the contextual Smoothened pathway in external-granule-layer precursors.' - module: cerebellum_development step: granule_cell_migration step_label: Granule-cell inward migration classification: UNDECIDED default_rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) activators: - id: early_purkinje_plate_formation label: Reelin-dependent reorientation during early Purkinje-plate formation connection: via a container - id: gcp_smoothened_transducer label: SMO transducer in granule-cell precursors connection: via a container - id: purkinje_shh_signal label: Purkinje-derived SHH mitogenic signal connection: via a container - module: cerebellum_development step: dner_purkinje_signal step_label: Purkinje-cell DNER contribution to Bergmann-glial maturation classification: UNDECIDED default_rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) activators: - id: early_purkinje_plate_formation label: Reelin-dependent reorientation during early Purkinje-plate formation connection: via a container - id: gcp_smoothened_transducer label: SMO transducer in granule-cell precursors connection: via a container - id: purkinje_shh_signal label: Purkinje-derived SHH mitogenic signal connection: via a container - module: cerebellum_development step: ptpn11_erk_bg_specification step_label: PTPN11-ERK Bergmann-glial specification program classification: UNDECIDED default_rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) rule: (early_purkinje_plate_formation | gcp_smoothened_transducer | purkinje_shh_signal) activators: - id: early_purkinje_plate_formation label: Reelin-dependent reorientation during early Purkinje-plate formation connection: via a container - id: gcp_smoothened_transducer label: SMO transducer in granule-cell precursors connection: via a container - id: purkinje_shh_signal label: Purkinje-derived SHH mitogenic signal connection: via a container - module: cerebellum_development step: regional_foliation step_label: Regional cerebellar foliation classification: UNDECIDED default_rule: (dner_purkinje_signal | gcp_smoothened_transducer | granule_cell_migration | ptpn11_erk_bg_specification) rule: (dner_purkinje_signal | gcp_smoothened_transducer | granule_cell_migration | ptpn11_erk_bg_specification) activators: - id: dner_purkinje_signal label: Purkinje-cell DNER contribution to Bergmann-glial maturation connection: via a container - id: gcp_smoothened_transducer label: SMO transducer in granule-cell precursors connection: via a container - id: granule_cell_migration label: Granule-cell inward migration connection: via a container - id: ptpn11_erk_bg_specification label: PTPN11-ERK Bergmann-glial specification program connection: 'PROVIDES_INPUT_FOR: PTPN11-ERK-dependent Bergmann-glial specification enables normal cerebellar foliation.' - module: chitin_perception step: pbl27_rlck step_label: PBL27/OsRLCK185 RLCK phosphorylation of the MAP3K classification: ALTERNATIVE_VARIANTS default_rule: (atcerk1_kinase | oscerk1_kinase) rule: (atcerk1_kinase | oscerk1_kinase) activators: - id: atcerk1_kinase label: CERK1 receptor kinase connection: via a container - id: oscerk1_kinase label: OsCERK1 receptor kinase connection: via a container - module: chitin_perception step: bik1_rlck step_label: BIK1 phosphorylation of RBOHD classification: ALTERNATIVE_VARIANTS default_rule: (atcerk1_kinase | oscerk1_kinase) rule: (atcerk1_kinase | oscerk1_kinase) activators: - id: atcerk1_kinase label: CERK1 receptor kinase connection: via a container - id: oscerk1_kinase label: OsCERK1 receptor kinase connection: via a container - module: cholesterol_synthesis_post_lanosterol step: ebp_step step_label: Delta(8)-sterol to Delta(7)-sterol classification: UNDECIDED default_rule: (dhcr24_step | hsd17b7_step) rule: (dhcr24_step | hsd17b7_step) activators: - id: dhcr24_step label: Delta24-sterol to 24,25-dihydro sterol (desmosterol to cholesterol; zymosterol to zymostenol) connection: 'PROVIDES_INPUT_FOR: In the modified Kandutsch-Russell arm, zymostenol made by DHCR24 is isomerised by EBP to lathosterol and continues through SC5D and DHCR7 to cholesterol (PMID:26114596).' - id: hsd17b7_step label: 3-keto sterol to 3-beta-hydroxy sterol connection: 'PROVIDES_INPUT_FOR: In the Bloch arm, zymosterol (the Delta8-sterol left after two C4-demethylation rounds) is isomerised by EBP.' - module: cholesterol_synthesis_post_lanosterol step: dhcr24_step step_label: Delta24-sterol to 24,25-dihydro sterol (desmosterol to cholesterol; zymosterol to zymostenol) classification: UNDECIDED default_rule: (dhcr7_step | hsd17b7_step) rule: (dhcr7_step | hsd17b7_step) activators: - id: dhcr7_step label: 7-dehydrocholesterol to cholesterol connection: 'PROVIDES_INPUT_FOR: In the Bloch arm, desmosterol made by DHCR7 is reduced by DHCR24 to cholesterol.' - id: hsd17b7_step label: 3-keto sterol to 3-beta-hydroxy sterol connection: 'PROVIDES_INPUT_FOR: In the modified Kandutsch-Russell arm, zymosterol is reduced by DHCR24 to zymostenol.' - module: ciliary_transition_zone step: mks_module step_label: MKS module classification: UNDECIDED default_rule: (cep290_module | mks5_assembly_hub) rule: (cep290_module | mks5_assembly_hub) activators: - id: cep290_module label: CEP290 central TZ module connection: 'PRECEDES: In worms CEP-290 is required for MKS-module proteins to reach the TZ.' - id: mks5_assembly_hub label: RPGRIP1L/MKS-5 transition-zone assembly hub connection: 'PRECEDES: MKS-5 is required for every MKS-module protein to reach the TZ.' - module: coenzyme_a_biosynthesis step: pantothenate_synthetase_step step_label: (R)-pantoate and beta-alanine to pantothenate classification: UNDECIDED default_rule: (aminopropanal_dehydrogenase_step | aspartate_decarboxylation_route | ketopantoate_reductase_step) rule: (aminopropanal_dehydrogenase_step | aspartate_decarboxylation_route | ketopantoate_reductase_step) activators: - id: aminopropanal_dehydrogenase_step label: 3-Aminopropanal to beta-alanine connection: via a container - id: aspartate_decarboxylation_route label: PanD aspartate decarboxylation (bacteria) connection: via a container - id: ketopantoate_reductase_step label: 2-dehydropantoate to (R)-pantoate connection: via a container - module: coenzyme_a_biosynthesis step: pantoate_kinase_step step_label: Pantoate to 4-phosphopantoate classification: UNDECIDED default_rule: (aminopropanal_dehydrogenase_step | aspartate_decarboxylation_route | ketopantoate_reductase_step) rule: (aminopropanal_dehydrogenase_step | aspartate_decarboxylation_route | ketopantoate_reductase_step) activators: - id: aminopropanal_dehydrogenase_step label: 3-Aminopropanal to beta-alanine connection: via a container - id: aspartate_decarboxylation_route label: PanD aspartate decarboxylation (bacteria) connection: via a container - id: ketopantoate_reductase_step label: 2-dehydropantoate to (R)-pantoate connection: via a container - module: coenzyme_a_biosynthesis step: phosphopantothenoylcysteine_ligase_step step_label: 4'-phosphopantothenate to phosphopantothenoylcysteine classification: ALTERNATIVE_VARIANTS default_rule: (pantothenate_kinase_step | phosphopantothenate_synthetase_step) rule: (pantothenate_kinase_step | phosphopantothenate_synthetase_step) activators: - id: pantothenate_kinase_step label: Pantothenate to 4'-phosphopantothenate connection: via a container - id: phosphopantothenate_synthetase_step label: 4-phosphopantoate and beta-alanine to 4'-phosphopantothenate connection: via a container - module: coenzyme_q10_biosynthesis step: c1_decarboxylation step_label: C1 decarboxylation (COQ4) and C1 hydroxylation (COQ6) classification: UNDECIDED default_rule: (c5_hydroxylation | synthome_regulation) rule: (c5_hydroxylation | synthome_regulation) activators: - id: c5_hydroxylation label: Ubiquinone biosynthesis monooxygenase (COQ6) connection: 'PROVIDES_INPUT_FOR: After C5 hydroxylation (and COQ3 O-methylation, not modelled), the 4-hydroxy-3-methoxy-5-polyprenylbenzoate intermediate is decarboxylated at C1 by COQ4 and the resulting phenol is hydroxylated at C1 by COQ6. In human cells COQ4 decarboxylation can also precede C5 hydroxylation, so this edge records the canonical rather than an obligate order.' - id: synthome_regulation label: Atypical UbiB-family kinase/ATPase (COQ8A + COQ8B) connection: 'POSITIVELY_REGULATES: The COQ8A/COQ8B atypical kinase/ATPases are required for assembly and activity of the COQ synthome (represented here on the COQ4 organizer node); loss destabilises the whole complex.' - module: coenzyme_q10_biosynthesis step: c6_hydroxylation step_label: 3-demethoxyubiquinone hydroxylase (COQ7) classification: UNDECIDED default_rule: (c2_methylation | substrate_presentation) rule: (c2_methylation | substrate_presentation) activators: - id: c2_methylation label: 2-methoxy-6-polyprenyl-1,4-benzoquinol methylase (COQ5) connection: 'PROVIDES_INPUT_FOR: The C2-methylated product, demethoxyubiquinol (DMQ), is the substrate for the COQ7 di-iron hydroxylase.' - id: substrate_presentation label: Lipid-binding presenter (COQ9) connection: 'POSITIVELY_REGULATES: COQ9 binds and presents the lipophilic DMQ substrate to COQ7, activating hydroxylation.' - module: complex_i_assembly_factors step: ci_qmodule_intermediate step_label: Q-module intermediate assembly (NDUFAF3-NDUFAF4, NDUFAF6) classification: UNDECIDED default_rule: (ci_membrane_arm_assembly | ci_subunit_maturation) rule: (ci_membrane_arm_assembly | ci_subunit_maturation) activators: - id: ci_membrane_arm_assembly label: MCIA membrane-arm assembly (NDUFAF1, TIMMDC1) connection: 'PROVIDES_INPUT_FOR: The MCIA-built membrane-arm intermediate is joined by the NDUFAF3/NDUFAF4/NDUFAF6-chaperoned Q-module intermediate.' - id: ci_subunit_maturation label: Core-subunit modification and Fe-S/FAD delivery (NDUFAF5, NDUFAF7, NUBPL, FOXRED1) connection: 'POSITIVELY_REGULATES: NDUFAF5/NDUFAF7 arginine modifications, NUBPL Fe-S delivery and FOXRED1 redox maturation of the core subunits are prerequisites for productive Q-module intermediate assembly.' - module: complex_iv_assembly_factors step: subunit_incorporation step_label: incorporation of the early COX7/COX8 nuclear subunits classification: UNDECIDED default_rule: (cua_metallation | cub_metallation) rule: (cua_metallation | cub_metallation) activators: - id: cua_metallation label: MT-CO2 CuA site copper delivery and disulfide relay connection: 'PROVIDES_INPUT_FOR: Metallated MT-CO2 joins the MT-CO1 module as the nuclear subunits are incorporated.' - id: cub_metallation label: copper insertion into the MT-CO1 CuB site connection: 'PROVIDES_INPUT_FOR: The metallated MT-CO1 seed recruits the nuclear subunits via PET100/PET117.' - module: conidiation_regulatory_cascade step: brla_induction step_label: BrlA master-switch induction classification: UNDECIDED default_rule: (flbB | flbC | flbD | flbE | fluG) rule: (flbB | flbC | flbD | flbE | fluG) activators: - id: flbB label: FlbB bZIP factor connection: via a container - id: flbC label: FlbC C2H2 factor connection: via a container - id: flbD label: FlbD Myb factor connection: via a container - id: flbE label: FlbE accessory factor connection: via a container - id: fluG label: FluG developmental signal factor connection: via a container - module: conidiation_regulatory_cascade step: neu_fl step_label: FL fluffy master regulator classification: UNDECIDED default_rule: (neu_acon2 | neu_frq | neu_wc1 | neu_wc2) rule: (neu_acon2 | neu_frq | neu_wc1 | neu_wc2) activators: - id: neu_acon2 label: ACON-2 cAMP phosphodiesterase gate connection: 'POSITIVELY_REGULATES: ACON-2 (cAMP phosphodiesterase) acts upstream of FL to permit conidiation.' - id: neu_frq label: FRQ circadian clock protein connection: via a container - id: neu_wc1 label: WC-1 blue-light photoreceptor / TF connection: via a container - id: neu_wc2 label: WC-2 White Collar Complex partner connection: via a container - module: creatine_phosphocreatine_system step: shuttle_part step_label: Phosphocreatine shuttle / creatine kinase system (see MODULE:phosphocreatine_shuttle) classification: UNDECIDED default_rule: (biosynthesis_part | transport_part) rule: (biosynthesis_part | transport_part) activators: - id: biosynthesis_part label: Creatine biosynthesis (see MODULE:creatine_biosynthesis) connection: 'PROVIDES_INPUT_FOR: Locally synthesized creatine also feeds the kinase system directly.' - id: transport_part label: Creatine transport (SLC6A8) connection: 'PROVIDES_INPUT_FOR: Imported creatine is the substrate of the creatine kinase energy buffer.' - module: cuproptosis step: fdx1_trigger step_label: FDX1-mediated Cu(II) reduction (master trigger) classification: UNDECIDED default_rule: (atox1_copper_chaperone | copper_exporting_atpase | ctr1_copper_import) rule: (atox1_copper_chaperone | copper_exporting_atpase | ctr1_copper_import) activators: - id: atox1_copper_chaperone label: ATOX1 cytosolic copper chaperone connection: via a container - id: copper_exporting_atpase label: Copper-exporting P-type ATPases (ATP7A / ATP7B) connection: via a container - id: ctr1_copper_import label: SLC31A1 (CTR1) high-affinity copper import connection: via a container - module: cuproptosis step: lipoylated_targets step_label: Lipoylated pyruvate dehydrogenase complex (copper targets) classification: UNDECIDED default_rule: (fdx1_trigger | lipoylation_machinery) rule: (fdx1_trigger | lipoylation_machinery) activators: - id: fdx1_trigger label: FDX1-mediated Cu(II) reduction (master trigger) connection: 'PROVIDES_INPUT_FOR: FDX1-generated Cu(I) is the species that binds lipoylated DLAT.' - id: lipoylation_machinery label: Mitochondrial protein-lipoylation machinery connection: 'PROVIDES_INPUT_FOR: The lipoylation machinery installs the lipoyl groups on DLAT that copper attacks.' - module: de_novo_purine_synthesis step: purC_step step_label: SAICAR synthetase classification: ALTERNATIVE_VARIANTS default_rule: (ade2_purE_domain_substep | direct_air_carboxylase_route | purE_substep) rule: (ade2_purE_domain_substep | direct_air_carboxylase_route | purE_substep) activators: - id: ade2_purE_domain_substep label: N5-CAIR mutase (ADE2 PurE-like domain) connection: via a container - id: direct_air_carboxylase_route label: Direct AIR carboxylase route connection: via a container - id: purE_substep label: N5-CAIR mutase connection: via a container - module: dolichol_phosphate_sugar_donor_supply step: mpdu1_step step_label: presentation/utilisation of Dol-P-Man and Dol-P-Glc classification: UNDECIDED default_rule: (alg5_step | dpm_complex_step) rule: (alg5_step | dpm_complex_step) activators: - id: alg5_step label: UDP-glucose + Dol-P to dolichyl-phosphate-glucose (Dol-P-Glc) connection: 'PROVIDES_INPUT_FOR: Dol-P-Glc made by ALG5 is presented by MPDU1 for lumenal glycosyltransferases.' - id: dpm_complex_step label: GDP-mannose + Dol-P to dolichyl-phosphate-mannose (Dol-P-Man) connection: 'PROVIDES_INPUT_FOR: Dol-P-Man made by the DPM synthase is presented by MPDU1 for lumenal glycosyltransferases.' - module: emp_glycolysis step: gpi_step step_label: D-glucose 6-phosphate to D-fructose 6-phosphate classification: ALTERNATIVE_VARIANTS default_rule: (adp_kinase_entry_variant | atp_kinase_entry_variant | glucan_entry_variant | pts_entry_variant) rule: (adp_kinase_entry_variant | atp_kinase_entry_variant | glucan_entry_variant | pts_entry_variant) activators: - id: adp_kinase_entry_variant label: ADP-dependent glucokinase entry (archaeal) connection: via a container - id: atp_kinase_entry_variant label: ATP-dependent hexose kinase entry connection: via a container - id: glucan_entry_variant label: Glucose-1-phosphate entry from a glucan or disaccharide connection: via a container - id: pts_entry_variant label: Phosphotransferase-system (transport-coupled) entry connection: via a container - module: emp_glycolysis step: gapdh_step step_label: G3P + phosphate + NAD(P)+ to 1,3-bisphospho-D-glycerate classification: UNDECIDED default_rule: (aldolase_step | tpi_step) rule: (aldolase_step | tpi_step) activators: - id: aldolase_step label: D-fructose 1,6-bisphosphate to DHAP + D-glyceraldehyde 3-phosphate connection: via a container - id: tpi_step label: Glycerone phosphate to D-glyceraldehyde 3-phosphate connection: via a container - module: emp_glycolysis step: nonphosphorylating_nadp_variant step_label: Non-phosphorylating NADP+ oxidation (GAPN bypass) classification: UNDECIDED default_rule: (aldolase_step | tpi_step) rule: (aldolase_step | tpi_step) activators: - id: aldolase_step label: D-fructose 1,6-bisphosphate to DHAP + D-glyceraldehyde 3-phosphate connection: via a container - id: tpi_step label: Glycerone phosphate to D-glyceraldehyde 3-phosphate connection: via a container - module: emp_glycolysis step: ferredoxin_oxidation_variant step_label: Ferredoxin-dependent oxidation (archaeal GAPOR) classification: UNDECIDED default_rule: (aldolase_step | tpi_step) rule: (aldolase_step | tpi_step) activators: - id: aldolase_step label: D-fructose 1,6-bisphosphate to DHAP + D-glyceraldehyde 3-phosphate connection: via a container - id: tpi_step label: Glycerone phosphate to D-glyceraldehyde 3-phosphate connection: via a container - module: emp_glycolysis step: pgam_step step_label: 3-phospho-D-glycerate to 2-phospho-D-glycerate classification: ALTERNATIVE_VARIANTS default_rule: (ferredoxin_oxidation_variant | nonphosphorylating_nadp_variant | pgk_step) rule: (ferredoxin_oxidation_variant | nonphosphorylating_nadp_variant | pgk_step) activators: - id: ferredoxin_oxidation_variant label: Ferredoxin-dependent oxidation (archaeal GAPOR) connection: via a container - id: nonphosphorylating_nadp_variant label: Non-phosphorylating NADP+ oxidation (GAPN bypass) connection: via a container - id: pgk_step label: 1,3-bisphospho-D-glycerate + ADP to 3-phospho-D-glycerate + ATP connection: via a container - module: er_unfolded_protein_response step: bip_chaperones step_label: BiP ER HSP70 chaperones classification: UNDECIDED default_rule: (atf6_arm | hac1_transcription_factor | xbp1_transcription_factor) rule: (atf6_arm | hac1_transcription_factor | xbp1_transcription_factor) activators: - id: atf6_arm label: ATF6 arm connection: 'POSITIVELY_REGULATES: ATF6 induces BiP in mammals; worm atf-6 contributes to HSP-4 induction by thapsigargin.' - id: hac1_transcription_factor label: Hac1 bZIP transcription factor connection: via a container - id: xbp1_transcription_factor label: XBP1s bZIP transcription factor connection: via a container - module: ergosterol_biosynthesis step: erg1_step step_label: squalene + O2 + reduced P450 reductase to (S)-2,3-epoxysqualene classification: UNDECIDED default_rule: (erg9_step | ncp1_activity) rule: (erg9_step | ncp1_activity) activators: - id: erg9_step label: 2 farnesyl diphosphate + NAD(P)H to squalene (via presqualene diphosphate) connection: 'PRECEDES: Squalene from ERG9 is epoxidised by ERG1.' - id: ncp1_activity label: NADPH-cytochrome P450 reductase (NCP1) connection: 'PROVIDES_INPUT_FOR: Reduced P450 reductase is a co-substrate of squalene epoxidase.' - module: ergosterol_biosynthesis step: erg7_step step_label: (S)-2,3-epoxysqualene to lanosterol classification: UNDECIDED default_rule: (erg1_step | erg27_activity) rule: (erg1_step | erg27_activity) activators: - id: erg1_step label: squalene + O2 + reduced P450 reductase to (S)-2,3-epoxysqualene connection: 'PRECEDES: 2,3-Oxidosqualene from ERG1 is cyclised by ERG7 to lanosterol.' - id: erg27_activity label: 3-ketosteroid reductase (ERG27) connection: 'POSITIVELY_REGULATES: Erg27 binds lanosterol synthase Erg7, protects it from degradation and is required for its activity in lipid particles (S. cerevisiae).' - module: ergosterol_biosynthesis step: erg11_step step_label: lanosterol to 4,4-dimethylcholesta-8,14,24-trienol + formate classification: UNDECIDED default_rule: (erg7_step | ncp1_activity) rule: (erg7_step | ncp1_activity) activators: - id: erg7_step label: (S)-2,3-epoxysqualene to lanosterol connection: via a container - id: ncp1_activity label: NADPH-cytochrome P450 reductase (NCP1) connection: 'PROVIDES_INPUT_FOR: Reduced P450 reductase supplies the three oxidations of CYP51.' - module: ergosterol_biosynthesis step: erg25_step step_label: 4-methyl sterol to 4-carboxy sterol (three successive oxidations; twice per sterol) classification: UNDECIDED default_rule: (cyb5_activity | erg24_step) rule: (cyb5_activity | erg24_step) activators: - id: cyb5_activity label: microsomal cytochrome b5 (CYB5) connection: 'PROVIDES_INPUT_FOR: Ferrocytochrome b5 supplies the C-4 methyl oxidase.' - id: erg24_step label: 4,4-dimethylcholesta-8,14,24-trienol + NADPH to 4,4-dimethylzymosterol connection: 'PRECEDES: ' - module: ergosterol_biosynthesis step: erg3_step step_label: episterol to ergosta-5,7,24(28)-trienol classification: UNDECIDED default_rule: (cyb5_activity | erg2_step) rule: (cyb5_activity | erg2_step) activators: - id: cyb5_activity label: microsomal cytochrome b5 (CYB5) connection: 'PROVIDES_INPUT_FOR: Ferrocytochrome b5 supplies the C-5 desaturase.' - id: erg2_step label: fecosterol to episterol connection: 'PRECEDES: ' - module: ergosterol_biosynthesis step: erg5_step step_label: ergosta-5,7,24(28)-trienol to ergosta-5,7,22,24(28)-tetraenol classification: UNDECIDED default_rule: (erg3_step | ncp1_activity) rule: (erg3_step | ncp1_activity) activators: - id: erg3_step label: episterol to ergosta-5,7,24(28)-trienol connection: 'PRECEDES: ' - id: ncp1_activity label: NADPH-cytochrome P450 reductase (NCP1) connection: 'PROVIDES_INPUT_FOR: Reduced P450 reductase supplies the CYP61 C-22 desaturase.' - module: erythromycin_biosynthesis step: eryBV_step step_label: EryBV attaches L-mycarose to erythronolide B classification: UNDECIDED default_rule: (eryF_step | mycarose_pathway) rule: (eryF_step | mycarose_pathway) activators: - id: eryF_step label: EryF hydroxylates 6-dEB to erythronolide B connection: 'PROVIDES_INPUT_FOR: Erythronolide B is the acceptor for mycarosylation.' - id: mycarose_pathway label: TDP-L-mycarose biosynthesis (EryB*) connection: 'PROVIDES_INPUT_FOR: Supplies the TDP-L-mycarose glycosyl donor.' - module: erythromycin_biosynthesis step: eryCIII_step step_label: EryCIII (activated by EryCII) attaches D-desosamine, forming erythromycin D classification: UNDECIDED default_rule: (desosamine_pathway | eryBV_step) rule: (desosamine_pathway | eryBV_step) activators: - id: desosamine_pathway label: TDP-D-desosamine biosynthesis (EryC* + EryBVII) connection: 'PROVIDES_INPUT_FOR: Supplies the TDP-D-desosamine glycosyl donor.' - id: eryBV_step label: EryBV attaches L-mycarose to erythronolide B connection: 'PROVIDES_INPUT_FOR: 3-O-mycarosyl-erythronolide B is the acceptor for desosaminylation.' - module: ether_lipid_plasmalogen_biosynthesis step: ether_bond_formation step_label: Alkyldihydroxyacetone-phosphate synthase (AGPS) classification: UNDECIDED default_rule: (dhap_acylation | fatty_alcohol_synthesis) rule: (dhap_acylation | fatty_alcohol_synthesis) activators: - id: dhap_acylation label: Glyceronephosphate O-acyltransferase (GNPAT/DHAPAT) connection: 'PROVIDES_INPUT_FOR: GNPAT-made acyl-DHAP is the AGPS substrate whose acyl group is exchanged for the fatty alcohol.' - id: fatty_alcohol_synthesis label: Fatty acyl-CoA reductase (FAR1 / FAR2) connection: 'PROVIDES_INPUT_FOR: FAR-made fatty alcohol is the alkyl donor AGPS uses to form the ether bond.' - module: eukaryotic_thiamine_biosynthesis step: hmpp_kinase_step step_label: HMP-P to HMP-PP classification: UNDECIDED default_rule: (hmp_kinase_step | thi5_hmpp_synthase_step) rule: (hmp_kinase_step | thi5_hmpp_synthase_step) activators: - id: hmp_kinase_step label: HMP to HMP-P (salvage) connection: 'PROVIDES_INPUT_FOR: Salvaged HMP enters as HMP-P.' - id: thi5_hmpp_synthase_step label: PLP and protein histidine to HMP-P (THI5 family) connection: 'PRECEDES: ' - module: eukaryotic_thiamine_biosynthesis step: tmp_synthase_step step_label: Thiazole phosphate + HMP-PP to thiamine monophosphate (THI6) classification: UNDECIDED default_rule: (adt_processing_step | het_kinase_step | hmpp_kinase_step) rule: (adt_processing_step | het_kinase_step | hmpp_kinase_step) activators: - id: adt_processing_step label: ADP-thiazole to thiazole phosphate connection: 'PROVIDES_INPUT_FOR: Supplies the thiazole phosphate.' - id: het_kinase_step label: Hydroxyethylthiazole to thiazole phosphate (THI6 kinase domain) connection: 'PROVIDES_INPUT_FOR: Salvaged thiazole enters as thiazole phosphate.' - id: hmpp_kinase_step label: HMP-P to HMP-PP connection: 'PROVIDES_INPUT_FOR: Supplies HMP-PP.' - module: ferroptosis step: ferroptosis_execution step_label: Ferroptosis execution classification: UNDECIDED default_rule: (labile_iron_supply | pufa_phospholipid_supply) & !(dhodh_coq_defense | fsp1_coq_defense | gch1_bh4_defense | gpx4_gsh_defense) rule: (labile_iron_supply | pufa_phospholipid_supply) & !(dhodh_coq_defense | fsp1_coq_defense | gch1_bh4_defense | gpx4_gsh_defense) activators: - id: labile_iron_supply label: Labile-iron supply and buffering connection: 'PROVIDES_INPUT_FOR: Labile Fe(II) catalyses the radical chemistry that peroxidises PUFA-phospholipids.' - id: pufa_phospholipid_supply label: PUFA-phospholipid supply connection: 'PROVIDES_INPUT_FOR: PUFA-phospholipids are the oxidisable substrate consumed in the execution event.' - module: ferroptosis step: gpx4_gsh_defense step_label: GPX4-glutathione defense classification: UNDECIDED default_rule: (atf4_isr_inducer | nrf2_master_antioxidant) & !tp53_context_regulator rule: (atf4_isr_inducer | nrf2_master_antioxidant) & !tp53_context_regulator activators: - id: atf4_isr_inducer label: ATF4 integrated-stress-response transcription factor connection: 'POSITIVELY_REGULATES: ATF4 induces SLC7A11, supplying cysteine to the GPX4 axis.' - id: nrf2_master_antioxidant label: NFE2L2 (NRF2) antioxidant transcription factor connection: 'POSITIVELY_REGULATES: NRF2 transcriptionally induces system xc-, glutathione synthesis, and GPX4.' - module: floral_meristem_identity step: lfy_program step_label: LEAFY floral meristem identity program classification: UNDECIDED default_rule: (ap1_floral_fate | integrator_input) & !tfl1_inflorescence_maintenance rule: (ap1_floral_fate | integrator_input) & !tfl1_inflorescence_maintenance activators: - id: ap1_floral_fate label: AP1/CAL/FUL establish floral fate connection: 'POSITIVELY_REGULATES: AP1 (with CAL and FUL) up-regulates LFY, closing the LFY-AP1 positive feedback loop that makes the switch to floral fate sharp.' - id: integrator_input label: Floral integrators activate meristem identity genes connection: 'POSITIVELY_REGULATES: SOC1 (with AGL24) binds and activates the LFY promoter.' - module: floral_meristem_identity step: ap1_floral_fate step_label: AP1/CAL/FUL establish floral fate classification: UNDECIDED default_rule: (integrator_input | lfy_program) & !tfl1_inflorescence_maintenance rule: (integrator_input | lfy_program) & !tfl1_inflorescence_maintenance activators: - id: integrator_input label: Floral integrators activate meristem identity genes connection: 'POSITIVELY_REGULATES: The FT-FD complex activates AP1 at the shoot apex, independently of LFY.' - id: lfy_program label: LEAFY floral meristem identity program connection: 'POSITIVELY_REGULATES: LFY directly induces early AP1 expression in floral anlagen.' - module: floral_organ_identity_abce step: whorl_quartets step_label: Whorl-specific floral quartet complexes classification: UNDECIDED default_rule: (b_function | e_function) rule: (b_function | e_function) activators: - id: b_function label: B function (AP3/PI obligate heterodimer) connection: via a container - id: e_function label: E function (SEP1-SEP4) connection: via a container - module: folate_one_carbon_interconversion step: methenyl_formyl_hydrolysis step_label: 5,10-methenyl-THF to 10-formyl-THF hydrolysis classification: UNDECIDED default_rule: (formyl_folate_salvage | methylene_methenyl_redox) rule: (formyl_folate_salvage | methylene_methenyl_redox) activators: - id: formyl_folate_salvage label: 5-formyl-THF salvage connection: 'PROVIDES_INPUT_FOR: Salvaged 5,10-methenyl-THF rejoins the methenyl/formyl carrier-state interconversion.' - id: methylene_methenyl_redox label: 5,10-methylene-THF to 5,10-methenyl-THF redox connection: 'PROVIDES_INPUT_FOR: 5,10-methenyl-THF produced by the dehydrogenase reaction is the cyclohydrolase substrate; the two activities are often fused but are chemically distinct.' - module: g1_s_transition step: e2f_activator step_label: Activator E2F transcription factor classification: UNDECIDED default_rule: (g1_cdk_priming | g1s_cdk_activation) & !rb_corepressor rule: (g1_cdk_priming | g1s_cdk_activation) & !rb_corepressor activators: - id: g1_cdk_priming label: Growth-coupled G1 cyclin-CDK activation connection: via a container - id: g1s_cdk_activation label: G1/S cyclin-CDK activation connection: via a container - module: g1_s_transition step: sbf_mbf step_label: SBF/MBF transcription factor classification: UNDECIDED default_rule: (g1_cdk_priming | g1s_cdk_activation) & !whi5_corepressor rule: (g1_cdk_priming | g1s_cdk_activation) & !whi5_corepressor activators: - id: g1_cdk_priming label: Growth-coupled G1 cyclin-CDK activation connection: via a container - id: g1s_cdk_activation label: G1/S cyclin-CDK activation connection: via a container - module: g1_s_transition step: fission_yeast_mbf step_label: Fission-yeast MBF (Cdc10-Res1-Res2) classification: UNDECIDED default_rule: (g1_cdk_priming | g1s_cdk_activation) rule: (g1_cdk_priming | g1s_cdk_activation) activators: - id: g1_cdk_priming label: Growth-coupled G1 cyclin-CDK activation connection: via a container - id: g1s_cdk_activation label: G1/S cyclin-CDK activation connection: via a container - module: g1_s_transition step: g1s_cdk_activation step_label: G1/S cyclin-CDK activation classification: UNDECIDED default_rule: (e2f_activator | fission_yeast_mbf | sbf_mbf | scf_ligase) rule: (e2f_activator | fission_yeast_mbf | sbf_mbf | scf_ligase) activators: - id: e2f_activator label: Activator E2F transcription factor connection: via a container - id: fission_yeast_mbf label: Fission-yeast MBF (Cdc10-Res1-Res2) connection: via a container - id: sbf_mbf label: SBF/MBF transcription factor connection: via a container - id: scf_ligase label: SCF ubiquitin ligase with CKI-specific F-box adaptor connection: via a container - module: g2_m_transition step: cdk1_cyclinb_assembly step_label: Cyclin B-CDK1 assembly and CAK phosphorylation classification: UNDECIDED default_rule: (cdc25_activation | endosulfine | pp2a_b55) rule: (cdc25_activation | endosulfine | pp2a_b55) activators: - id: cdc25_activation label: Cdc25 dephosphorylation of CDK1 Tyr15/Thr14 connection: 'POSITIVELY_REGULATES: Cdc25 dephosphorylation converts the poised complex into active cyclin B-CDK1.' - id: endosulfine label: Endosulfine PP2A-B55 inhibitor connection: via a container - id: pp2a_b55 label: PP2A-B55 CDK-counteracting phosphatase connection: via a container - module: g2_m_transition step: wee1_inhibition step_label: Inhibitory Tyr15/Thr14 phosphorylation by Wee1/Myt1 classification: UNDECIDED default_rule: (cdk1_cyclinb_assembly | checkpoint_restraint) & !(cdk1_cyclinb_assembly | polo_reinforcement) rule: (cdk1_cyclinb_assembly | checkpoint_restraint) & !(cdk1_cyclinb_assembly | polo_reinforcement) activators: - id: cdk1_cyclinb_assembly label: Cyclin B-CDK1 assembly and CAK phosphorylation connection: 'NEGATIVELY_REGULATES: Active CDK1 phosphorylates and inactivates Wee1, priming its destruction (double-negative feedback).' - id: checkpoint_restraint label: Checkpoint kinase restraint of Cdc25 and activation of Wee1 connection: 'POSITIVELY_REGULATES: Checkpoint signalling stabilises and upregulates Wee1/Mik1.' - module: g2_m_transition step: cdc25_activation step_label: Cdc25 dephosphorylation of CDK1 Tyr15/Thr14 classification: UNDECIDED default_rule: (cdk1_cyclinb_assembly | polo_reinforcement | wee1_inhibition) & !checkpoint_restraint rule: (cdk1_cyclinb_assembly | polo_reinforcement | wee1_inhibition) & !checkpoint_restraint activators: - id: cdk1_cyclinb_assembly label: Cyclin B-CDK1 assembly and CAK phosphorylation connection: 'POSITIVELY_REGULATES: Active CDK1 phosphorylates and activates Cdc25 (positive feedback).' - id: polo_reinforcement label: Polo-like kinase activation of Cdc25 and inhibition of Wee1 connection: 'POSITIVELY_REGULATES: Polo kinase phosphorylates and activates Cdc25.' - id: wee1_inhibition label: Inhibitory Tyr15/Thr14 phosphorylation by Wee1/Myt1 connection: 'PROVIDES_INPUT_FOR: Tyr15/Thr14-phosphorylated CDK1 is the substrate of Cdc25.' - module: galactose_leloir_pathway step: galt_step step_label: alpha-D-galactose 1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose classification: UNDECIDED default_rule: (gale_step | galk1_step) rule: (gale_step | galk1_step) activators: - id: gale_step label: UDP-galactose to UDP-glucose (reversible) connection: 'PROVIDES_INPUT_FOR: UDP-glucose regenerated by GALE is the co-substrate GALT requires, closing the UDP-sugar recycling loop that makes the pathway catalytic in UDP-glucose.' - id: galk1_step label: alpha-D-galactose + ATP to alpha-D-galactose 1-phosphate + ADP connection: 'PROVIDES_INPUT_FOR: alpha-D-galactose 1-phosphate from GALK1 is the substrate of GALT.' - module: gibberellin_della_signaling step: pif_growth_output step_label: PIF-driven growth transcription classification: UNDECIDED default_rule: (della_degradation | della_recognition) rule: (della_degradation | della_recognition) activators: - id: della_degradation label: SCF(SLY1)-mediated DELLA ubiquitination and degradation connection: 'POSITIVELY_REGULATES: Proteasomal removal of DELLA releases PIFs to bind promoters (derepression).' - id: della_recognition label: DELLA capture by GA-GID1 connection: 'POSITIVELY_REGULATES: Proteolysis-independent route - GA-GID1 binding occludes DELLA surfaces needed for partner binding, relieving DELLA inhibition without degradation. The positive sign refers to the GA-GID1 recognition step as a whole; the DELLA coregulator activity in that step, taken alone, negatively regulates PIF output, and it is the GA-GID1 capture of DELLA that relieves this repression.' - module: glucarate_galactarate_catabolism step: kdgd_step step_label: 5-dehydro-4-deoxyglucarate to 2,5-dioxopentanoate classification: ALTERNATIVE_VARIANTS default_rule: (galactarate_entry | glucarate_entry) rule: (galactarate_entry | glucarate_entry) activators: - id: galactarate_entry label: D-galactarate entry connection: 'PRECEDES: ' - id: glucarate_entry label: D-glucarate entry connection: 'PRECEDES: ' - module: glutathione_synthesis_gamma_glutamyl_cycle step: extracellular_gsh_breakdown step_label: gamma-glutamyl transpeptidase (GGT) classification: UNDECIDED default_rule: (glutathione_recycling | glutathione_synthesis) rule: (glutathione_recycling | glutathione_synthesis) activators: - id: glutathione_recycling label: Glutathione-disulfide reductase (GSR) connection: 'POSITIVELY_REGULATES: GSR keeps the glutathione pool reduced (GSSG -> 2 GSH), sustaining the GSH available for turnover.' - id: glutathione_synthesis label: Glutathione synthetase (GSS) connection: 'PROVIDES_INPUT_FOR: GSH synthesised by GSS is (extracellularly) catabolised by GGT1.' - module: glutathione_synthesis_gamma_glutamyl_cycle step: oxoproline_to_glutamate step_label: 5-oxoprolinase (OPLAH) classification: UNDECIDED default_rule: (gamma_glutamyl_cyclization | intracellular_gsh_degradation) rule: (gamma_glutamyl_cyclization | intracellular_gsh_degradation) activators: - id: gamma_glutamyl_cyclization label: gamma-glutamylcyclotransferase (GGCT) connection: 'PROVIDES_INPUT_FOR: The 5-oxoproline made by GGCT is hydrolysed to glutamate by OPLAH.' - id: intracellular_gsh_degradation label: Glutathione-specific gamma-glutamylcyclotransferase (CHAC1) connection: 'PROVIDES_INPUT_FOR: The 5-oxoproline released by CHAC1 is likewise converted to glutamate by OPLAH.' - module: glutathione_synthesis_gamma_glutamyl_cycle step: cysgly_hydrolysis step_label: Cys-Gly dipeptidase (DUG1/CNDP2 M20A family) classification: UNDECIDED default_rule: (dug2_dug3_gsh_cleavage | extracellular_gsh_breakdown | intracellular_gsh_degradation) rule: (dug2_dug3_gsh_cleavage | extracellular_gsh_breakdown | intracellular_gsh_degradation) activators: - id: dug2_dug3_gsh_cleavage label: Dug2-Dug3 glutamine-amidotransferase complex connection: 'PROVIDES_INPUT_FOR: Cys-Gly from Dug2-Dug3 is hydrolysed by Dug1.' - id: extracellular_gsh_breakdown label: gamma-glutamyl transpeptidase (GGT) connection: 'PROVIDES_INPUT_FOR: Cys-Gly released by GGT is hydrolysed by the Cys-Gly dipeptidase.' - id: intracellular_gsh_degradation label: Glutathione-specific gamma-glutamylcyclotransferase (CHAC1) connection: 'PROVIDES_INPUT_FOR: Cys-Gly released by ChaC enzymes is hydrolysed by the Cys-Gly dipeptidase.' - module: glutathione_thioredoxin_redox_systems step: thiol_peroxidase_step step_label: Thioredoxin-dependent thiol peroxidases classification: UNDECIDED default_rule: (sod_step | trx_step) rule: (sod_step | trx_step) activators: - id: sod_step label: Superoxide dismutase connection: 'PROVIDES_INPUT_FOR: Hydrogen peroxide made by superoxide dismutase is reduced by thiol peroxidases.' - id: trx_step label: Thioredoxin connection: 'PROVIDES_INPUT_FOR: Reduced thioredoxin regenerates the oxidized thiol peroxidases.' - module: glycogen_biosynthesis step: gys_step step_label: glycogen(n) + UDP-glucose to glycogen(n+1) + UDP classification: UNDECIDED default_rule: (gbe1_step | gyg1_step | ugp2_step) rule: (gbe1_step | gyg1_step | ugp2_step) activators: - id: gbe1_step label: linear alpha-1,4-glucan to alpha-1,6-branched glycogen connection: 'PROVIDES_INPUT_FOR: Branching multiplies the non-reducing ends, which glycogen synthase continues to elongate (the synthase/branching cycle).' - id: gyg1_step label: glycogenin + n UDP-glucose to oligoglucosyl-glycogenin primer + n UDP connection: 'PROVIDES_INPUT_FOR: The oligoglucosyl-glycogenin primer is the substrate that glycogen synthase elongates.' - id: ugp2_step label: glucose-1-phosphate + UTP to UDP-glucose + diphosphate connection: 'PROVIDES_INPUT_FOR: UDP-glucose from UGP2 is the donor for glycogen-synthase elongation.' - module: glycogen_synthesis_and_mobilization step: glgb_branch_formation step_label: GlgB-dependent glycogen branching classification: ALTERNATIVE_VARIANTS default_rule: (glga_adp_chain_extension | glga_udp_chain_extension) rule: (glga_adp_chain_extension | glga_udp_chain_extension) activators: - id: glga_adp_chain_extension label: ADP-glucose-dependent GlgA chain extension connection: 'PROVIDES_INPUT_FOR: GlgB branches alpha-1,4-glucan from the ADP-glucose route.' - id: glga_udp_chain_extension label: UDP-glucose-dependent Pseudomonas GlgA chain extension connection: 'PROVIDES_INPUT_FOR: GlgB can branch alpha-1,4-glucan produced by Pseudomonas GlgA.' - module: glycogen_synthesis_and_mobilization step: glgp_chain_phosphorolysis step_label: GlgP-dependent glycogen phosphorolysis classification: UNDECIDED default_rule: (glgb_branch_formation | glgx_branch_removal) rule: (glgb_branch_formation | glgx_branch_removal) activators: - id: glgb_branch_formation label: GlgB-dependent glycogen branching connection: 'PROVIDES_INPUT_FOR: Branched glycogen produced by the synthetic arm is the stored polymer mobilized by GlgP and GlgX.' - id: glgx_branch_removal label: GlgX-dependent glycogen debranching connection: 'PROVIDES_INPUT_FOR: Debranching exposes linear alpha-1,4 chain ends for continued GlgP phosphorolysis.' - module: glycolate_glyoxylate_assimilation step: tartronate_semialdehyde_reduction step_label: Tartronate semialdehyde to glycerate classification: UNDECIDED default_rule: (glyoxylate_carboligase | hydroxypyruvate_isomerization) rule: (glyoxylate_carboligase | hydroxypyruvate_isomerization) activators: - id: glyoxylate_carboligase label: Glyoxylate to tartronate semialdehyde connection: 'PROVIDES_INPUT_FOR: Glyoxylate carboligase produces tartronate semialdehyde (2-hydroxy-3-oxopropanoate), the substrate reduced by GlxR.' - id: hydroxypyruvate_isomerization label: Hydroxypyruvate isomerization connection: 'PROVIDES_INPUT_FOR: Hyi can provide the same tartronate-semialdehyde intermediate from hydroxypyruvate, connecting hydroxypyruvate metabolism to the GlxR reduction step.' - module: glycosphingolipid_biosynthesis step: ganglio_gm2gd2 step_label: GM2/GD2 synthase (B4GALNT1) classification: UNDECIDED default_rule: (ganglio_gd3 | ganglio_gm3) rule: (ganglio_gd3 | ganglio_gm3) activators: - id: ganglio_gd3 label: GD3 synthase (ST8SIA1) connection: 'PROVIDES_INPUT_FOR: GD3 (b-series) is likewise elongated by B4GALNT1 to GD2.' - id: ganglio_gm3 label: GM3 synthase (ST3GAL5) connection: 'PROVIDES_INPUT_FOR: GM3 (a-series) is elongated with GalNAc by B4GALNT1 to GM2.' - module: glycosphingolipid_lysosomal_degradation step: asah1_step step_label: ceramide to sphingosine + fatty acid classification: UNDECIDED default_rule: (galc_step | gba_step | smpd1_step) rule: (galc_step | gba_step | smpd1_step) activators: - id: galc_step label: galactosylceramide to ceramide connection: 'PROVIDES_INPUT_FOR: GALC produces ceramide, hydrolysed by ASAH1 to sphingosine.' - id: gba_step label: glucosylceramide to ceramide connection: 'PROVIDES_INPUT_FOR: GBA produces ceramide, hydrolysed by ASAH1 to sphingosine.' - id: smpd1_step label: sphingomyelin to ceramide connection: 'PROVIDES_INPUT_FOR: SMPD1 produces ceramide, hydrolysed by ASAH1 to sphingosine.' - module: heat_shock_response step: hsp70_folding_cycle step_label: Cytosolic Hsp70 folding cycle with J-domain, HSP110 and BAG cofactors classification: UNDECIDED default_rule: (hsf_activation | shsp_holdase) rule: (hsf_activation | shsp_holdase) activators: - id: hsf_activation label: HSF activation and HSE-dependent transcription connection: 'POSITIVELY_REGULATES: HSF drives Hsp70 transcription through HSEs. Worm HSF-1 binds the distal HSEs of hsp-1 during heat shock. In yeast, basal Hsp70 (SSA2) expression is one of the two essential Hsf1 outputs.' - id: shsp_holdase label: Small HSP holdases connection: 'PROVIDES_INPUT_FOR: Holdase-bound, refolding-competent clients are handed to the ATP-dependent chaperones.' - module: hedgehog_signaling step: smo_transducer step_label: Smoothened transducer classification: UNDECIDED default_rule: (hh_coreceptor | hspg_ligand_distribution | patched_receptor | vertebrate_secreted_accessories) & !patched_receptor rule: (hh_coreceptor | hspg_ligand_distribution | patched_receptor | vertebrate_secreted_accessories) & !patched_receptor activators: - id: hh_coreceptor label: Ig/FNIII Hedgehog co-receptor connection: via a container - id: hspg_ligand_distribution label: Heparan-sulfate proteoglycan ligand distribution (pan-metazoan) connection: via a container - id: patched_receptor label: Patched receptor connection: 'NEGATIVELY_REGULATES: Unliganded Patched holds Smoothened off; this is the edge the ligand removes, and it is the reason the pathway is drawn as de-repression.' - id: vertebrate_secreted_accessories label: Vertebrate secreted and GPI-anchored accessories (SCUBE2, GAS1, HHIP) connection: via a container - module: hedgehog_signaling step: smo_pka_inhibition step_label: Smoothened pseudosubstrate inhibition of protein kinase A classification: UNDECIDED default_rule: (hh_coreceptor | hspg_ligand_distribution | patched_receptor | vertebrate_secreted_accessories) rule: (hh_coreceptor | hspg_ligand_distribution | patched_receptor | vertebrate_secreted_accessories) activators: - id: hh_coreceptor label: Ig/FNIII Hedgehog co-receptor connection: via a container - id: hspg_ligand_distribution label: Heparan-sulfate proteoglycan ligand distribution (pan-metazoan) connection: via a container - id: patched_receptor label: Patched receptor connection: via a container - id: vertebrate_secreted_accessories label: Vertebrate secreted and GPI-anchored accessories (SCUBE2, GAS1, HHIP) connection: via a container - module: hedgehog_signaling step: btrc_slimb_adaptor step_label: Slimb/beta-TrCP SCF substrate adaptor classification: UNDECIDED default_rule: (ck1_processive_kinase | gsk3_processive_kinase) rule: (ck1_processive_kinase | gsk3_processive_kinase) activators: - id: ck1_processive_kinase label: Casein kinase 1 connection: 'PROVIDES_INPUT_FOR: The completed phosphodegron is the adaptor''s substrate.' - id: gsk3_processive_kinase label: Glycogen synthase kinase 3 connection: 'PROVIDES_INPUT_FOR: GSK3 phosphorylation contributes to the same phosphodegron.' - module: hedgehog_signaling step: ci_gli_activation step_label: SUFU release and Fused-family phosphorylation of Ci/GLI classification: UNDECIDED default_rule: (smo_pka_inhibition | smo_transducer) rule: (smo_pka_inhibition | smo_transducer) activators: - id: smo_pka_inhibition label: Smoothened pseudosubstrate inhibition of protein kinase A connection: via a container - id: smo_transducer label: Smoothened transducer connection: via a container - module: heme_biosynthesis step: alad_step step_label: ALA condensation classification: ALTERNATIVE_VARIANTS default_rule: (c4_alas_step | c5_heml_activity) rule: (c4_alas_step | c5_heml_activity) activators: - id: c4_alas_step label: C4/Shemin ALA formation connection: via a container - id: c5_heml_activity label: Glutamate-1-semialdehyde 2,1-aminomutase connection: via a container - module: hexosamine_biosynthesis step: glcnac_mutase step_label: Phosphoacetylglucosamine mutase (PGM3) classification: UNDECIDED default_rule: (glcn6p_acetylation | glcnac_salvage) rule: (glcn6p_acetylation | glcnac_salvage) activators: - id: glcn6p_acetylation label: Glucosamine-6-phosphate N-acetyltransferase (GNPNAT1) connection: 'PROVIDES_INPUT_FOR: The GlcNAc-6-P made by GNPNAT1 is converted to GlcNAc-1-P by PGM3.' - id: glcnac_salvage label: N-acetylglucosamine kinase (NAGK) connection: 'PROVIDES_INPUT_FOR: NAGK feeds salvaged GlcNAc-6-P into the pathway at the PGM3 step (the same node GNPNAT1 produces), recycling free GlcNAc from glycoconjugate degradation into UDP-GlcNAc.' - module: homocysteine_metabolism step: mtr_step step_label: L-homocysteine + 5-methyl-THF to L-methionine + THF classification: UNDECIDED default_rule: (cobalamin_support | mthfr_step) rule: (cobalamin_support | mthfr_step) activators: - id: cobalamin_support label: reactivation (MTRR) and processing (MMACHC) of MTR's cobalamin cofactor connection: 'POSITIVELY_REGULATES: MTRR reactivates and MMACHC supplies MTR''s methylcobalamin cofactor; without this support the remethylation step fails (cblE/cblC/cblG).' - id: mthfr_step label: 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate connection: 'PROVIDES_INPUT_FOR: 5-methyltetrahydrofolate made by MTHFR is the methyl donor consumed by methionine synthase (MTR) in remethylation.' - module: intraflagellar_transport step: kinesin_ii_import step_label: Heterotrimeric kinesin-II transport of IFT trains classification: UNDECIDED default_rule: (ift_a_complex | ift_b_complex) & !dyf5_regulation rule: (ift_a_complex | ift_b_complex) & !dyf5_regulation activators: - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_complex label: IFT-B complex connection: via a container - module: intraflagellar_transport step: accessory_kinesin2_transport step_label: Accessory homodimeric kinesin-2 transport classification: UNDECIDED default_rule: (dyf5_regulation | kinesin_ii_import) rule: (dyf5_regulation | kinesin_ii_import) activators: - id: dyf5_regulation label: MAK/CILK1-family kinase regulation of IFT connection: 'POSITIVELY_REGULATES: In worm dyf-5 mutants OSM-3 moves slowly and is not attached to IFT particles, so DYF-5 is needed for OSM-3 docking.' - id: kinesin_ii_import label: Heterotrimeric kinesin-II transport of IFT trains connection: 'PRECEDES: Where an accessory motor is present (worm OSM-3), kinesin-II hands IFT trains over to it in the handover zone on the proximal axoneme.' - module: jak_stat_signaling step: stat_recruitment_phosphorylation step_label: STAT recruitment and phosphorylation classification: UNDECIDED default_rule: (alt_stat_inputs | receptor_phosphorylation) rule: (alt_stat_inputs | receptor_phosphorylation) activators: - id: alt_stat_inputs label: RTK / Src / GPCR inputs into STATs connection: 'PROVIDES_INPUT_FOR: RTK/Src/GPCR tyrosine kinases can phosphorylate STATs independently of cytokine-receptor JAKs.' - id: receptor_phosphorylation label: Receptor tail phosphorylation and STAT docking-site creation connection: 'PROVIDES_INPUT_FOR: Receptor phosphotyrosines provide the SH2 docking sites that recruit STATs.' - module: jak_stat_signaling step: stat_transcription step_label: STAT-dependent transcription classification: DECLARED default_rule: (mapk_branch_interface | stat_dimerization_import) & !(pias_restraint | ptp_dephosphorylation) rule: stat_dimerization_import & !(ptp_dephosphorylation | pias_restraint) activators: - id: mapk_branch_interface label: Ras-MAPK branch interface connection: 'POSITIVELY_REGULATES: ERK serine-phosphorylates STATs (e.g. Ser727), converging back to tune STAT transcriptional output.' - id: stat_dimerization_import label: STAT dimerization and nuclear import connection: 'PROVIDES_INPUT_FOR: Nuclear STAT dimers bind GAS/ISRE elements to activate transcription.' - module: lignin_monolignol_biosynthesis step: monolignol_export step_label: Monolignol transport across the plasma membrane classification: UNDECIDED default_rule: (c3h_step | cad_step | ccoaomt_step | comt_step | hct_step) rule: (c3h_step | cad_step | ccoaomt_step | comt_step | hct_step) activators: - id: c3h_step label: p-Coumaroyl shikimate 3'-hydroxylase (C3'H / CYP98A) connection: via a container - id: cad_step label: Cinnamyl alcohol dehydrogenase (CAD) connection: via a container - id: ccoaomt_step label: Caffeoyl-CoA O-methyltransferase (CCoAOMT) connection: via a container - id: comt_step label: Caffeate/5-hydroxyconiferaldehyde O-methyltransferase (COMT) connection: via a container - id: hct_step label: Hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyltransferase (HCT) connection: via a container - module: lipid_a_raetz_biosynthesis step: lpxB_step step_label: Lipid A disaccharide synthesis classification: UNDECIDED default_rule: (lpxD_step | lpxH_step) rule: (lpxD_step | lpxH_step) activators: - id: lpxD_step label: UDP-3-O-acyl-glucosamine N-acylation connection: 'PROVIDES_INPUT_FOR: LpxB also consumes UDP-2,3-diacylglucosamine directly as the donor half of the disaccharide, so the LpxD product feeds both branches.' - id: lpxH_step label: UDP-2,3-diacylglucosamine hydrolysis connection: 'PRECEDES: ' - module: malate_aspartate_shuttle step: mas_carriers step_label: Inner-membrane carriers (SLC25A11 OGC, SLC25A12 AGC1) classification: UNDECIDED default_rule: (mas_cytosolic_arm | mas_matrix_arm) rule: (mas_cytosolic_arm | mas_matrix_arm) activators: - id: mas_cytosolic_arm label: Cytosolic arm (MDH1, GOT1) connection: 'PROVIDES_INPUT_FOR: Cytosolic MDH1 supplies malate to the OGC; GOT1 consumes the aspartate delivered by AGC1.' - id: mas_matrix_arm label: Matrix arm (MDH2, GOT2) connection: 'PROVIDES_INPUT_FOR: Matrix GOT2 supplies aspartate to AGC1 and 2-oxoglutarate to the OGC, closing the cycle.' - module: metaphase_anaphase_transition_and_mitotic_exit step: cdh1_coactivator step_label: Cdh1/Hct1/Ste9 coactivator classification: UNDECIDED default_rule: (apc_c | cdc14_scer | clp1_spom | cohesin_kleisin | metazoan_pp2a_b55_reactivation) rule: (apc_c | cdc14_scer | clp1_spom | cohesin_kleisin | metazoan_pp2a_b55_reactivation) activators: - id: apc_c label: Anaphase-promoting complex/cyclosome connection: via a container - id: cdc14_scer label: Cdc14 phosphatase connection: via a container - id: clp1_spom label: Clp1/Flp1 phosphatase connection: via a container - id: cohesin_kleisin label: Cohesin kleisin subunit (separase substrate) connection: via a container - id: metazoan_pp2a_b55_reactivation label: Metazoan PP2A-B55 reactivation connection: via a container - module: metazoan_autophagosome_biogenesis step: lgg1_early step_label: GABARAP-type LGG-1 in autophagosome formation classification: UNDECIDED default_rule: (atg8_conjugation | cargo_recruitment) rule: (atg8_conjugation | cargo_recruitment) activators: - id: atg8_conjugation label: ATG4 priming and ATG7-ATG3-ATG12-ATG5-ATG16 conjugation connection: via a container - id: cargo_recruitment label: p62/SQSTM1 cargo receptor connection: via a container - module: metazoan_autophagosome_biogenesis step: lc3_elongation step_label: LC3-subfamily Atg8 in phagophore elongation classification: UNDECIDED default_rule: (atg8_conjugation | cargo_recruitment) rule: (atg8_conjugation | cargo_recruitment) activators: - id: atg8_conjugation label: ATG4 priming and ATG7-ATG3-ATG12-ATG5-ATG16 conjugation connection: via a container - id: cargo_recruitment label: p62/SQSTM1 cargo receptor connection: via a container - module: metazoan_autophagosome_biogenesis step: maturation_fusion step_label: EPG5-dependent autophagosome-lysosome fusion classification: ALTERNATIVE_VARIANTS default_rule: (gabarap_fusion | lgg2_late) rule: (gabarap_fusion | lgg2_late) activators: - id: gabarap_fusion label: GABARAP-subfamily Atg8 at autophagosome-lysosome fusion connection: via a container - id: lgg2_late label: LC3-type LGG-2 in autophagosome maturation connection: via a container - module: methionine_biosynthesis step: metB_node step_label: Cystathionine gamma-synthase classification: ALTERNATIVE_VARIANTS default_rule: (o_acetyl_activation | o_succinyl_activation) rule: (o_acetyl_activation | o_succinyl_activation) activators: - id: o_acetyl_activation label: O-acetylhomoserine formation connection: via a container - id: o_succinyl_activation label: O-succinylhomoserine formation connection: via a container - module: methionine_biosynthesis step: direct_sulfhydrylation step_label: Direct sulfhydrylation of O-acetylhomoserine (metY) classification: ALTERNATIVE_VARIANTS default_rule: (o_acetyl_activation | o_succinyl_activation) rule: (o_acetyl_activation | o_succinyl_activation) activators: - id: o_acetyl_activation label: O-acetylhomoserine formation connection: 'PROVIDES_INPUT_FOR: Homoserine O-acetyltransferase supplies O-acetyl-L-homoserine to the MetY direct-sulfhydrylation route.' - id: o_succinyl_activation label: O-succinylhomoserine formation connection: via a container - module: methionine_biosynthesis step: direct_sulfhydrylation_metZ step_label: Direct sulfhydrylation of O-succinylhomoserine (metZ) classification: ALTERNATIVE_VARIANTS default_rule: (o_acetyl_activation | o_succinyl_activation) rule: (o_acetyl_activation | o_succinyl_activation) activators: - id: o_acetyl_activation label: O-acetylhomoserine formation connection: via a container - id: o_succinyl_activation label: O-succinylhomoserine formation connection: 'PROVIDES_INPUT_FOR: Homoserine O-succinyltransferase supplies O-succinyl-L-homoserine to the MetZ direct-sulfhydrylation route.' - module: methionine_biosynthesis step: methylation step_label: Homocysteine methylation to methionine classification: ALTERNATIVE_VARIANTS default_rule: (direct_sulfhydrylation | direct_sulfhydrylation_metZ | metC_node) rule: (direct_sulfhydrylation | direct_sulfhydrylation_metZ | metC_node) activators: - id: direct_sulfhydrylation label: Direct sulfhydrylation of O-acetylhomoserine (metY) connection: via a container - id: direct_sulfhydrylation_metZ label: Direct sulfhydrylation of O-succinylhomoserine (metZ) connection: via a container - id: metC_node label: Cystathionine beta-lyase connection: via a container - module: methionine_cycle step: mat1_activity step_label: MAT-I methionine adenosyltransferase activity classification: ALTERNATIVE_VARIANTS default_rule: (bhmt_route | mete_route | ms_route) & !amet_pool rule: (bhmt_route | mete_route | ms_route) & !amet_pool activators: - id: bhmt_route label: Betaine-dependent remethylation (BHMT) connection: via a container - id: mete_route label: Folate-dependent remethylation, cobalamin-independent (MetE-type methionine synthase) connection: via a container - id: ms_route label: Folate-dependent remethylation, cobalamin-dependent (MetH/MTR-type methionine synthase) connection: via a container - module: methionine_cycle step: mat3_activity step_label: MAT-III methionine adenosyltransferase activity classification: UNDECIDED default_rule: (amet_pool | bhmt_route | met_pool | mete_route | ms_route) rule: (amet_pool | bhmt_route | met_pool | mete_route | ms_route) activators: - id: amet_pool label: S-adenosyl-L-methionine (SAM) pool connection: 'POSITIVELY_REGULATES: SAM allosterically activates MAT-III (feed-forward). Contrast with MAT-I, which SAM competitively inhibits - same reaction, opposite isozyme logic.' - id: bhmt_route label: Betaine-dependent remethylation (BHMT) connection: via a container - id: met_pool label: L-methionine pool connection: 'POSITIVELY_REGULATES: Methionine feed-forward activates MAT-III.' - id: mete_route label: Folate-dependent remethylation, cobalamin-independent (MetE-type methionine synthase) connection: via a container - id: ms_route label: Folate-dependent remethylation, cobalamin-dependent (MetH/MTR-type methionine synthase) connection: via a container - module: methionine_cycle step: mat_single_chain_activity step_label: Methionine adenosyltransferase (MAT2A/MetK/SAM1-type) classification: ALTERNATIVE_VARIANTS default_rule: (bhmt_route | mete_route | ms_route) rule: (bhmt_route | mete_route | ms_route) activators: - id: bhmt_route label: Betaine-dependent remethylation (BHMT) connection: via a container - id: mete_route label: Folate-dependent remethylation, cobalamin-independent (MetE-type methionine synthase) connection: via a container - id: ms_route label: Folate-dependent remethylation, cobalamin-dependent (MetH/MTR-type methionine synthase) connection: via a container - module: methionine_cycle step: meth_activity step_label: SAM-dependent methyltransferase activity (general) classification: ALTERNATIVE_VARIANTS default_rule: (mat1_activity | mat3_activity | mat_single_chain_activity) & !ahcys_pool rule: (mat1_activity | mat3_activity | mat_single_chain_activity) & !ahcys_pool activators: - id: mat1_activity label: MAT-I methionine adenosyltransferase activity connection: via a container - id: mat3_activity label: MAT-III methionine adenosyltransferase activity connection: via a container - id: mat_single_chain_activity label: Methionine adenosyltransferase (MAT2A/MetK/SAM1-type) connection: via a container - module: methionine_cycle step: gnmt_activity step_label: Glycine N-methyltransferase activity classification: UNDECIDED default_rule: (amet_pool | mat1_activity | mat3_activity) & !(ahcys_pool | mlthf_pool) rule: (amet_pool | mat1_activity | mat3_activity) & !(ahcys_pool | mlthf_pool) activators: - id: amet_pool label: S-adenosyl-L-methionine (SAM) pool connection: 'POSITIVELY_REGULATES: SAM allosterically activates GNMT, opening the SAM overflow valve when methyl donor is in excess.' - id: mat1_activity label: MAT-I methionine adenosyltransferase activity connection: via a container - id: mat3_activity label: MAT-III methionine adenosyltransferase activity connection: via a container - module: methionine_cycle step: ahc_step step_label: S-adenosyl-L-homocysteine -> L-homocysteine classification: UNDECIDED default_rule: (gnmt_activity | meth_activity) rule: (gnmt_activity | meth_activity) activators: - id: gnmt_activity label: Glycine N-methyltransferase activity connection: via a container - id: meth_activity label: SAM-dependent methyltransferase activity (general) connection: via a container - module: methionine_cycle step: ms_route step_label: Folate-dependent remethylation, cobalamin-dependent (MetH/MTR-type methionine synthase) classification: UNDECIDED default_rule: (ahc_step | mthfr_activity) rule: (ahc_step | mthfr_activity) activators: - id: ahc_step label: S-adenosyl-L-homocysteine -> L-homocysteine connection: via a container - id: mthfr_activity label: Methylenetetrahydrofolate reductase activity connection: via a container - module: methionine_cycle step: mete_route step_label: Folate-dependent remethylation, cobalamin-independent (MetE-type methionine synthase) classification: UNDECIDED default_rule: (ahc_step | mthfr_activity) rule: (ahc_step | mthfr_activity) activators: - id: ahc_step label: S-adenosyl-L-homocysteine -> L-homocysteine connection: via a container - id: mthfr_activity label: Methylenetetrahydrofolate reductase activity connection: via a container - module: methionine_cycle step: cbs_activity step_label: Cystathionine beta-synthase activity classification: UNDECIDED default_rule: (ahc_step | amet_pool) rule: (ahc_step | amet_pool) activators: - id: ahc_step label: S-adenosyl-L-homocysteine -> L-homocysteine connection: via a container - id: amet_pool label: S-adenosyl-L-methionine (SAM) pool connection: 'POSITIVELY_REGULATES: SAM allosterically activates CBS, diverting homocysteine to transsulfuration when methyl donor is abundant.' - module: methionine_salvage_mta_cycle step: mtr1p_isomerase_step step_label: MTR-1-P to S-methyl-5-thio-D-ribulose 1-phosphate classification: ALTERNATIVE_VARIANTS default_rule: (mta_phosphorylase_route | mtr_kinase_step) rule: (mta_phosphorylase_route | mtr_kinase_step) activators: - id: mta_phosphorylase_route label: Direct phosphorolysis (MTA phosphorylase) connection: via a container - id: mtr_kinase_step label: 5-methylthioribose to S-methyl-5-thio-alpha-D-ribose 1-phosphate connection: via a container - module: methionine_salvage_mta_cycle step: acireductone_dioxygenase_step step_label: acireductone + O2 to 4-methylthio-2-oxobutanoate + formate classification: ALTERNATIVE_VARIANTS default_rule: (bifunctional_e1_variant | hkmtp_phosphatase_step) rule: (bifunctional_e1_variant | hkmtp_phosphatase_step) activators: - id: bifunctional_e1_variant label: Bifunctional enolase-phosphatase E1 (fungi, animals, many bacteria) connection: via a container - id: hkmtp_phosphatase_step label: 2-hydroxy-3-keto-5-methylthiopentenyl 1-phosphate to acireductone connection: via a container - module: methylcitrate_cycle step: methylisocitrate_formation step_label: 2-methyl-cis-aconitate hydration classification: ALTERNATIVE_VARIANTS default_rule: (prpD_direct_route | prpF_isomerization) rule: (prpD_direct_route | prpF_isomerization) activators: - id: prpD_direct_route label: Direct PrpD route connection: via a container - id: prpF_isomerization label: PrpF methylaconitate isomerization connection: via a container - module: mitochondrial_complex_v step: complex_v_f1 step_label: F1 sector (alpha3-beta3 catalytic head + central stalk) classification: UNDECIDED default_rule: (complex_v_assembly | complex_v_fo) rule: (complex_v_assembly | complex_v_fo) activators: - id: complex_v_assembly label: ATP synthase assembly (F1 chaperone and dimerisation) connection: 'POSITIVELY_REGULATES: ATPAF2 builds the F1 alpha3-beta3 catalytic core and TMEM70 promotes assembly/dimerisation of the holoenzyme.' - id: complex_v_fo label: Fo sector (c-ring and small membrane subunits) connection: 'PROVIDES_INPUT_FOR: Proton conduction through the Fo c-ring rotates the central stalk, driving ATP synthesis at the F1 catalytic head.' - module: mitochondrial_upr step: uprmt_transcription_factor step_label: ATFS-1/ATF5 nuclear transcriptional activation classification: UNDECIDED default_rule: (atf4_isr_activation | atfs1_import_checkpoint | dve1_activator | hri_eif2a_phosphorylation | jmjd31_demethylase | lin65_cofactor | ubl5_coactivator) & !atfs1_import_checkpoint rule: (atf4_isr_activation | atfs1_import_checkpoint | dve1_activator | hri_eif2a_phosphorylation | jmjd31_demethylase | lin65_cofactor | ubl5_coactivator) & !atfs1_import_checkpoint activators: - id: atf4_isr_activation label: ATF4 translation and transcriptional activation connection: via a container - id: atfs1_import_checkpoint label: ATFS-1 mitochondrial import and matrix activity connection: 'NEGATIVELY_REGULATES: Nematode variant: efficient mitochondrial import and degradation of ATFS-1 keeps it out of the nucleus; reduced import releases the nuclear pool.' - id: dve1_activator label: DVE-1 homeodomain transcription factor connection: via a container - id: hri_eif2a_phosphorylation label: HRI eIF2alpha kinase connection: 'POSITIVELY_REGULATES: Mammalian variant: eIF2alpha phosphorylation favours ATF5 synthesis.' - id: jmjd31_demethylase label: JMJD-3.1 H3K27 demethylase connection: via a container - id: lin65_cofactor label: LIN-65 nuclear cofactor of MET-2 connection: via a container - id: ubl5_coactivator label: UBL-5 DVE-1-associated coactivator connection: via a container - module: mitochondrial_upr step: chaperone_output step_label: HSP60 and mtHSP70 matrix chaperone output classification: UNDECIDED default_rule: (dve1_activator | jmjd31_demethylase | lin65_cofactor | ubl5_coactivator | uprmt_transcription_factor) rule: (dve1_activator | jmjd31_demethylase | lin65_cofactor | ubl5_coactivator | uprmt_transcription_factor) activators: - id: dve1_activator label: DVE-1 homeodomain transcription factor connection: via a container - id: jmjd31_demethylase label: JMJD-3.1 H3K27 demethylase connection: via a container - id: lin65_cofactor label: LIN-65 nuclear cofactor of MET-2 connection: via a container - id: ubl5_coactivator label: UBL-5 DVE-1-associated coactivator connection: via a container - id: uprmt_transcription_factor label: ATFS-1/ATF5 nuclear transcriptional activation connection: 'POSITIVELY_REGULATES: Nuclear ATFS-1 or ATF5 induces HSP60 and mtHSP70 transcription.' - module: mitophagy step: atg8_capture step_label: Atg8-family docking of mitophagy receptors on the phagophore classification: ALTERNATIVE_VARIANTS default_rule: (allo1_receptor | bnip3_nix_receptor | fundc1_receptor | ubiquitin_binding_receptors) rule: (allo1_receptor | bnip3_nix_receptor | fundc1_receptor | ubiquitin_binding_receptors) activators: - id: allo1_receptor label: ALLO-1 allophagy receptor for paternal organelles (nematode) connection: via a container - id: bnip3_nix_receptor label: BNIP3/NIX-family outer-membrane mitophagy receptor connection: via a container - id: fundc1_receptor label: FUNDC1-family ubiquitin-independent mitophagy receptor connection: via a container - id: ubiquitin_binding_receptors label: Optineurin and NDP52 ubiquitin-binding mitophagy receptors (vertebrate) connection: via a container - module: muth_independent_mismatch_repair step: repair_gap_filling step_label: DNA polymerase-dependent gap filling classification: UNDECIDED default_rule: (excision_nuclease_choice | ssb_excision_scaffold) rule: (excision_nuclease_choice | ssb_excision_scaffold) activators: - id: excision_nuclease_choice label: Orientation-dependent mismatch-excision nucleases connection: via a container - id: ssb_excision_scaffold label: Single-stranded DNA-binding repair scaffold connection: via a container - module: nad_biosynthesis_salvage step: namn_adenylylation step_label: NaMN adenylylation alternatives classification: ALTERNATIVE_VARIANTS default_rule: (nadc_step | nicotinate_preiss_handler_route | nmn_deamidating_route | pncb_after_pnca_step) rule: (nadc_step | nicotinate_preiss_handler_route | nmn_deamidating_route | pncb_after_pnca_step) activators: - id: nadc_step label: Quinolinate phosphoribosyltransferase step connection: via a container - id: nicotinate_preiss_handler_route label: Direct nicotinate Preiss-Handler entry connection: via a container - id: nmn_deamidating_route label: NMN deamidation to NaMN connection: via a container - id: pncb_after_pnca_step label: PncB step after PncA connection: via a container - module: nad_de_novo_and_salvage_fungal step: namn_adenylyltransferase_step step_label: NaMN to nicotinate adenine dinucleotide (NaAD) classification: ALTERNATIVE_VARIANTS default_rule: (nicotinate_phosphoribosyltransferase_step | nrk1_nicotinate_riboside_kinase_activity | quinolinate_phosphoribosyltransferase_step) rule: (nicotinate_phosphoribosyltransferase_step | nrk1_nicotinate_riboside_kinase_activity | quinolinate_phosphoribosyltransferase_step) activators: - id: nicotinate_phosphoribosyltransferase_step label: Nicotinate to NaMN connection: via a container - id: nrk1_nicotinate_riboside_kinase_activity label: Nrk1 nicotinic acid riboside kinase connection: 'PROVIDES_INPUT_FOR: ' - id: quinolinate_phosphoribosyltransferase_step label: Quinolinate to NaMN connection: via a container - module: neural_crest_gene_regulatory_network step: pax3_border step_label: Pax3 border specifier classification: UNDECIDED default_rule: (gbx2_border | msx1_border | pou5f3_competence | tfap2a_border) rule: (gbx2_border | msx1_border | pou5f3_competence | tfap2a_border) activators: - id: gbx2_border label: Gbx2 border specifier connection: 'POSITIVELY_REGULATES: Gbx2 acts upstream of Pax3, placed by epistasis; direct binding to the pax3 locus is not demonstrated.' - id: msx1_border label: Msx1 border specifier connection: 'POSITIVELY_REGULATES: Msx1 induces Pax3 cell-autonomously.' - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: 'POSITIVELY_REGULATES: Pou5f3 gain of function expands pax3 (and zic1, snai2) expression.' - id: tfap2a_border label: AP-2alpha border initiator connection: 'POSITIVELY_REGULATES: AP-2alpha activates pax3 directly: translation-independent induction, promoter-reporter, site mutation and EMSA/supershift (frog).' - module: neural_crest_gene_regulatory_network step: foxd3_spec step_label: FoxD3 crest specifier classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: 'POSITIVELY_REGULATES: Pax3/Zic1 activate foxd3 without new protein synthesis (immediate-response target); enhancer occupancy in frog not shown.' - id: pax7_border label: Pax7 border specifier connection: 'POSITIVELY_REGULATES: Pax7 binds the FoxD3 NC1 enhancer in vivo (ChIP) with Msx1 and Ets1; its knockdown abolishes NC1/NC2 activity (chick).' - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: 'POSITIVELY_REGULATES: Pax3/Zic1 activate foxd3 without new protein synthesis (immediate-response target); enhancer occupancy in frog not shown.' - module: neural_crest_gene_regulatory_network step: snai1_spec step_label: Snail1 early crest specifier classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: via a container - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: 'POSITIVELY_REGULATES: Zic1 binds a snail1 element (EMSA) and activates snail1 without new protein synthesis.' - module: neural_crest_gene_regulatory_network step: snai2_spec step_label: Snai2 crest specifier classification: UNDECIDED default_rule: (pax3_border | snai1_spec) & !twist1_snai2_inhibition rule: (pax3_border | snai1_spec) & !twist1_snai2_inhibition activators: - id: pax3_border label: Pax3 border specifier connection: 'POSITIVELY_REGULATES: Pax3 binds and activates snail2 directly.' - id: snai1_spec label: Snail1 early crest specifier connection: 'POSITIVELY_REGULATES: Snail1 acts upstream of Slug/Snai2 in crest specification.' - module: neural_crest_gene_regulatory_network step: tfap2b_spec step_label: "AP-2beta (TFAP2A\u2013TFAP2B) crest specifier" classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: 'POSITIVELY_REGULATES: Pax3/Zic1 activate tfap2b without new protein synthesis (frog immediate-response target).' - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: 'POSITIVELY_REGULATES: TFAP2A/C occupies the TFAP2B locus and is required for its activation at the onset of specification (chick).' - id: zic1_border label: Zic1 border specifier connection: 'POSITIVELY_REGULATES: Pax3/Zic1 activate tfap2b without new protein synthesis (frog immediate-response target).' - module: neural_crest_gene_regulatory_network step: tfap2a_spec step_label: AP-2alpha crest specifier classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: via a container - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: via a container - module: neural_crest_gene_regulatory_network step: sox8_spec step_label: Sox8 crest specifier classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: 'POSITIVELY_REGULATES: Pax3/Zic1 activate sox8 with snail1 and myc.' - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: via a container - module: neural_crest_gene_regulatory_network step: sox9_variant step_label: Sox9 classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: via a container - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: via a container - module: neural_crest_gene_regulatory_network step: sox10_variant step_label: Sox10 classification: UNDECIDED default_rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) rule: (id3_competence | myc_competence | pax3_border | pax7_border | pou5f3_competence | tfap2c_border | zic1_border) activators: - id: id3_competence label: Id3 bHLH inhibitor connection: via a container - id: myc_competence label: c-Myc competence factor connection: via a container - id: pax3_border label: Pax3 border specifier connection: via a container - id: pax7_border label: Pax7 border specifier connection: via a container - id: pou5f3_competence label: Oct25 (Pou5f3) competence factor connection: via a container - id: tfap2c_border label: "AP-2gamma (TFAP2A\u2013TFAP2C) border inducer" connection: via a container - id: zic1_border label: Zic1 border specifier connection: via a container - module: neural_crest_gene_regulatory_network step: neural_crest_emigration step_label: Neural crest delamination and migration classification: UNDECIDED default_rule: (foxd3_spec | snai2_spec | sox10_variant | sox8_spec | sox9_variant | tfap2a_spec | tfap2b_spec) rule: (foxd3_spec | snai2_spec | sox10_variant | sox8_spec | sox9_variant | tfap2a_spec | tfap2b_spec) activators: - id: foxd3_spec label: FoxD3 crest specifier connection: via a container - id: snai2_spec label: Snai2 crest specifier connection: via a container - id: sox10_variant label: Sox10 connection: via a container - id: sox8_spec label: Sox8 crest specifier connection: via a container - id: sox9_variant label: Sox9 connection: via a container - id: tfap2a_spec label: AP-2alpha crest specifier connection: via a container - id: tfap2b_spec label: "AP-2beta (TFAP2A\u2013TFAP2B) crest specifier" connection: via a container - module: neural_crest_gene_regulatory_network step: twist1_ectomesenchyme step_label: Twist1 ectomesenchyme driver classification: UNDECIDED default_rule: (neural_crest_emigration | pax3_border) rule: (neural_crest_emigration | pax3_border) activators: - id: neural_crest_emigration label: Neural crest delamination and migration connection: via a container - id: pax3_border label: Pax3 border specifier connection: 'POSITIVELY_REGULATES: Pax3 activates twist1 directly.' - module: nicotine_biosynthesis step: a622_step step_label: nicotinic acid N-glucoside reduction (A622 / NaGR) classification: UNDECIDED default_rule: (mpo_step | ugt_step) rule: (mpo_step | ugt_step) activators: - id: mpo_step label: N-methylputrescine -> N-methyl-Delta1-pyrrolinium cation (N-methylputrescine oxidase) connection: via a container - id: ugt_step label: nicotinic acid -> nicotinic acid N-glucoside (UGT1 / NaGT) connection: 'PROVIDES_INPUT_FOR: Nicotinic acid N-glucoside made by UGT1 is the substrate reduced by A622/NaGR.' - module: nitrogen_assimilation_glutamate_glutamine step: glutamine_synthetase_step step_label: L-glutamate + ammonium + ATP to L-glutamine classification: UNDECIDED default_rule: (glutamate_deamination_step | gs_gogat_route | nadp_gdh_route) rule: (glutamate_deamination_step | gs_gogat_route | nadp_gdh_route) activators: - id: glutamate_deamination_step label: L-glutamate + NAD+ to 2-oxoglutarate + ammonium connection: 'PRECEDES: On glutamate as nitrogen source, ammonium released by NAD-dependent glutamate dehydrogenase is fixed by glutamine synthetase.' - id: gs_gogat_route label: Glutamine amide transfer by NADH-dependent glutamate synthase (GS-GOGAT cycle) connection: via a container - id: nadp_gdh_route label: Reductive amination by NADP-dependent glutamate dehydrogenase connection: via a container - module: nitrogen_cycle step: ammonia_assimilation step_label: Ammonia assimilation (GS/GOGAT cycle) classification: UNDECIDED default_rule: (assim_nitrite_reduction | nitrogen_fixation) rule: (assim_nitrite_reduction | nitrogen_fixation) activators: - id: assim_nitrite_reduction label: Assimilatory nitrite reduction connection: 'PROVIDES_INPUT_FOR: ' - id: nitrogen_fixation label: Nitrogen fixation connection: 'PROVIDES_INPUT_FOR: Fixed ammonia feeds the GS/GOGAT assimilation cycle.' - module: notch_signaling step: notch_receptor_engagement step_label: Notch receptor binds ligand in trans classification: UNDECIDED default_rule: (notch_fringe_elongation | notch_ligand_presentation) & !notch_cis_inhibition rule: (notch_fringe_elongation | notch_ligand_presentation) & !notch_cis_inhibition activators: - id: notch_fringe_elongation label: Fringe GlcNAc elongation of Notch O-fucose connection: via a container - id: notch_ligand_presentation label: DSL ligand presentation and E3-dependent activation connection: 'CAUSES: Activated ligand binds the receptor in trans and applies endocytic pulling force.' - module: notch_signaling step: notch_target_output step_label: Notch target gene output classification: UNDECIDED default_rule: (csl_dna_binding | mastermind_coactivation) rule: (csl_dna_binding | mastermind_coactivation) activators: - id: csl_dna_binding label: CSL DNA-binding transcription factor connection: via a container - id: mastermind_coactivation label: Mastermind-family coactivator recruitment connection: via a container - module: nucleokinesis step: dynein_lis1_nude_motor step_label: Dynein-dynactin-LIS1-NDEL1 nuclear motor classification: UNDECIDED default_rule: (nuclear_envelope_motor_coupling | perinuclear_microtubule_track) rule: (nuclear_envelope_motor_coupling | perinuclear_microtubule_track) activators: - id: nuclear_envelope_motor_coupling label: Nuclear-envelope motor coupling connection: 'PROVIDES_INPUT_FOR: Envelope anchors (nesprin-2, BICD2, CENPF-NDE1/NDEL1) attach dynein to the nucleus, so that minus-end motility is converted into nuclear translocation.' - id: perinuclear_microtubule_track label: DCX-stabilized perinuclear microtubule cage connection: 'PROVIDES_INPUT_FOR: The DCX-stabilized, centrosome-anchored microtubule cage is the track along which dynein pulls the nucleus.' - module: oxphos step: quinone_pool step_label: Quinone pool (ubiquinone/menaquinone) classification: UNDECIDED default_rule: (auxiliary_quinone_dehydrogenases | complex_I | complex_II) rule: (auxiliary_quinone_dehydrogenases | complex_I | complex_II) activators: - id: auxiliary_quinone_dehydrogenases label: Auxiliary dehydrogenases feeding the quinone pool connection: 'PROVIDES_INPUT_FOR: ETF-QO, glycerol-3-phosphate dehydrogenase, and DHODH reduce the quinone pool from other pathways.' - id: complex_I label: Complex I (NADH:ubiquinone oxidoreductase) connection: 'PROVIDES_INPUT_FOR: Complex I reduces ubiquinone to ubiquinol, charging the quinone pool.' - id: complex_II label: Complex II (succinate dehydrogenase / succinate:quinone oxidoreductase) connection: 'PROVIDES_INPUT_FOR: Complex II reduces the quinone pool from succinate (TCA cycle).' - module: oxphos step: complex_V_activity step_label: Proton-motive-force-driven ATP synthesis (rotational) classification: UNDECIDED default_rule: (complex_IV | respiratory_chain_variants) & !if1_inhibitor rule: (complex_IV | respiratory_chain_variants) & !if1_inhibitor activators: - id: complex_IV label: Complex IV (cytochrome c oxidase) connection: via a container - id: respiratory_chain_variants label: Lineage-specific entry and terminal-oxidase variants connection: via a container - module: oxphos step: atp_synthase_F1 step_label: F1 catalytic head classification: UNDECIDED default_rule: (complex_IV | respiratory_chain_variants) rule: (complex_IV | respiratory_chain_variants) activators: - id: complex_IV label: Complex IV (cytochrome c oxidase) connection: via a container - id: respiratory_chain_variants label: Lineage-specific entry and terminal-oxidase variants connection: via a container - module: oxphos step: atp_synthase_Fo step_label: Fo proton-translocating sector classification: UNDECIDED default_rule: (complex_IV | respiratory_chain_variants) rule: (complex_IV | respiratory_chain_variants) activators: - id: complex_IV label: Complex IV (cytochrome c oxidase) connection: via a container - id: respiratory_chain_variants label: Lineage-specific entry and terminal-oxidase variants connection: via a container - module: pentose_phosphate_nonoxidative_branch step: tkt_step step_label: D-xylulose-5-P + D-ribose-5-P to sedoheptulose-7-P + D-glyceraldehyde-3-P classification: UNDECIDED default_rule: (rpe_step | rpia_step) rule: (rpe_step | rpia_step) activators: - id: rpe_step label: D-ribulose-5-phosphate to D-xylulose-5-phosphate connection: 'PROVIDES_INPUT_FOR: Xylulose-5-phosphate from RPE is the other transketolase substrate.' - id: rpia_step label: D-ribulose-5-phosphate to D-ribose-5-phosphate connection: 'PROVIDES_INPUT_FOR: Ribose-5-phosphate from RPIA is a transketolase substrate.' - module: pentose_phosphate_pathway step: transketolase_first_step step_label: 'Transketolase: xylulose 5-phosphate plus ribose 5-phosphate' classification: UNDECIDED default_rule: (ribose_5_phosphate_isomerase_step | ribulose_phosphate_epimerase_step) rule: (ribose_5_phosphate_isomerase_step | ribulose_phosphate_epimerase_step) activators: - id: ribose_5_phosphate_isomerase_step label: Ribose-5-phosphate isomerase connection: 'PROVIDES_INPUT_FOR: Ribose 5-phosphate is one substrate for the first transketolase step.' - id: ribulose_phosphate_epimerase_step label: Ribulose-phosphate 3-epimerase connection: 'PROVIDES_INPUT_FOR: Xylulose 5-phosphate is the ketose donor for the first transketolase step.' - module: pentose_phosphate_pathway step: transketolase_second_step step_label: 'Transketolase: xylulose 5-phosphate plus erythrose 4-phosphate' classification: UNDECIDED default_rule: (ribulose_phosphate_epimerase_step | transaldolase_step) rule: (ribulose_phosphate_epimerase_step | transaldolase_step) activators: - id: ribulose_phosphate_epimerase_step label: Ribulose-phosphate 3-epimerase connection: 'PROVIDES_INPUT_FOR: Xylulose 5-phosphate also supplies the second transketolase step.' - id: transaldolase_step label: Transaldolase connection: 'PROVIDES_INPUT_FOR: Erythrose 4-phosphate from transaldolase is used by the second transketolase step.' - module: peptidoglycan_precursor_biosynthesis step: murF_pentapeptide_ligation step_label: MurF pentapeptide ligation classification: UNDECIDED default_rule: (ddl_dipeptide_synthesis | murE_third_residue_ligation) rule: (ddl_dipeptide_synthesis | murE_third_residue_ligation) activators: - id: ddl_dipeptide_synthesis label: D-Ala-D-Ala synthesis connection: 'PROVIDES_INPUT_FOR: Ddl supplies the D-Ala-D-Ala substrate to MurF.' - id: murE_third_residue_ligation label: MurE third stem-residue ligation connection: 'PROVIDES_INPUT_FOR: MurE supplies UDP-MurNAc-tripeptide to MurF.' - module: peptidoglycan_recycling step: anmK_step step_label: AnmK formation of MurNAc-6-phosphate classification: UNDECIDED default_rule: (ampD_peptide_release_step | nagZ_glycan_processing_step) rule: (ampD_peptide_release_step | nagZ_glycan_processing_step) activators: - id: ampD_peptide_release_step label: AmpD cleavage of the anhMurNAc-stem bond connection: 'PRECEDES: ' - id: nagZ_glycan_processing_step label: NagZ cleavage of muropeptide GlcNAc connection: 'PRECEDES: ' - module: peptidoglycan_recycling step: mpl_step step_label: Mpl ligation of the recovered tripeptide to UDP-MurNAc classification: UNDECIDED default_rule: (ampD_peptide_release_step | murU_step) rule: (ampD_peptide_release_step | murU_step) activators: - id: ampD_peptide_release_step label: AmpD cleavage of the anhMurNAc-stem bond connection: 'PROVIDES_INPUT_FOR: ' - id: murU_step label: MurU formation of UDP-MurNAc connection: 'PROVIDES_INPUT_FOR: ' - module: peroxisomal_beta_oxidation step: acyl_coa_oxidation step_label: Acyl-CoA oxidases classification: UNDECIDED default_rule: (intraperoxisomal_activation | thiolytic_cleavage) rule: (intraperoxisomal_activation | thiolytic_cleavage) activators: - id: intraperoxisomal_activation label: Peroxisomal acyl-CoA synthetase connection: via a container - id: thiolytic_cleavage label: Peroxisomal thiolases connection: 'PRECEDES: The chain-shortened acyl-CoA (minus two carbons) re-enters the oxidase step, iterating the spiral until the substrate is fully shortened.' - module: peroxisomal_beta_oxidation step: hydration_dehydrogenation step_label: Multifunctional proteins (D-specific MFE-2; L-specific bifunctional protein) classification: UNDECIDED default_rule: (acyl_coa_oxidation | enoyl_coa_isomerisation) rule: (acyl_coa_oxidation | enoyl_coa_isomerisation) activators: - id: acyl_coa_oxidation label: Acyl-CoA oxidases connection: 'PRECEDES: The 2-trans-enoyl-CoA made by the oxidase is hydrated and dehydrogenated by the multifunctional proteins.' - id: enoyl_coa_isomerisation label: Peroxisomal delta3-delta2-enoyl-CoA isomerase connection: via a container - module: peroxisome-lifecycle step: matrix_cargo_targeting step_label: Matrix protein cargo targeting classification: ALTERNATIVE_VARIANTS default_rule: (pex16_supported_pmp_route | pex3_family_membrane_docking | rrbp1_supported_er_biogenesis_route) rule: (pex16_supported_pmp_route | pex3_family_membrane_docking | rrbp1_supported_er_biogenesis_route) activators: - id: pex16_supported_pmp_route label: Pex16-supported membrane biogenesis route connection: via a container - id: pex3_family_membrane_docking label: Pex3-family membrane docking unit connection: via a container - id: rrbp1_supported_er_biogenesis_route label: RRBP1-supported ER-linked membrane biogenesis route connection: via a container - module: phagophore_assembly_site step: atg1_atg13_phosphorylation_dissolution step_label: Atg1-dependent Atg13 phosphorylation and Atg1 complex dissociation classification: UNDECIDED default_rule: (pas_atg2_atg18 | pas_atg8_conjugation | pas_membrane_component | pas_pi3k_complex_i) rule: (pas_atg2_atg18 | pas_atg8_conjugation | pas_membrane_component | pas_pi3k_complex_i) activators: - id: pas_atg2_atg18 label: Atg2-Atg18 complex at the PAS connection: via a container - id: pas_atg8_conjugation label: Atg8 conjugation machinery at the PAS connection: 'POSITIVELY_REGULATES: Atg8-PE produced on the growing phagophore activates Atg1, closing the negative-feedback loop that disassembles the site.' - id: pas_membrane_component label: Atg9 vesicle cluster at the PAS connection: via a container - id: pas_pi3k_complex_i label: Class III PI3K complex I at the PAS connection: via a container - module: phagophore_organelle_contact_site step: atg2_tether step_label: ATG2-family ER-phagophore membrane tether classification: UNDECIDED default_rule: (atg9_rim_scramblase | wipi4_atg18_clamp) rule: (atg9_rim_scramblase | wipi4_atg18_clamp) activators: - id: atg9_rim_scramblase label: ATG9-family lipid scramblase at the phagophore rim connection: 'POSITIVELY_REGULATES: Atg9 binding confines Atg2 to the growing phagophore extremities; disrupting the Atg2-Atg9 interaction gives an aberrant distribution of Atg2 and of ER contact sites on forming phagophores.' - id: wipi4_atg18_clamp label: Atg18/WIPI4-family PI3P clamp on the ATG2 tip connection: 'POSITIVELY_REGULATES: The PI3P-bound propeller stabilizes the ATG2 tip on the phagophore, orienting the tether and accelerating transfer.' - module: phagophore_organelle_contact_site step: lipid_flux_through_site step_label: Lipid flux through the contact site classification: UNDECIDED default_rule: (atg2_clr_rim_anchor | atg2_tether | donor_membrane_face) & !escrt_iii_rim_sealing rule: (atg2_clr_rim_anchor | atg2_tether | donor_membrane_face) & !escrt_iii_rim_sealing activators: - id: atg2_clr_rim_anchor label: ATG2 C-terminal CLR amphipathic helix anchoring to the phagophore connection: via a container - id: atg2_tether label: ATG2-family ER-phagophore membrane tether connection: via a container - id: donor_membrane_face label: Donor membrane face of the contact site connection: via a container - module: phenylalanine_tyrosine_biosynthesis step: aromatic_transamination_step step_label: phenylpyruvate / 4-hydroxyphenylpyruvate to L-phenylalanine / L-tyrosine classification: UNDECIDED default_rule: (pdh_step | pdt_step) rule: (pdh_step | pdt_step) activators: - id: pdh_step label: prephenate to 4-hydroxyphenylpyruvate connection: 'PRECEDES: ' - id: pdt_step label: prephenate to phenylpyruvate connection: 'PRECEDES: ' - module: photosynthesis step: rubisco_carboxylation step_label: Rubisco carboxylation of RuBP classification: UNDECIDED default_rule: (atp_synthase | carbon_concentrating_mechanism | light_harvesting) rule: (atp_synthase | carbon_concentrating_mechanism | light_harvesting) activators: - id: atp_synthase label: Thylakoid (chloroplast/cyanobacterial) ATP synthase connection: via a container - id: carbon_concentrating_mechanism label: Carbon-concentrating mechanism connection: 'POSITIVELY_REGULATES: The CCM raises CO2 around Rubisco, favoring carboxylation over oxygenation.' - id: light_harvesting label: Light-harvesting antenna connection: via a container - module: photosynthesis step: cbb_gapdh step_label: NADP-dependent glyceraldehyde-3-phosphate dehydrogenase classification: UNDECIDED default_rule: (atp_synthase | light_harvesting) & !cp12_scaffold rule: (atp_synthase | light_harvesting) & !cp12_scaffold activators: - id: atp_synthase label: Thylakoid (chloroplast/cyanobacterial) ATP synthase connection: via a container - id: light_harvesting label: Light-harvesting antenna connection: via a container - module: photosynthesis step: cbb_prk step_label: Phosphoribulokinase classification: UNDECIDED default_rule: (atp_synthase | light_harvesting) & !cp12_scaffold rule: (atp_synthase | light_harvesting) & !cp12_scaffold activators: - id: atp_synthase label: Thylakoid (chloroplast/cyanobacterial) ATP synthase connection: via a container - id: light_harvesting label: Light-harvesting antenna connection: via a container - module: photosynthesis step: cbb_sbpase_fbpase step_label: Bisphosphatase regeneration steps (FBPase, SBPase) classification: UNDECIDED default_rule: (atp_synthase | light_harvesting) rule: (atp_synthase | light_harvesting) activators: - id: atp_synthase label: Thylakoid (chloroplast/cyanobacterial) ATP synthase connection: via a container - id: light_harvesting label: Light-harvesting antenna connection: via a container - module: photosynthesis step: rubisco_activation step_label: Rubisco activase and inhibitor removal classification: UNDECIDED default_rule: (atp_synthase | light_harvesting) rule: (atp_synthase | light_harvesting) activators: - id: atp_synthase label: Thylakoid (chloroplast/cyanobacterial) ATP synthase connection: via a container - id: light_harvesting label: Light-harvesting antenna connection: via a container - module: pirna_mediated_germline_silencing step: insect_piwi_heterochromatin step_label: Piwi-directed H3K9me3 heterochromatin (Drosophila) classification: ALTERNATIVE_VARIANTS default_rule: (piwil2_slicer | wago1_cytoplasmic_effector) rule: (piwil2_slicer | wago1_cytoplasmic_effector) activators: - id: piwil2_slicer label: PIWIL2/MILI ping-pong slicer connection: via a container - id: wago1_cytoplasmic_effector label: WAGO-1 cytoplasmic 22G-RNA effector connection: via a container - module: pirna_mediated_germline_silencing step: piwil4_nuclear step_label: PIWIL4/MIWI2 nuclear piRNA effector classification: ALTERNATIVE_VARIANTS default_rule: (piwil2_slicer | wago1_cytoplasmic_effector) rule: (piwil2_slicer | wago1_cytoplasmic_effector) activators: - id: piwil2_slicer label: PIWIL2/MILI ping-pong slicer connection: 'PROVIDES_INPUT_FOR: MILI slicing produces the secondary piRNAs that load MIWI2 and are needed for its nuclear localization. This is PIWIL2''s only route to DNA methylation.' - id: wago1_cytoplasmic_effector label: WAGO-1 cytoplasmic 22G-RNA effector connection: via a container - module: pirna_mediated_germline_silencing step: hrde1_nuclear_ago step_label: HRDE-1 nuclear 22G-RNA Argonaute classification: ALTERNATIVE_VARIANTS default_rule: (piwil2_slicer | wago1_cytoplasmic_effector) rule: (piwil2_slicer | wago1_cytoplasmic_effector) activators: - id: piwil2_slicer label: PIWIL2/MILI ping-pong slicer connection: via a container - id: wago1_cytoplasmic_effector label: WAGO-1 cytoplasmic 22G-RNA effector connection: via a container - module: pirna_mediated_germline_silencing step: wago4_inheritance_ago step_label: WAGO-4 Z granule 22G-RNA Argonaute classification: ALTERNATIVE_VARIANTS default_rule: (piwil2_slicer | wago1_cytoplasmic_effector) rule: (piwil2_slicer | wago1_cytoplasmic_effector) activators: - id: piwil2_slicer label: PIWIL2/MILI ping-pong slicer connection: via a container - id: wago1_cytoplasmic_effector label: WAGO-1 cytoplasmic 22G-RNA effector connection: via a container - module: polyamine_metabolism step: putrescine_to_spermidine step_label: Spermidine synthase classification: UNDECIDED default_rule: (ornithine_to_putrescine | sam_decarboxylation) rule: (ornithine_to_putrescine | sam_decarboxylation) activators: - id: ornithine_to_putrescine label: Putrescine formation connection: 'PRECEDES: ' - id: sam_decarboxylation label: S-adenosylmethionine decarboxylase connection: 'PROVIDES_INPUT_FOR: AdoMetDC supplies the dcSAM aminopropyl donor used by spermidine synthase.' - module: polyamine_metabolism step: spermidine_to_spermine step_label: Spermine synthase classification: UNDECIDED default_rule: (putrescine_to_spermidine | sam_decarboxylation) rule: (putrescine_to_spermidine | sam_decarboxylation) activators: - id: putrescine_to_spermidine label: Spermidine synthase connection: 'PRECEDES: ' - id: sam_decarboxylation label: S-adenosylmethionine decarboxylase connection: 'PROVIDES_INPUT_FOR: AdoMetDC also supplies the dcSAM used by spermine synthase.' - module: polyamine_metabolism step: polyamine_oxidation step_label: FAD-dependent polyamine oxidation classification: UNDECIDED default_rule: (polyamine_acetylation | spermidine_to_spermine) rule: (polyamine_acetylation | spermidine_to_spermine) activators: - id: polyamine_acetylation label: Polyamine N-acetylation connection: 'PROVIDES_INPUT_FOR: N1-acetylpolyamines are oxidised by PAOX (animals) or Fms1 (yeast), completing back-conversion.' - id: spermidine_to_spermine label: Spermine synthase connection: 'PROVIDES_INPUT_FOR: Free spermine is oxidised directly to spermidine by SMOX or Fms1.' - module: pqq_biosynthesis step: pqqc_ring_closure step_label: PqqC terminal PQQ formation classification: UNDECIDED default_rule: (pqqa_proteolysis | pqqb_oxygenation) rule: (pqqa_proteolysis | pqqb_oxygenation) activators: - id: pqqa_proteolysis label: PqqA-derived precursor proteolysis connection: 'PROVIDES_INPUT_FOR: Proteolysis is required to generate the small-molecule precursor used late in the pathway.' - id: pqqb_oxygenation label: PqqB-dependent precursor oxygenation connection: 'PROVIDES_INPUT_FOR: PqqB-dependent oxygenation contributes to formation of the late PqqC substrate.' - module: primary_cilium_life_cycle step: myo5a_vesicle_delivery step_label: Myosin-Va preciliary vesicle delivery classification: UNDECIDED default_rule: (cp110_cep97_cap | ttbk2_cap_removal) rule: (cp110_cep97_cap | ttbk2_cap_removal) activators: - id: cp110_cep97_cap label: CP110-CEP97 distal cap suppresses ciliogenesis connection: via a container - id: ttbk2_cap_removal label: TTBK2 triggers CP110 cap removal connection: via a container - module: primary_cilium_life_cycle step: ift81_ift74_tubulin step_label: IFT81-IFT74 tubulin module classification: UNDECIDED default_rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control activators: - id: cep290_tz_scaffold label: CEP290 transition zone scaffold connection: via a container - id: mks_module label: MKS module connection: via a container - id: nphp_module label: NPHP module connection: via a container - module: primary_cilium_life_cycle step: kinesin2_anterograde step_label: Heterotrimeric kinesin-2 classification: UNDECIDED default_rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control activators: - id: cep290_tz_scaffold label: CEP290 transition zone scaffold connection: via a container - id: mks_module label: MKS module connection: via a container - id: nphp_module label: NPHP module connection: via a container - module: primary_cilium_life_cycle step: dynein2_retrograde step_label: Dynein-2 classification: UNDECIDED default_rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control rule: (cep290_tz_scaffold | mks_module | nphp_module) & !cilium_length_control activators: - id: cep290_tz_scaffold label: CEP290 transition zone scaffold connection: via a container - id: mks_module label: MKS module connection: via a container - id: nphp_module label: NPHP module connection: via a container - module: primary_cilium_life_cycle step: arl13b_arl3_gef step_label: ARL13B activates ARL3 classification: UNDECIDED default_rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) activators: - id: ift81_ift74_tubulin label: IFT81-IFT74 tubulin module connection: via a container - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_scaffold label: IFT-B scaffold subunits connection: via a container - module: primary_cilium_life_cycle step: arl3_cargo_release step_label: ARL3 releases lipidated cargo classification: UNDECIDED default_rule: (arl13b_arl3_gef | pde6d_prenyl_carrier | unc119b_myristoyl_carrier) & !rp2_arl3_gap rule: (arl13b_arl3_gef | pde6d_prenyl_carrier | unc119b_myristoyl_carrier) & !rp2_arl3_gap activators: - id: arl13b_arl3_gef label: ARL13B activates ARL3 connection: 'POSITIVELY_REGULATES: ARL13B loads ARL3 with GTP.' - id: pde6d_prenyl_carrier label: PDE6D carries farnesylated cargo connection: 'PROVIDES_INPUT_FOR: PDE6D-bound cargo is released by ARL3-GTP.' - id: unc119b_myristoyl_carrier label: UNC119B carries myristoylated cargo connection: 'PROVIDES_INPUT_FOR: UNC119B-bound cargo is released by ARL3-GTP.' - module: primary_cilium_life_cycle step: pde6d_prenyl_carrier step_label: PDE6D carries farnesylated cargo classification: UNDECIDED default_rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) activators: - id: ift81_ift74_tubulin label: IFT81-IFT74 tubulin module connection: via a container - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_scaffold label: IFT-B scaffold subunits connection: via a container - module: primary_cilium_life_cycle step: unc119b_myristoyl_carrier step_label: UNC119B carries myristoylated cargo classification: UNDECIDED default_rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) activators: - id: ift81_ift74_tubulin label: IFT81-IFT74 tubulin module connection: via a container - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_scaffold label: IFT-B scaffold subunits connection: via a container - module: primary_cilium_life_cycle step: inpp5e_pip2_hydrolysis step_label: INPP5E sets ciliary phosphoinositides classification: UNDECIDED default_rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) activators: - id: ift81_ift74_tubulin label: IFT81-IFT74 tubulin module connection: via a container - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_scaffold label: IFT-B scaffold subunits connection: via a container - module: primary_cilium_life_cycle step: tulp3_gpcr_import step_label: TULP3 links IFT-A to membrane cargo classification: UNDECIDED default_rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) rule: (ift81_ift74_tubulin | ift_a_complex | ift_b_scaffold) activators: - id: ift81_ift74_tubulin label: IFT81-IFT74 tubulin module connection: via a container - id: ift_a_complex label: IFT-A complex connection: via a container - id: ift_b_scaffold label: IFT-B scaffold subunits connection: via a container - module: primary_cilium_life_cycle step: aurka_disassembly_kinase step_label: Aurora A drives disassembly classification: UNDECIDED default_rule: (nedd9_aurka_activation | pitchfork_aurka_activation) rule: (nedd9_aurka_activation | pitchfork_aurka_activation) activators: - id: nedd9_aurka_activation label: NEDD9 activates Aurora A connection: 'POSITIVELY_REGULATES: NEDD9 activates Aurora A.' - id: pitchfork_aurka_activation label: Pitchfork activates Aurora A connection: 'POSITIVELY_REGULATES: Pitchfork activates Aurora A.' - module: primary_cilium_life_cycle step: nedd9_aurka_activation step_label: NEDD9 activates Aurora A classification: UNDECIDED default_rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) activators: - id: arl3_cargo_release label: ARL3 releases lipidated cargo connection: via a container - id: inpp5e_pip2_hydrolysis label: INPP5E sets ciliary phosphoinositides connection: via a container - id: tulp3_gpcr_import label: TULP3 links IFT-A to membrane cargo connection: via a container - module: primary_cilium_life_cycle step: pitchfork_aurka_activation step_label: Pitchfork activates Aurora A classification: UNDECIDED default_rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) activators: - id: arl3_cargo_release label: ARL3 releases lipidated cargo connection: via a container - id: inpp5e_pip2_hydrolysis label: INPP5E sets ciliary phosphoinositides connection: via a container - id: tulp3_gpcr_import label: TULP3 links IFT-A to membrane cargo connection: via a container - module: primary_cilium_life_cycle step: plk1_kinase step_label: PLK1 activates KIF2A classification: UNDECIDED default_rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) activators: - id: arl3_cargo_release label: ARL3 releases lipidated cargo connection: via a container - id: inpp5e_pip2_hydrolysis label: INPP5E sets ciliary phosphoinositides connection: via a container - id: tulp3_gpcr_import label: TULP3 links IFT-A to membrane cargo connection: via a container - module: primary_cilium_life_cycle step: tctex1_resorption step_label: Phosphorylated Tctex-1 promotes resorption classification: UNDECIDED default_rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) rule: (arl3_cargo_release | inpp5e_pip2_hydrolysis | tulp3_gpcr_import) activators: - id: arl3_cargo_release label: ARL3 releases lipidated cargo connection: via a container - id: inpp5e_pip2_hydrolysis label: INPP5E sets ciliary phosphoinositides connection: via a container - id: tulp3_gpcr_import label: TULP3 links IFT-A to membrane cargo connection: via a container - module: primordial_germ_cell_specification step: pgc_genome_protection step_label: piRNA-guided transposon silencing in the germline classification: ALTERNATIVE_VARIANTS default_rule: (pgc_tripartite_network | preformation) rule: (pgc_tripartite_network | preformation) activators: - id: pgc_tripartite_network label: PRDM1/PRDM14/TFAP2C germline network connection: via a container - id: preformation label: Preformation via inherited germ plasm connection: via a container - module: proline_metabolism step: pycr_proline_formation step_label: P5C reductase-dependent L-proline formation classification: UNDECIDED default_rule: (aldh18a1_semialdehyde_formation | oat_p5c_supply | split_semialdehyde_formation) rule: (aldh18a1_semialdehyde_formation | oat_p5c_supply | split_semialdehyde_formation) activators: - id: aldh18a1_semialdehyde_formation label: P5CS glutamate-5-semialdehyde dehydrogenase reaction connection: via a container - id: oat_p5c_supply label: OAT transamination into the P5C pool connection: 'PROVIDES_INPUT_FOR: ' - id: split_semialdehyde_formation label: Monofunctional gamma-glutamyl-phosphate reductase reaction connection: via a container - module: proline_metabolism step: aldh4a1_glutamate_formation step_label: P5C dehydrogenase completion of proline catabolism classification: UNDECIDED default_rule: (oat_p5c_supply | prodh_p5c_formation) rule: (oat_p5c_supply | prodh_p5c_formation) activators: - id: oat_p5c_supply label: OAT transamination into the P5C pool connection: 'PROVIDES_INPUT_FOR: ' - id: prodh_p5c_formation label: Proline dehydrogenase oxidation of L-proline to P5C connection: 'PROVIDES_INPUT_FOR: ' - module: propionyl_coa_catabolism step: mmut_step step_label: (R)-methylmalonyl-CoA to succinyl-CoA classification: UNDECIDED default_rule: (adocbl_supply | mcee_step) rule: (adocbl_supply | mcee_step) activators: - id: adocbl_supply label: AdoCbl synthesis (MMAB) and MMAA-gated loading onto the mutase connection: 'POSITIVELY_REGULATES: MMAB synthesises AdoCbl and MMAA gates its loading/maintenance on MMUT; without this cofactor supply the mutase step cannot proceed (cblA/cblB methylmalonic aciduria phenocopy mut-type deficiency).' - id: mcee_step label: (S)-methylmalonyl-CoA to (R)-methylmalonyl-CoA connection: 'PROVIDES_INPUT_FOR: (R)-methylmalonyl-CoA from MCEE is the substrate of MMUT.' - module: protein_prenylation_caax_processing step: caax_proteolysis step_label: CAAX endoprotease (RCE1) classification: UNDECIDED default_rule: (farnesylation | geranylgeranylation_I) rule: (farnesylation | geranylgeranylation_I) activators: - id: farnesylation label: Farnesyltransferase (FNTA alpha + FNTB beta) connection: 'PROVIDES_INPUT_FOR: Farnesylated CAAX proteins are processed by RCE1 (-AAX removal).' - id: geranylgeranylation_I label: Geranylgeranyltransferase type I (FNTA alpha + PGGT1B beta) connection: 'PROVIDES_INPUT_FOR: GGTase-I-modified CAAX proteins are processed by RCE1 (-AAX removal).' - module: purine_nucleotide_catabolism step: adenosine_deamination step_label: Adenosine deaminase (ADA) classification: UNDECIDED default_rule: (cyto_amp_5nt | ecto_amp_5nt) rule: (cyto_amp_5nt | ecto_amp_5nt) activators: - id: cyto_amp_5nt label: Cytosolic 5'-nucleotidase 1A (NT5C1A) connection: 'PROVIDES_INPUT_FOR: NT5C1A-made adenosine is deaminated by ADA.' - id: ecto_amp_5nt label: Ecto-5'-nucleotidase / CD73 (NT5E) connection: 'PROVIDES_INPUT_FOR: Extracellular adenosine from CD73 (after re-uptake) feeds the adenosine pool deaminated by ADA.' - module: purine_nucleotide_catabolism step: nucleoside_phosphorolysis step_label: Purine-nucleoside phosphorylase (PNP) classification: UNDECIDED default_rule: (adenosine_deamination | imp_gmp_5nt) rule: (adenosine_deamination | imp_gmp_5nt) activators: - id: adenosine_deamination label: Adenosine deaminase (ADA) connection: 'PROVIDES_INPUT_FOR: ADA-made inosine is phosphorolysed by PNP.' - id: imp_gmp_5nt label: Cytosolic 5'-nucleotidase 2 (NT5C2) connection: 'PROVIDES_INPUT_FOR: NT5C2-made inosine/guanosine are phosphorolysed by PNP.' - module: purine_nucleotide_catabolism step: purine_oxidation step_label: Xanthine dehydrogenase/oxidase (XDH) classification: UNDECIDED default_rule: (guanine_deamination | nucleoside_phosphorolysis) rule: (guanine_deamination | nucleoside_phosphorolysis) activators: - id: guanine_deamination label: Guanine deaminase (GDA) connection: 'PROVIDES_INPUT_FOR: GDA-made xanthine is oxidised to urate by XDH.' - id: nucleoside_phosphorolysis label: Purine-nucleoside phosphorylase (PNP) connection: 'PROVIDES_INPUT_FOR: PNP-liberated hypoxanthine is oxidised by XDH.' - module: purine_nucleotide_interconversion step: adss_step step_label: IMP + L-aspartate + GTP to adenylosuccinate + GDP + Pi classification: UNDECIDED default_rule: (ampd_step | ndp_kinase_step) rule: (ampd_step | ndp_kinase_step) activators: - id: ampd_step label: AMP + H2O to IMP + ammonia connection: 'PROVIDES_INPUT_FOR: AMP deaminase regenerates IMP, which adenylosuccinate synthetase re-uses toward AMP (the purine nucleotide cycle).' - id: ndp_kinase_step label: GDP + ATP to GTP + ADP connection: 'PROVIDES_INPUT_FOR: GTP is the phosphate donor of adenylosuccinate synthetase (cross-regulation of the two arms).' - module: purine_salvage_and_catabolism step: hprt1_step step_label: hypoxanthine/guanine + PRPP to IMP/GMP + PPi classification: UNDECIDED default_rule: (adenine_moiety_deamination | pnp_step) rule: (adenine_moiety_deamination | pnp_step) activators: - id: adenine_moiety_deamination label: Adenine or adenosine deamination connection: 'PROVIDES_INPUT_FOR: Hypoxanthine from adenine deaminase is salvaged to IMP by HGPRT.' - id: pnp_step label: inosine/guanosine + Pi to hypoxanthine/guanine + (deoxy)ribose-1-phosphate connection: 'PROVIDES_INPUT_FOR: Hypoxanthine/guanine released by PNP can be salvaged back to IMP/GMP by HGPRT (the salvage-vs-catabolism branch point).' - module: purine_salvage_and_catabolism step: purine_base_oxidation step_label: hypoxanthine to xanthine to urate classification: UNDECIDED default_rule: (guanine_deamination_step | pnp_step) rule: (guanine_deamination_step | pnp_step) activators: - id: guanine_deamination_step label: guanine + H2O to xanthine + NH3 connection: 'PROVIDES_INPUT_FOR: Xanthine is oxidised to urate by XDH or Xan1 where present.' - id: pnp_step label: inosine/guanosine + Pi to hypoxanthine/guanine + (deoxy)ribose-1-phosphate connection: 'PROVIDES_INPUT_FOR: Hypoxanthine released by PNP is oxidised to xanthine/urate by XDH where present.' - module: pyrenoid_ccm step: rubisco_carboxylation step_label: Rubisco carboxylation in the pyrenoid matrix classification: UNDECIDED default_rule: (lumenal_co2_release | starch_sheath_barrier) rule: (lumenal_co2_release | starch_sheath_barrier) activators: - id: lumenal_co2_release label: Lumenal bicarbonate dehydration (CAH3) connection: 'PROVIDES_INPUT_FOR: CO2 released in the tubules diffuses into the Rubisco matrix.' - id: starch_sheath_barrier label: Starch sheath around the matrix connection: 'POSITIVELY_REGULATES: Slowing CO2 escape from the matrix raises the CO2 concentration at Rubisco.' - module: pyrenoid_ccm step: lumenal_co2_release step_label: Lumenal bicarbonate dehydration (CAH3) classification: UNDECIDED default_rule: (pyrenoid_tubule_biogenesis | thylakoid_bicarbonate_entry) rule: (pyrenoid_tubule_biogenesis | thylakoid_bicarbonate_entry) activators: - id: pyrenoid_tubule_biogenesis label: Pyrenoid tubule biogenesis connection: 'POSITIVELY_REGULATES: Tubules that traverse the matrix place CAH3-generated CO2 at the Rubisco condensate, and RBMP2 builds the reticulated region where CAH3 concentrates (CAH3 is mislocalized in rbmp2); without tubules the matrix forms aberrant condensates and growth at limiting CO2 is impaired.' - id: thylakoid_bicarbonate_entry label: Thylakoid bicarbonate entry (bestrophin-like channels) connection: 'PROVIDES_INPUT_FOR: Lumenal bicarbonate is the substrate for CAH3.' - module: pyrenoid_ccm step: thylakoid_bicarbonate_entry step_label: Thylakoid bicarbonate entry (bestrophin-like channels) classification: UNDECIDED default_rule: (ccm_induction | ci_uptake | stromal_co2_recapture) rule: (ccm_induction | ci_uptake | stromal_co2_recapture) activators: - id: ccm_induction label: CIA5/CCM1-dependent low-CO2 induction connection: 'POSITIVELY_REGULATES: CIA5 is required for low-CO2 induction of BST1-3.' - id: ci_uptake label: Plasma membrane and chloroplast envelope bicarbonate uptake connection: 'PROVIDES_INPUT_FOR: Stromal bicarbonate imported by HLA3 and LCIA is the substrate moved into the lumen.' - id: stromal_co2_recapture label: LCIB/LCIC CO2 recapture at the pyrenoid periphery connection: 'PROVIDES_INPUT_FOR: Bicarbonate formed by LCIB/LCIC from leaked or incoming CO2 joins the stromal pool that enters the thylakoid lumen.' - module: pyrimidine_nucleotide_catabolism step: uridine_phosphorolysis step_label: Uridine phosphorylase (UPP1 / UPP2) classification: UNDECIDED default_rule: (cytidine_deamination | pyrimidine_5nt) rule: (cytidine_deamination | pyrimidine_5nt) activators: - id: cytidine_deamination label: Cytidine deaminase (CDA) connection: 'PROVIDES_INPUT_FOR: CDA-made uridine is phosphorolysed by UPP1/UPP2.' - id: pyrimidine_5nt label: Pyrimidine 5'-nucleotidase (NT5C3A) connection: 'PROVIDES_INPUT_FOR: NT5C3A-made uridine is phosphorolysed by UPP1/UPP2.' - module: pyrimidine_nucleotide_catabolism step: dihydropyrimidine_reduction step_label: Dihydropyrimidine dehydrogenase (DPYD) classification: UNDECIDED default_rule: (thymidine_phosphorolysis | uridine_phosphorolysis) rule: (thymidine_phosphorolysis | uridine_phosphorolysis) activators: - id: thymidine_phosphorolysis label: Thymidine phosphorylase (TYMP) connection: 'PROVIDES_INPUT_FOR: TYMP-liberated thymine enters reductive catabolism at DPYD.' - id: uridine_phosphorolysis label: Uridine phosphorylase (UPP1 / UPP2) connection: 'PROVIDES_INPUT_FOR: UPP-liberated uracil enters reductive catabolism at DPYD.' - module: pyrimidine_salvage step: uracil_prt_step step_label: uracil + PRPP to UMP + PPi classification: UNDECIDED default_rule: (cytosine_deamination_step | nucleoside_cleavage) rule: (cytosine_deamination_step | nucleoside_cleavage) activators: - id: cytosine_deamination_step label: cytosine + H2O to uracil + NH3 connection: 'PROVIDES_INPUT_FOR: Uracil from cytosine deamination is converted to UMP.' - id: nucleoside_cleavage label: uridine/cytidine to uracil/cytosine connection: 'PROVIDES_INPUT_FOR: Uracil released by nucleoside cleavage is converted to UMP.' - module: retinal_determination_network step: six_factor step_label: Six-family homeodomain transcription factor classification: UNDECIDED default_rule: (eya_cofactor | pax6_selector) rule: (eya_cofactor | pax6_selector) activators: - id: eya_cofactor label: Eyes absent transcriptional coactivator-phosphatase connection: 'POSITIVELY_REGULATES: EYA is recruited by So/SIX1-2 and acts as their coactivator. In mammalian Six1-Dach-Eya complexes its phosphatase was reported to switch Six1-Dach from repression to activation; this phosphatase dependence is not seen in Drosophila eye development. Does not apply to SIX3/6, which do not bind Eya.' - id: pax6_selector label: Pax6 selector transcription factor connection: 'POSITIVELY_REGULATES: Pax6 (Ey) directly activates the eye-specific enhancer of sine oculis and is required for its expression.' - module: retinal_determination_network step: eya_cofactor step_label: Eyes absent transcriptional coactivator-phosphatase classification: UNDECIDED default_rule: (dach_cofactor | pax6_selector) rule: (dach_cofactor | pax6_selector) activators: - id: dach_cofactor label: Dachshund nuclear cofactor connection: 'POSITIVELY_REGULATES: Reciprocal arm of the dac/eya positive feedback loop.' - id: pax6_selector label: Pax6 selector transcription factor connection: 'POSITIVELY_REGULATES: Eyeless is required for and induces eyes absent expression in the eye disc.' - module: retinoid_visual_cycle step: cis_retinol_oxidation step_label: 11-cis retinol dehydrogenase (RDH5) classification: UNDECIDED default_rule: (cralbp_carrier | isomerohydrolysis | photoisomerase) rule: (cralbp_carrier | isomerohydrolysis | photoisomerase) activators: - id: cralbp_carrier label: Cellular retinaldehyde-binding protein (RLBP1) connection: 'POSITIVELY_REGULATES: CRALBP (RLBP1) presents 11-cis-retinol to RDH5 and carries 11-cis-retinoids, enhancing cycle flux.' - id: isomerohydrolysis label: Retinoid isomerohydrolase (RPE65) connection: 'PROVIDES_INPUT_FOR: The 11-cis-retinol made by RPE65 is oxidized by RDH5 to 11-cis-retinal.' - id: photoisomerase label: RPE-retinal photoisomerase (RGR) connection: 'PROVIDES_INPUT_FOR: RGR photoisomerizes all-trans- to 11-cis-retinal, an alternative light-driven source of the chromophore.' - module: riboflavin_biosynthesis step: phosphoribitylaminouracil_phosphatase_step step_label: Pyrimidine-intermediate dephosphorylation classification: ALTERNATIVE_VARIANTS default_rule: (rib2_deaminase_step | ribd_reductase_step) rule: (rib2_deaminase_step | ribd_reductase_step) activators: - id: rib2_deaminase_step label: 2,5-diamino-6-ribitylamino-4(3H)-pyrimidinone 5'-phosphate deamination connection: via a container - id: ribd_reductase_step label: Pyrimidine side-chain reduction connection: via a container - module: riboflavin_biosynthesis step: lumazine_synthase_step step_label: 6,7-dimethyl-8-ribityllumazine formation classification: UNDECIDED default_rule: (dhbp_branch | phosphoribitylaminouracil_phosphatase_step) rule: (dhbp_branch | phosphoribitylaminouracil_phosphatase_step) activators: - id: dhbp_branch label: 3,4-dihydroxy-2-butanone 4-phosphate formation connection: 'PROVIDES_INPUT_FOR: ' - id: phosphoribitylaminouracil_phosphatase_step label: Pyrimidine-intermediate dephosphorylation connection: 'PROVIDES_INPUT_FOR: Dephosphorylation supplies 5-amino-6-(D-ribitylamino)uracil to lumazine synthase.' - module: root_radial_patterning_shr_scr step: shr_nuclear_capture step_label: Nuclear capture of SHR by SCR and BIRD/IDD proteins classification: UNDECIDED default_rule: (shr_mobile_signal | shr_scr_bird_activation) rule: (shr_mobile_signal | shr_scr_bird_activation) activators: - id: shr_mobile_signal label: SHR movement from stele and nuclear entry in the endodermis/QC layer connection: 'PRECEDES: SHR protein that has moved into the adjacent layer is captured in the nucleus.' - id: shr_scr_bird_activation label: SHR-SCR-BIRD activation of SCR, MGP and CYCD6;1 connection: 'POSITIVELY_REGULATES: SHR-SCR-BIRD activation of SCR and MGP reinforces SHR capture (positive feedback/feed-forward loops).' - module: root_radial_patterning_shr_scr step: shr_scr_bird_activation step_label: SHR-SCR-BIRD activation of SCR, MGP and CYCD6;1 classification: UNDECIDED default_rule: (cycd6_formative_division | shr_nuclear_capture) rule: (cycd6_formative_division | shr_nuclear_capture) activators: - id: cycd6_formative_division label: CYCD6;1-CDKB1-driven formative periclinal division connection: 'POSITIVELY_REGULATES: CYCD6;1-CDKB1 phosphorylation of RBR relieves RBR inhibition of SCR (nested feed-forward loop).' - id: shr_nuclear_capture label: Nuclear capture of SHR by SCR and BIRD/IDD proteins connection: 'CAUSES: The assembled SHR-SCR-BIRD complex activates target transcription.' - module: scer_hog1_cascade step: hog1_map3k step_label: Ssk2/Ssk22 MAP kinase kinase kinase activation classification: UNDECIDED default_rule: (ssk1_rr | ste50_ste11_activation) rule: (ssk1_rr | ste50_ste11_activation) activators: - id: ssk1_rr label: Ssk1 response regulator connection: via a container - id: ste50_ste11_activation label: Ste50-dependent Ste11 MAP3K activation of Pbs2 connection: via a container - module: selenocysteine_biosynthesis_incorporation step: bacterial_sela_conversion step_label: SelA-dependent Sec-tRNA(Sec) synthesis classification: UNDECIDED default_rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) activators: - id: selenophosphate_synthesis label: Selenophosphate synthesis connection: via a container - id: ser_trna_sec_synthesis label: Ser-tRNA(Sec) synthesis connection: via a container - module: selenocysteine_biosynthesis_incorporation step: pstk_phosphoseryl_trna_formation step_label: PSTK-dependent phosphoseryl-tRNA(Sec) formation classification: UNDECIDED default_rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) activators: - id: selenophosphate_synthesis label: Selenophosphate synthesis connection: via a container - id: ser_trna_sec_synthesis label: Ser-tRNA(Sec) synthesis connection: via a container - module: selenocysteine_biosynthesis_incorporation step: secisbp2_recognition step_label: SECISBP2-dependent SECIS recognition classification: UNDECIDED default_rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) rule: (selenophosphate_synthesis | ser_trna_sec_synthesis) activators: - id: selenophosphate_synthesis label: Selenophosphate synthesis connection: via a container - id: ser_trna_sec_synthesis label: Ser-tRNA(Sec) synthesis connection: via a container - module: selenocysteine_biosynthesis_incorporation step: eefsec_delivery step_label: EEFSEC-dependent Sec-tRNA(Sec) delivery classification: UNDECIDED default_rule: (secisbp2_recognition | sepsecs_sec_trna_formation) rule: (secisbp2_recognition | sepsecs_sec_trna_formation) activators: - id: secisbp2_recognition label: SECISBP2-dependent SECIS recognition connection: 'PROVIDES_INPUT_FOR: SECISBP2 supplies the RNA recoding context used by EEFSEC.' - id: sepsecs_sec_trna_formation label: SepSecS-dependent Sec-tRNA(Sec) formation connection: 'PROVIDES_INPUT_FOR: SepSecS-produced Sec-tRNA(Sec) is delivered by EEFSEC.' - module: sialic_acid_metabolism step: neu5ac_to_cmpneu5ac step_label: CMP-N-acetylneuraminate synthetase (CMAS) classification: UNDECIDED default_rule: (lysosomal_sialic_acid_export | neu5ac9p_to_neu5ac) rule: (lysosomal_sialic_acid_export | neu5ac9p_to_neu5ac) activators: - id: lysosomal_sialic_acid_export label: Lysosomal sialic acid transporter (SLC17A5, sialin) connection: 'PROVIDES_INPUT_FOR: Salvaged free Neu5Ac exported by SLC17A5 can be reactivated by CMAS to CMP-Neu5Ac.' - id: neu5ac9p_to_neu5ac label: N-acylneuraminate-9-phosphatase (NANP) connection: 'PROVIDES_INPUT_FOR: The free Neu5Ac released by NANP is activated by CMAS to CMP-Neu5Ac.' - module: spytag_spycatcher step: fbab_fibronectin_adhesion step_label: FbaB fibronectin binding and host-cell adhesion/invasion classification: UNDECIDED default_rule: (fbab_cell_wall_anchoring | fbab_cnab2_isopeptide | fbab_thioester_host_capture) rule: (fbab_cell_wall_anchoring | fbab_cnab2_isopeptide | fbab_thioester_host_capture) activators: - id: fbab_cell_wall_anchoring label: LPXTG/sortase anchoring of FbaB to the cell wall connection: 'PROVIDES_INPUT_FOR: Cell-wall anchoring displays FbaB at the surface so it can engage host fibronectin.' - id: fbab_cnab2_isopeptide label: CnaB2 intramolecular Lys-Asp isopeptide bond (SpyTag/SpyCatcher scaffold) connection: 'PROVIDES_INPUT_FOR: The CnaB2 isopeptide bond mechanically stabilizes the adhesin for force-bearing fibronectin engagement during invasion.' - id: fbab_thioester_host_capture label: FbaB N-terminal thioester (TED) domain covalent host binding connection: 'POSITIVELY_REGULATES: Covalent TED-mediated host capture is inferred to reinforce non-covalent fibronectin-mediated adhesion.' - module: synaptic_vesicle_exocytosis step: cis_snare_disassembly step_label: NSF / alpha-SNAP disassembly of the cis-SNARE complex classification: UNDECIDED default_rule: (presynaptic_calcium_influx | vesicle_priming) rule: (presynaptic_calcium_influx | vesicle_priming) activators: - id: presynaptic_calcium_influx label: Action-potential-gated Ca2+ entry through Cav2 channels connection: via a container - id: vesicle_priming label: Munc13/Munc18-1 priming and SNARE assembly templating connection: via a container - module: taurine_biosynthesis_and_transport step: taurine_transport step_label: Taurine transporter TauT (SLC6A6) classification: UNDECIDED default_rule: (cysteamine_dioxygenation | cysteinesulfinate_decarboxylation) rule: (cysteamine_dioxygenation | cysteinesulfinate_decarboxylation) activators: - id: cysteamine_dioxygenation label: Cysteamine (2-aminoethanethiol) dioxygenase (ADO) connection: 'PRECEDES: Hypotaurine from the ADO route likewise feeds the taurine pool that SLC6A6 imports.' - id: cysteinesulfinate_decarboxylation label: Cysteinesulfinic acid decarboxylase (CSAD) connection: 'PRECEDES: Hypotaurine (from CSAD or ADO) is oxidised to taurine, whose cellular pool SLC6A6 also replenishes by uptake.' - module: tetrahydrobiopterin_metabolism step: aaah_utilization step_label: aromatic amino acid hydroxylation consumes BH4, producing pterin-4a-carbinolamine classification: UNDECIDED default_rule: (qdpr_step | spr_step) rule: (qdpr_step | spr_step) activators: - id: qdpr_step label: quinonoid dihydrobiopterin + NADH to tetrahydrobiopterin (BH4) connection: 'PROVIDES_INPUT_FOR: BH4 regenerated by QDPR re-enters the hydroxylase reactions, closing the recycling loop that supplies most BH4 at steady state.' - id: spr_step label: 6-pyruvoyltetrahydropterin to tetrahydrobiopterin (BH4) connection: 'PROVIDES_INPUT_FOR: De novo BH4 made by SPR is the reduced-pteridine cofactor consumed by the aromatic amino acid hydroxylases.' - module: tetrahydrofolate_biosynthesis step: pterin_activation_and_condensation_steps step_label: 7,8-dihydroneopterin to 7,8-dihydropteroate classification: UNDECIDED default_rule: (adc_lyase_step | dihydroneopterin_dephosphorylation_step) rule: (adc_lyase_step | dihydroneopterin_dephosphorylation_step) activators: - id: adc_lyase_step label: 4-Amino-4-deoxychorismate to p-aminobenzoate connection: via a container - id: dihydroneopterin_dephosphorylation_step label: 7,8-dihydroneopterin triphosphate to 7,8-dihydroneopterin connection: 'PRECEDES: ' - module: thiamine_diphosphate_biosynthesis step: thiI_this_sulfurtransfer_role step_label: 'ThiI: sulfur transfer to ThiS' classification: UNDECIDED default_rule: (cysteine_desulfurase_activity | thiF_this_adenylylation_activity) rule: (cysteine_desulfurase_activity | thiF_this_adenylylation_activity) activators: - id: cysteine_desulfurase_activity label: 'IscS: cysteine desulfurase sulfur donor' connection: 'PROVIDES_INPUT_FOR: ' - id: thiF_this_adenylylation_activity label: 'ThiF: ThiS sulfur-carrier activation' connection: 'PROVIDES_INPUT_FOR: ' - module: thiamine_diphosphate_biosynthesis step: thiG_step step_label: Thiazole phosphate synthesis classification: UNDECIDED default_rule: (dehydroglycine_supply | dxs_step | thiS_sulfur_carrier_role) rule: (dehydroglycine_supply | dxs_step | thiS_sulfur_carrier_role) activators: - id: dehydroglycine_supply label: Alternative dehydroglycine supply routes connection: 'PROVIDES_INPUT_FOR: ' - id: dxs_step label: DXP formation connection: 'PROVIDES_INPUT_FOR: ' - id: thiS_sulfur_carrier_role label: 'ThiS: sulfur carrier protein' connection: 'PROVIDES_INPUT_FOR: ' - module: thiamine_diphosphate_biosynthesis step: thiE_coupling_step step_label: HMP diphosphate plus thiazole phosphate to thiamine phosphate classification: UNDECIDED default_rule: (thiD_step | thiG_step) rule: (thiD_step | thiG_step) activators: - id: thiD_step label: HMP phosphate to HMP diphosphate connection: 'PROVIDES_INPUT_FOR: ' - id: thiG_step label: Thiazole phosphate synthesis connection: 'PROVIDES_INPUT_FOR: ' - module: thiamine_uptake_and_activation step: mito_thdp_import step_label: Mitochondrial thiamine pyrophosphate carrier (SLC25A19) classification: UNDECIDED default_rule: (thiamine_activation | thtp_homeostasis) rule: (thiamine_activation | thtp_homeostasis) activators: - id: thiamine_activation label: Thiamine pyrophosphokinase (TPK1) connection: 'PROVIDES_INPUT_FOR: TPK1-made ThDP is imported into mitochondria by SLC25A19.' - id: thtp_homeostasis label: Thiamine triphosphatase (THTPA) connection: 'PROVIDES_INPUT_FOR: THTPA regenerates ThDP from ThTP, contributing to the cytosolic ThDP pool.' - module: triacylglycerol_biosynthesis step: lpa_acylation step_label: 1-Acylglycerol-3-phosphate O-acyltransferases (AGPAT/SLC1, MBOAT ALE1, LOA1) classification: ALTERNATIVE_VARIANTS default_rule: (acyl_dhap_reduction | g3p_route) rule: (acyl_dhap_reduction | g3p_route) activators: - id: acyl_dhap_reduction label: NADPH-dependent 1-acyl-DHAP reductase (AYR1) connection: via a container - id: g3p_route label: Glycerol-3-phosphate route connection: via a container - module: type_ii_fatty_acid_synthesis step: malonyl_acp_loading step_label: FabD malonyl-ACP loading classification: UNDECIDED default_rule: (acetyl_coa_carboxylation | acp_carrier_role) rule: (acetyl_coa_carboxylation | acp_carrier_role) activators: - id: acetyl_coa_carboxylation label: Acetyl-CoA carboxylase connection: 'PROVIDES_INPUT_FOR: AccABCD supplies malonyl-CoA to FabD.' - id: acp_carrier_role label: Acyl carrier protein connection: 'PROVIDES_INPUT_FOR: Holo-ACP accepts malonate from FabD.' - module: type_ii_fatty_acid_synthesis step: elongation_cycle step_label: Four-reaction FAS-II elongation cycle classification: ALTERNATIVE_VARIANTS default_rule: (kasIII_route | mad_route_first_condensation) rule: (kasIII_route | mad_route_first_condensation) activators: - id: kasIII_route label: KAS-III acyl-CoA-dependent initiation connection: via a container - id: mad_route_first_condensation label: Acetyl-ACP and malonyl-ACP condensation connection: via a container - module: ubiquinone_biosynthesis step: hydroxybenzoate_prenylation step_label: Polyprenylation of 4-hydroxybenzoate classification: UNDECIDED default_rule: (chorismate_lyase_route | hydroxybenzaldehyde_oxidation_step | polyprenyl_diphosphate_tail_synthesis) rule: (chorismate_lyase_route | hydroxybenzaldehyde_oxidation_step | polyprenyl_diphosphate_tail_synthesis) activators: - id: chorismate_lyase_route label: Chorismate lyase (UbiC) route (bacteria) connection: via a container - id: hydroxybenzaldehyde_oxidation_step label: 4-Hydroxybenzaldehyde to 4-hydroxybenzoate connection: via a container - id: polyprenyl_diphosphate_tail_synthesis label: Long-chain all-trans-polyprenyl diphosphate synthesis connection: 'PROVIDES_INPUT_FOR: ' - module: ubiquinone_biosynthesis step: flavin_prenyltransferase_activity step_label: 'UbiX: flavin prenyltransferase' classification: UNDECIDED default_rule: (hydroxybenzoate_prenylation | ubiquinone_biosynthesis_accessory_system) rule: (hydroxybenzoate_prenylation | ubiquinone_biosynthesis_accessory_system) activators: - id: hydroxybenzoate_prenylation label: Polyprenylation of 4-hydroxybenzoate connection: via a container - id: ubiquinone_biosynthesis_accessory_system label: Ubiquinone biosynthesis assembly and accessory factors connection: via a container - module: ubiquinone_biosynthesis step: coq6_c5_hydroxylation_step step_label: 4-Hydroxy-3-polyprenylbenzoate to 3,4-dihydroxy-5-polyprenylbenzoate classification: UNDECIDED default_rule: (hydroxybenzoate_prenylation | ubiquinone_biosynthesis_accessory_system) rule: (hydroxybenzoate_prenylation | ubiquinone_biosynthesis_accessory_system) activators: - id: hydroxybenzoate_prenylation label: Polyprenylation of 4-hydroxybenzoate connection: via a container - id: ubiquinone_biosynthesis_accessory_system label: Ubiquinone biosynthesis assembly and accessory factors connection: via a container - module: urea_cycle step: ornithine_citrulline_transport step_label: citrulline export / ornithine import across the inner membrane (SLC25A15) classification: UNDECIDED default_rule: (arg1_step | otc_step) rule: (arg1_step | otc_step) activators: - id: arg1_step label: L-arginine + H2O to L-ornithine + urea connection: 'PROVIDES_INPUT_FOR: L-ornithine regenerated by ARG1 is re-imported to the matrix by SLC25A15 (in exchange for citrulline), closing the cycle.' - id: otc_step label: carbamoyl phosphate + L-ornithine to L-citrulline + Pi connection: 'PROVIDES_INPUT_FOR: Citrulline made by OTC in the matrix is exported to the cytosol by SLC25A15.' - module: urea_cycle step: ass1_step step_label: L-citrulline + L-aspartate + ATP to argininosuccinate + AMP + PPi classification: UNDECIDED default_rule: (citrin_aspartate_supply | ornithine_citrulline_transport) rule: (citrin_aspartate_supply | ornithine_citrulline_transport) activators: - id: citrin_aspartate_supply label: mitochondrial aspartate export for the ASS1 step (SLC25A13, citrin) connection: 'PROVIDES_INPUT_FOR: Citrin (SLC25A13) supplies the cytosolic aspartate that ASS1 condenses with citrulline (the second nitrogen donor).' - id: ornithine_citrulline_transport label: citrulline export / ornithine import across the inner membrane (SLC25A15) connection: 'PROVIDES_INPUT_FOR: Cytosolic citrulline delivered by SLC25A15 is a substrate of ASS1.' - module: ureide_urea_catabolism step: ureidoglycolate_breakdown_step step_label: (S)-ureidoglycolate to glyoxylate classification: ALTERNATIVE_VARIANTS default_rule: (allantoicase_route | ureidoglycine_aminohydrolase_step) rule: (allantoicase_route | ureidoglycine_aminohydrolase_step) activators: - id: allantoicase_route label: Allantoicase (urea-releasing; fungi, some animals) connection: via a container - id: ureidoglycine_aminohydrolase_step label: (S)-2-ureidoglycine to (S)-ureidoglycolate + NH4+ connection: via a container - module: ureide_urea_catabolism step: urease_route step_label: Nickel urease (one step; most fungi, plants, many bacteria) classification: UNDECIDED default_rule: (allantoicase_route | ureidoglycine_aminohydrolase_step | ureidoglycolate_breakdown_step) rule: (allantoicase_route | ureidoglycine_aminohydrolase_step | ureidoglycolate_breakdown_step) activators: - id: allantoicase_route label: Allantoicase (urea-releasing; fungi, some animals) connection: via a container - id: ureidoglycine_aminohydrolase_step label: (S)-2-ureidoglycine to (S)-ureidoglycolate + NH4+ connection: via a container - id: ureidoglycolate_breakdown_step label: (S)-ureidoglycolate to glyoxylate connection: via a container - module: ureide_urea_catabolism step: urea_carboxylase_step step_label: urea + HCO3- + ATP to allophanate + ADP + Pi classification: UNDECIDED default_rule: (allantoicase_route | ureidoglycine_aminohydrolase_step | ureidoglycolate_breakdown_step) rule: (allantoicase_route | ureidoglycine_aminohydrolase_step | ureidoglycolate_breakdown_step) activators: - id: allantoicase_route label: Allantoicase (urea-releasing; fungi, some animals) connection: via a container - id: ureidoglycine_aminohydrolase_step label: (S)-2-ureidoglycine to (S)-ureidoglycolate + NH4+ connection: via a container - id: ureidoglycolate_breakdown_step label: (S)-ureidoglycolate to glyoxylate connection: via a container - module: vitamin_b6_plp_metabolism step: plp_homeostasis step_label: PLP homeostasis (PDXP) classification: ALTERNATIVE_VARIANTS default_rule: (pdxs_pdxt_de_novo_variant | pnpo_step) rule: (pdxs_pdxt_de_novo_variant | pnpo_step) activators: - id: pdxs_pdxt_de_novo_variant label: De novo PLP synthesis by the PdxS/PdxT (SNZ/SNO) synthase connection: via a container - id: pnpo_step label: PNP and PMP oxidation to PLP connection: via a container - module: wnt_signaling step: wnt_receptor_engagement step_label: Wnt-Frizzled-co-receptor engagement classification: UNDECIDED default_rule: (rspo_lgr_potentiation | wnt_ligand_biogenesis) & !(rnf43_znrf3_receptor_turnover | secreted_antagonists) rule: (rspo_lgr_potentiation | wnt_ligand_biogenesis) & !(rnf43_znrf3_receptor_turnover | secreted_antagonists) activators: - id: rspo_lgr_potentiation label: R-spondin/LGR potentiation (positive) connection: 'POSITIVELY_REGULATES: R-spondin/LGR blocks RNF43/ZNRF3-mediated Frizzled turnover, raising surface receptor and sensitizing cells to Wnt.' - id: wnt_ligand_biogenesis label: Wnt ligand acylation and secretion connection: 'PROVIDES_INPUT_FOR: Secreted, acylated Wnt from the sending cell engages receptors on the receiving cell.'