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feat: flag non-enzymatic reactions as spontaneous - #1103
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✅ unchanged · ✨ improved vs Full workflow run · this comment is edited as results come in |
…hemistry # Conflicts: # data/testResults/README.md # data/testResults/memote_score.md # data/testResults/model_qc_comment.md # data/testResults/model_qc_summary.md
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/run gene-essentiality |
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🧬 Started gene-essentiality on |
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Gene essentiality was run on this pull request via GH Actions. Gene essentiality: effect of this changeChecked 0 gene(s) directly affected plus 0 more that share a metabolite with one of them. A gene counts as changed below only if the flip agrees in direction across at least 3 of the 5 cell-line models; fewer than that is grouped as likely noise from ftINIT's run-to-run variability instead.
Full detail: gene-essential_summary.md. ✅ unchanged · ✨ correct vs Hart 2015 · ❌ wrong vs Hart 2015 · ℹ️ not comparable to Hart 2015 The unscoped, every-gene matrix behind the table above is committed to gene-essential.csv.
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Diffusion and non-enzymatic reactions (#1101, #1103): - 14 missed diffusion transports (CO, ethanol, methanol, acetaldehyde, formaldehyde) flagged spontaneous; acetone diffuses mitochondria <=> cytosol <=> extracellular (MAR02222, MAR08364) and is not an MCT1 substrate (MAR08365 deprecated). - Plasma-membrane NH3 transport also by RHBG and RHCG (PMID:24077989); the NH4+ Rhea id is removed from NH3 transports. - Lipid nuclear transports named for what they move, with a note on lateral diffusion in the ER/nuclear envelope; flagged nuclear diffusions reversible. - MAM01739 is 5,6-dihydroxyindole (its ChEBI, KEGG and structure); the reactions that used it as aminochrome now use aminochrome (MAM02160); the two resulting duplicates are merged into the NQO1 and GSTM2 reactions, and the two glutathionyl-aminochrome ids into MAM01136. - MAR04840 (thiosulfate hydrolysis) has no chemical or enzymatic basis and is deprecated; H2S2O3 is merged into thiosulfate; mitochondrial TST transfers sulfur from GSSH to sulfite (MAR20203, RHEA:55976, PMID:25225291). - Further non-enzymatic reactions flagged (statin lactonisation, 1-pyrroline, aminochrome tautomerisation, mevalonolactone, PAH diols); Pictet-Spengler condensations are written as condensations. Annotations (#1084, #1086, #1087, #1090, #1033): - Deprecated MetaNetX reaction ids replaced by their matching successor or removed; R_-prefixed BiGG ids removed; KEGG ids of the lipoamide half-reactions and chloro-compound hydrolyses restored; ModelSEED ids that differ in proton coupling removed. - L-form PubChem/ChEBI ids for stereo-less amino-acid derivatives; iodide, ammonium and ascorbate ids of the ionic forms. - Chemically sensible protonation sites in 11 re-protonated SMILES; synaptamide structure; more precise names for kept ids of #1090 merges; (11Z)- and (7Z)-octadecenoylcarnitine and cis-vaccenoyl-CoA structures. - Gene rows of the Ca2+ channels, IPO4 and AQP11 completed; TRPV5 and TRPV6 added to MAR11311 (UniProt RHEA:29671, PMIDs 11097838, 19261737). - Genes without evidence removed from #1090 unions: CYP2J2 (MAR06700), ALDH3A1/ALDH9A1 (MAR01611); MAR04049 keeps CYP1A1 and CYP1B1.
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Corrections in #1105 to the reactions flagged here. The reasoning and evidence for the flags themselves are documented in #1112. Directions. A flagged reaction is kept in every ftINIT model, so a non-enzymatic reaction must run only in its chemical direction.
Acetoacetate decarboxylation (MAR04464). EC 4.1.1.4 is removed because the only enzymes for RHEA:19729 are bacterial, and a note is added. A weak activity attributed to serum albumin (PMID 4624981, PMID 963888) is mentioned in the note. Reactions that were already in v2.0.1 and are newly flagged or corrected in #1105 (aminochrome, Pictet-Spengler condensations, bromobenzene, statin lactonisation, 1-pyrroline, mevalonolactone, thiosulfate) are in #1112. |
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) * fix: corrections to #1039, #1041, #1040, #1090, #1028, #1099 and #1038 from the curation review - MAR20193: MCT1 carries succinate with 2 H+ (UniProt P53985, RHEA:29303, PMID:32946811); MCT4 has no succinate evidence, so the GPR is SLC16A1. - Vesicular secretion goes back to the HMR stoichiometries (2 ATP per 3 amines or acetylcholine, 1 ATP per 3 GABA, glycine or beta-alanine): VMAT exchanges 2 H+ per amine and the V-ATPase pumps about 10 H+ per 3 ATP (PMID:32165585), so 1 ATP per molecule overestimates the cost. - BGT1 (SLC6A12) couples 3 Na+ and 2 Cl- (human BGT-1, PMID:7589472). - MAR01857/MAR01861 exported bile salts straight from the peroxisome with 2 ATP and no gene; ABCB11 uses 1 ATP (RHEA:50052/50064), as in MAR01870/MAR01872. - Kept reactions record the reactions #1040 and #1041 deprecated into them. - #1090 GPR unions: MAR01762 and MAR01605 are CYP27A1 only, MAR01765 is CYP7B1 (CH25H only 25-hydroxylates, CYP2E1 and CYP27A1 do not 7alpha-hydroxylate); duplicate genes removed from joined GPRs. - MAR08607 has the cross-references and EC of glutamine transaminase K (RHEA:30391, EC 2.6.1.117); HCl keeps MNXM735978; MAM03543 has the (2E,4Z) structure its name and DECR1 require; renamed ids are recorded in metRetired; MAR00751 is merged into MAR06346 with its gene; MAR00036 uses one 15-deoxy-PGD2. - MAR00483 and MAR03838 carry the ids of their quinone reactions, and no deprecated reaction lists them as retired any more. - MAR08433/MAR08434 carry the BiGG/MetaNetX ids of their glycine cleavage steps. - LDHD, a mitochondrial FAD (R)-2-hydroxyacid dehydrogenase (UniProt Q86WU2), is removed from the NADH reactions MAR11476/MAR11479. * fix: corrections to #1101, #1103, #1084, #1086 and #1087 from the curation review - H2O2 crosses the plasma, ER and inner mitochondrial membranes through peroxiporins, as water does through aquaporins in the model: MAR08408 AQP3/AQP8/AQP9, MAR13002 AQP11/AQP8, MAR03946 AQP8 (PMID:20724658, PMID:31546170, PMID:22910329); no longer flagged spontaneous. AQP11 is added as a gene. - Histone import (MAR08024) is by importin-4 (PMID:36103578): GPR IPO4 (new gene), cytosol to nucleus only, not spontaneous. - Prostacyclin and thromboxane A2 hydrolysis are one-way (PMID:29320, PMID:1059088); MAR06877 is written as the spontaneous addition of cysteine to dopaquinone. - Leu-Gly-type errors of #1084: palmitoleoylcarnitine and selenohomocysteine get their own structures back. - ModelSEED ids of a different reaction (proton-pumping variants on plain hydrolases, 18:2 on 18:3 elongation, degenerate or plant reactions) or compound are removed or corrected. - #1087: unrelated ids on the NH4+/NH3 and xanthurenate protonation reactions removed; the respiratory chain BiGG ids NADH2_u10mi, CYOR_u10mi, CYOOm2i and CYOOm3i restored; the carnitine-shuttle MetaNetX ids it added use (R)-carnitine; ids inherited from misannotated metabolites removed; D-ribulose 1-phosphate ids removed from the D-xylulose 1-phosphate aldolase; RHEA:10160 restored on MAR09470. - PubChem ids that #1087 took from wrong model structures (a different compound, D-peptides, all-trans lipids) are replaced by the correct one where verified, otherwise removed; 14,15-DiHETE has CHEBI:133916 and 13(S)-HODE loses the 13R LIPID MAPS id. * fix: remaining corrections from the curation review (deprecated rows, #1099 ids, LDH GPRs, notes) - Deprecated rows of MAR00449, MAR08610 and MAM01690m are complete copies of their last model rows. - MAR08441 (choline to ubiquinone) loses the ids of the FAD reaction and cites the evidence for the quinone route (PMID:1218095, PMID:9630673, PMID:34428349). - #1099: the apo H protein is named as such (CHEBI:29969); the aminomethyl H protein has CHEBI:83143 and KEGG C01242 and records MAM02878m as retired; S-propanoyldihydrolipoamide loses the protein-bound ids; MAR20168 is named after LIPT1 and filed under lipoic acid metabolism. - TPO iodination (MAR06793/MAR06794) is tyrosine metabolism. - The 40 PXMP2 pore reactions note that Pxmp2 loss only partly restricts peroxisomal permeability (PMID:19352492). - MAR11476, MAR11479 and MAR05351 get every LDH with demonstrated activity (LDHA, LDHB, LDHC, LDHAL6A): LDH reduces the branched-chain 2-oxo acid (PMID:26014429) and 2-oxobutyrate (PMID:26059096); LDHAL6B has no demonstrated activity. * fix: remaining low-priority corrections from the curation review Diffusion and non-enzymatic reactions (#1101, #1103): - 14 missed diffusion transports (CO, ethanol, methanol, acetaldehyde, formaldehyde) flagged spontaneous; acetone diffuses mitochondria <=> cytosol <=> extracellular (MAR02222, MAR08364) and is not an MCT1 substrate (MAR08365 deprecated). - Plasma-membrane NH3 transport also by RHBG and RHCG (PMID:24077989); the NH4+ Rhea id is removed from NH3 transports. - Lipid nuclear transports named for what they move, with a note on lateral diffusion in the ER/nuclear envelope; flagged nuclear diffusions reversible. - MAM01739 is 5,6-dihydroxyindole (its ChEBI, KEGG and structure); the reactions that used it as aminochrome now use aminochrome (MAM02160); the two resulting duplicates are merged into the NQO1 and GSTM2 reactions, and the two glutathionyl-aminochrome ids into MAM01136. - MAR04840 (thiosulfate hydrolysis) has no chemical or enzymatic basis and is deprecated; H2S2O3 is merged into thiosulfate; mitochondrial TST transfers sulfur from GSSH to sulfite (MAR20203, RHEA:55976, PMID:25225291). - Further non-enzymatic reactions flagged (statin lactonisation, 1-pyrroline, aminochrome tautomerisation, mevalonolactone, PAH diols); Pictet-Spengler condensations are written as condensations. Annotations (#1084, #1086, #1087, #1090, #1033): - Deprecated MetaNetX reaction ids replaced by their matching successor or removed; R_-prefixed BiGG ids removed; KEGG ids of the lipoamide half-reactions and chloro-compound hydrolyses restored; ModelSEED ids that differ in proton coupling removed. - L-form PubChem/ChEBI ids for stereo-less amino-acid derivatives; iodide, ammonium and ascorbate ids of the ionic forms. - Chemically sensible protonation sites in 11 re-protonated SMILES; synaptamide structure; more precise names for kept ids of #1090 merges; (11Z)- and (7Z)-octadecenoylcarnitine and cis-vaccenoyl-CoA structures. - Gene rows of the Ca2+ channels, IPO4 and AQP11 completed; TRPV5 and TRPV6 added to MAR11311 (UniProt RHEA:29671, PMIDs 11097838, 19261737). - Genes without evidence removed from #1090 unions: CYP2J2 (MAR06700), ALDH3A1/ALDH9A1 (MAR01611); MAR04049 keeps CYP1A1 and CYP1B1. * chore: update model QC results [skip ci] * chore: update model QC results [skip ci] * fix: corrections to #1043, #1088, #1093-#1096 from an evidence review Retired pointers for merged ids (MAR09553, MAM02768c, MAM20076n, the cytosolic tocopherol copies); I-antigen MAM03584g merged into MAM02186g and MAR08317 into MAR00082 with B4GALT1-4; PTGS peroxidase steps MAR01307/MAR01392/MAR01393 use NADPH and are irreversible; tocopherol side-chain beta-oxidation gets ACAA2, and MAR06435/MAR06451 DECR1 and ECI1/ECI2 with separate NADPH and NAD+; CYP3A4 on MAR08034; references and notes for MAR03859, MAR04280, MAR20195, MAR20021-MAR20029 and the CYP4F2 13'-carboxylation steps. * fix: corrections to #1044 and #1089 from an evidence review Retinoate 4-hydroxylation and 4-oxo GPRs follow single-isoform human data (CYP2C9, CYP2B6, CYP2C19, CYP3A5, CYP26A1 added where shown), Rhea ids for the 9-cis steps, lumped MetaNetX ids removed from the split hydroxylations, ids for 4-hydroxy-9-cis-retinoate; retired pointers for the galactose merges and UniProt-backed references for GALK1, GALT and UGP2 on galactose-1-phosphate. * chore: update model QC results [skip ci] * feat: add CYP26C1 to the retinoate 4-hydroxylation and 4-oxo reactions UniProt Q6V0L0 gives human CYP26C1 the all-trans and 9-cis 4-hydroxylations and 4-oxo steps (RHEA:51984, 75851, 75847, 75855; PMID:14532297); it also 4-hydroxylates 13-cis-retinoate (PMID:29476041). * chore: update model QC results [skip ci] * chore: add gene essentiality test result [skip ci] * chore: add gene essentiality test result [skip ci] --------- Co-authored-by: github-actions[bot] <41898282+github-actions[bot]@users.noreply.github.com>
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#1106) * fix: corrections to #1039, #1041, #1040, #1090, #1028, #1099 and #1038 from the curation review - MAR20193: MCT1 carries succinate with 2 H+ (UniProt P53985, RHEA:29303, PMID:32946811); MCT4 has no succinate evidence, so the GPR is SLC16A1. - Vesicular secretion goes back to the HMR stoichiometries (2 ATP per 3 amines or acetylcholine, 1 ATP per 3 GABA, glycine or beta-alanine): VMAT exchanges 2 H+ per amine and the V-ATPase pumps about 10 H+ per 3 ATP (PMID:32165585), so 1 ATP per molecule overestimates the cost. - BGT1 (SLC6A12) couples 3 Na+ and 2 Cl- (human BGT-1, PMID:7589472). - MAR01857/MAR01861 exported bile salts straight from the peroxisome with 2 ATP and no gene; ABCB11 uses 1 ATP (RHEA:50052/50064), as in MAR01870/MAR01872. - Kept reactions record the reactions #1040 and #1041 deprecated into them. - #1090 GPR unions: MAR01762 and MAR01605 are CYP27A1 only, MAR01765 is CYP7B1 (CH25H only 25-hydroxylates, CYP2E1 and CYP27A1 do not 7alpha-hydroxylate); duplicate genes removed from joined GPRs. - MAR08607 has the cross-references and EC of glutamine transaminase K (RHEA:30391, EC 2.6.1.117); HCl keeps MNXM735978; MAM03543 has the (2E,4Z) structure its name and DECR1 require; renamed ids are recorded in metRetired; MAR00751 is merged into MAR06346 with its gene; MAR00036 uses one 15-deoxy-PGD2. - MAR00483 and MAR03838 carry the ids of their quinone reactions, and no deprecated reaction lists them as retired any more. - MAR08433/MAR08434 carry the BiGG/MetaNetX ids of their glycine cleavage steps. - LDHD, a mitochondrial FAD (R)-2-hydroxyacid dehydrogenase (UniProt Q86WU2), is removed from the NADH reactions MAR11476/MAR11479. * fix: corrections to #1101, #1103, #1084, #1086 and #1087 from the curation review - H2O2 crosses the plasma, ER and inner mitochondrial membranes through peroxiporins, as water does through aquaporins in the model: MAR08408 AQP3/AQP8/AQP9, MAR13002 AQP11/AQP8, MAR03946 AQP8 (PMID:20724658, PMID:31546170, PMID:22910329); no longer flagged spontaneous. AQP11 is added as a gene. - Histone import (MAR08024) is by importin-4 (PMID:36103578): GPR IPO4 (new gene), cytosol to nucleus only, not spontaneous. - Prostacyclin and thromboxane A2 hydrolysis are one-way (PMID:29320, PMID:1059088); MAR06877 is written as the spontaneous addition of cysteine to dopaquinone. - Leu-Gly-type errors of #1084: palmitoleoylcarnitine and selenohomocysteine get their own structures back. - ModelSEED ids of a different reaction (proton-pumping variants on plain hydrolases, 18:2 on 18:3 elongation, degenerate or plant reactions) or compound are removed or corrected. - #1087: unrelated ids on the NH4+/NH3 and xanthurenate protonation reactions removed; the respiratory chain BiGG ids NADH2_u10mi, CYOR_u10mi, CYOOm2i and CYOOm3i restored; the carnitine-shuttle MetaNetX ids it added use (R)-carnitine; ids inherited from misannotated metabolites removed; D-ribulose 1-phosphate ids removed from the D-xylulose 1-phosphate aldolase; RHEA:10160 restored on MAR09470. - PubChem ids that #1087 took from wrong model structures (a different compound, D-peptides, all-trans lipids) are replaced by the correct one where verified, otherwise removed; 14,15-DiHETE has CHEBI:133916 and 13(S)-HODE loses the 13R LIPID MAPS id. * fix: remaining corrections from the curation review (deprecated rows, #1099 ids, LDH GPRs, notes) - Deprecated rows of MAR00449, MAR08610 and MAM01690m are complete copies of their last model rows. - MAR08441 (choline to ubiquinone) loses the ids of the FAD reaction and cites the evidence for the quinone route (PMID:1218095, PMID:9630673, PMID:34428349). - #1099: the apo H protein is named as such (CHEBI:29969); the aminomethyl H protein has CHEBI:83143 and KEGG C01242 and records MAM02878m as retired; S-propanoyldihydrolipoamide loses the protein-bound ids; MAR20168 is named after LIPT1 and filed under lipoic acid metabolism. - TPO iodination (MAR06793/MAR06794) is tyrosine metabolism. - The 40 PXMP2 pore reactions note that Pxmp2 loss only partly restricts peroxisomal permeability (PMID:19352492). - MAR11476, MAR11479 and MAR05351 get every LDH with demonstrated activity (LDHA, LDHB, LDHC, LDHAL6A): LDH reduces the branched-chain 2-oxo acid (PMID:26014429) and 2-oxobutyrate (PMID:26059096); LDHAL6B has no demonstrated activity. * fix: remaining low-priority corrections from the curation review Diffusion and non-enzymatic reactions (#1101, #1103): - 14 missed diffusion transports (CO, ethanol, methanol, acetaldehyde, formaldehyde) flagged spontaneous; acetone diffuses mitochondria <=> cytosol <=> extracellular (MAR02222, MAR08364) and is not an MCT1 substrate (MAR08365 deprecated). - Plasma-membrane NH3 transport also by RHBG and RHCG (PMID:24077989); the NH4+ Rhea id is removed from NH3 transports. - Lipid nuclear transports named for what they move, with a note on lateral diffusion in the ER/nuclear envelope; flagged nuclear diffusions reversible. - MAM01739 is 5,6-dihydroxyindole (its ChEBI, KEGG and structure); the reactions that used it as aminochrome now use aminochrome (MAM02160); the two resulting duplicates are merged into the NQO1 and GSTM2 reactions, and the two glutathionyl-aminochrome ids into MAM01136. - MAR04840 (thiosulfate hydrolysis) has no chemical or enzymatic basis and is deprecated; H2S2O3 is merged into thiosulfate; mitochondrial TST transfers sulfur from GSSH to sulfite (MAR20203, RHEA:55976, PMID:25225291). - Further non-enzymatic reactions flagged (statin lactonisation, 1-pyrroline, aminochrome tautomerisation, mevalonolactone, PAH diols); Pictet-Spengler condensations are written as condensations. Annotations (#1084, #1086, #1087, #1090, #1033): - Deprecated MetaNetX reaction ids replaced by their matching successor or removed; R_-prefixed BiGG ids removed; KEGG ids of the lipoamide half-reactions and chloro-compound hydrolyses restored; ModelSEED ids that differ in proton coupling removed. - L-form PubChem/ChEBI ids for stereo-less amino-acid derivatives; iodide, ammonium and ascorbate ids of the ionic forms. - Chemically sensible protonation sites in 11 re-protonated SMILES; synaptamide structure; more precise names for kept ids of #1090 merges; (11Z)- and (7Z)-octadecenoylcarnitine and cis-vaccenoyl-CoA structures. - Gene rows of the Ca2+ channels, IPO4 and AQP11 completed; TRPV5 and TRPV6 added to MAR11311 (UniProt RHEA:29671, PMIDs 11097838, 19261737). - Genes without evidence removed from #1090 unions: CYP2J2 (MAR06700), ALDH3A1/ALDH9A1 (MAR01611); MAR04049 keeps CYP1A1 and CYP1B1. * chore: update model QC results [skip ci] * fix: pre-existing reaction and GPR errors found in the curation review - MAR01453 hydroxypyruvate reductase is 1:1 (it made reducing equivalents), with LDHA/LDHB (PMID:16198644). - No cytosolic NAD+ choline dehydrogenase or NAD+ D-lactate dehydrogenase exists in human: MAR04696 (with the cytosolic betaine aldehyde reactions MAR04697/MAR04698) and MAR08512 are deprecated; LDHD is removed from NAD reactions; choline is oxidised by CHDH in mitochondria. - CH25H only 25-hydroxylates cholesterol: the ER 26- and 20-hydroxylations MAR01785/MAR01781 (and MAR01783, which followed from 20-hydroxycholesterol) are deprecated. - NIS carries 2 Na+ per iodide (MAR06989 into MAR08924); pendrin exchanges 1 Cl- per I- (RHEA:72379); the H+/K+-ATPase exports its proton (MAR08892; MAR01444 merged into it). - HCl is replaced by chloride + H+; hydrogen bromide was bromide already and is renamed and re-annotated. - 15-deoxy-PGD2 forms by dehydration of PGD2 (one-way, spontaneous); the 1-pyrroline-5-carboxylate ring openings are non-enzymatic (no ALDH4A1); nuclear transports of CMP-Neu5Ac, UTP and deoxycytidine are diffusion, like the other nucleotides (NUP62CL and NUP210L, left on no reaction, are removed); MAR01597 and MAR10395 are deprecated. - CYP27A1 steps are mitochondrial monooxygenations; 15-oxo-PGE2 13-reduction by PTGR3 (MAR20018) is written in its direction. - 2-hydroxyglutarate: L- (MAM03188) and D-2-hydroxyglutarate (MAM20012) are separate; L2HGDH oxidises L-2HG in mitochondria (ubiquinone), new D2HGDH (MAR20204, via ETF) oxidises D-2HG; PHGDH makes D-2HG; MDH2 and LDHA/MDH1 make L-2HG; OAT1/NaDC3 transports. - MAR08773 is named for D-xylulose 1-phosphate. * fix: bile acid, globoside, 2-hydroxyglutarate export and PGD2 dehydration reactions - No human enzyme makes beta-GalNAc-globoside (para-Forssman): B3GALNT1 only makes globoside and B3GALNT2 does not act on glycolipids (PMID:14724282); its synthesis, reversed lysosomal breakdown and transports are deprecated. NAGA hydrolyses alpha-GalNAc-globoside with water (RHEA:48412). - MAR01787, MAR03259, MAR02184 and MAR02881 turned sterols without a 7alpha-hydroxyl into 7alpha-hydroxycholest-4-en-3-one; HSD3B7 acts only on 7alpha-hydroxylated sterols (PMID:11067870); deprecated. - CYP27A1 is mitochondrial (UniProt Q02318): duplicate and cytosolic copies of its steps are merged into the mitochondrial reactions. - 2-hydroxyglutarate efflux (MAR11733) is OAT4 exchange with estrone sulfate (PMID:18365245). - PGD2 dehydrates to delta-12-PGJ2 and PGJ2 non-enzymatically (one-way; PMID:6578214, PMID:11786541). * fix: review corrections on the reaction branch - Deprecations left dead ends: the Golgi GalNAc transport MAR08193, and MAR01578/MAR02895 (20-hydroxycholesterol and 7alpha-hydroxycholest-4-en-3-one in mitochondria, each in one reaction only) are deprecated with their metabolites. - OAT4 also exchanges D-2-hydroxyglutarate (MAR20211, PMID:18365245). - The L-glycerate ids MNXR100701/HPYRR2x belong to the LDH hydroxypyruvate reduction (MAR01453), not to GRHPR's D-glycerate reaction (MAR08782). - Pendrin 1:1 exchange cited (PMID:18565999); an unrelated citation removed from MAR11731; MAR02184 is deprecated without a merge target; chloride records the HMR id of the merged HCl. * chore: update model QC results [skip ci] * fix: MAR01453 lists its BiGG id once * chore: update model QC results [skip ci] * fix: deprecate the blocked ER copy MAR20031 of 4-nitrophenol hydroxylation into MAR08034 MAR20031 is MAR08034 (CYP2E1, RHEA:26205, MNXR102281) in the ER, where PNP and 4-nitrocatechol have no other reaction or transport, so it cannot carry flux. MAR08034 keeps the connected cytosolic copy and records MAR20031 in rxnRetired; PNP[r] and 4-nitrocatechol[r] are deprecated. * chore: update model QC results [skip ci] * fix: cholesterol synthesis goes through HSD17B7 and MSMO1 in the ER copy The Recon3D ER copy of the second C4 demethylation lumped it into 3-keto-4-methylzymosterol + O2 -> zymosterone (MAR00117, MAR00118) and had a gene-less hydrolytic demethylation (MAR02302), which bypassed HSD17B7 and MSMO1; these are deprecated and replaced by MSMO1 (MAR20217) and NSDHL (MAR20218) steps with the new MAM00955r. MAR00115 gets HSD17B7 instead of HSD17B4, MAR01500 and MAR02301 reduce with NADPH instead of producing it, and MAR00116 gets EC 1.14.18.9. * chore: update model QC results [skip ci] * fix: do not complete the ER copy of cholesterol synthesis The MSMO1 and NSDHL steps in the ER (and 4alpha-carboxyzymosterol[r]) are dropped: the cytosolic and ER copies of the pathway are to be reconciled into one, and cholesterol is made by the complete cytosolic copy. * chore: update model QC results [skip ci] * chore: update model QC results [skip ci] * chore: add gene essentiality test result [skip ci] --------- Co-authored-by: github-actions[bot] <41898282+github-actions[bot]@users.noreply.github.com>
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Sep 28, 2026
…errors (#1107) * fix: corrections to #1039, #1041, #1040, #1090, #1028, #1099 and #1038 from the curation review - MAR20193: MCT1 carries succinate with 2 H+ (UniProt P53985, RHEA:29303, PMID:32946811); MCT4 has no succinate evidence, so the GPR is SLC16A1. - Vesicular secretion goes back to the HMR stoichiometries (2 ATP per 3 amines or acetylcholine, 1 ATP per 3 GABA, glycine or beta-alanine): VMAT exchanges 2 H+ per amine and the V-ATPase pumps about 10 H+ per 3 ATP (PMID:32165585), so 1 ATP per molecule overestimates the cost. - BGT1 (SLC6A12) couples 3 Na+ and 2 Cl- (human BGT-1, PMID:7589472). - MAR01857/MAR01861 exported bile salts straight from the peroxisome with 2 ATP and no gene; ABCB11 uses 1 ATP (RHEA:50052/50064), as in MAR01870/MAR01872. - Kept reactions record the reactions #1040 and #1041 deprecated into them. - #1090 GPR unions: MAR01762 and MAR01605 are CYP27A1 only, MAR01765 is CYP7B1 (CH25H only 25-hydroxylates, CYP2E1 and CYP27A1 do not 7alpha-hydroxylate); duplicate genes removed from joined GPRs. - MAR08607 has the cross-references and EC of glutamine transaminase K (RHEA:30391, EC 2.6.1.117); HCl keeps MNXM735978; MAM03543 has the (2E,4Z) structure its name and DECR1 require; renamed ids are recorded in metRetired; MAR00751 is merged into MAR06346 with its gene; MAR00036 uses one 15-deoxy-PGD2. - MAR00483 and MAR03838 carry the ids of their quinone reactions, and no deprecated reaction lists them as retired any more. - MAR08433/MAR08434 carry the BiGG/MetaNetX ids of their glycine cleavage steps. - LDHD, a mitochondrial FAD (R)-2-hydroxyacid dehydrogenase (UniProt Q86WU2), is removed from the NADH reactions MAR11476/MAR11479. * fix: corrections to #1101, #1103, #1084, #1086 and #1087 from the curation review - H2O2 crosses the plasma, ER and inner mitochondrial membranes through peroxiporins, as water does through aquaporins in the model: MAR08408 AQP3/AQP8/AQP9, MAR13002 AQP11/AQP8, MAR03946 AQP8 (PMID:20724658, PMID:31546170, PMID:22910329); no longer flagged spontaneous. AQP11 is added as a gene. - Histone import (MAR08024) is by importin-4 (PMID:36103578): GPR IPO4 (new gene), cytosol to nucleus only, not spontaneous. - Prostacyclin and thromboxane A2 hydrolysis are one-way (PMID:29320, PMID:1059088); MAR06877 is written as the spontaneous addition of cysteine to dopaquinone. - Leu-Gly-type errors of #1084: palmitoleoylcarnitine and selenohomocysteine get their own structures back. - ModelSEED ids of a different reaction (proton-pumping variants on plain hydrolases, 18:2 on 18:3 elongation, degenerate or plant reactions) or compound are removed or corrected. - #1087: unrelated ids on the NH4+/NH3 and xanthurenate protonation reactions removed; the respiratory chain BiGG ids NADH2_u10mi, CYOR_u10mi, CYOOm2i and CYOOm3i restored; the carnitine-shuttle MetaNetX ids it added use (R)-carnitine; ids inherited from misannotated metabolites removed; D-ribulose 1-phosphate ids removed from the D-xylulose 1-phosphate aldolase; RHEA:10160 restored on MAR09470. - PubChem ids that #1087 took from wrong model structures (a different compound, D-peptides, all-trans lipids) are replaced by the correct one where verified, otherwise removed; 14,15-DiHETE has CHEBI:133916 and 13(S)-HODE loses the 13R LIPID MAPS id. * fix: remaining corrections from the curation review (deprecated rows, #1099 ids, LDH GPRs, notes) - Deprecated rows of MAR00449, MAR08610 and MAM01690m are complete copies of their last model rows. - MAR08441 (choline to ubiquinone) loses the ids of the FAD reaction and cites the evidence for the quinone route (PMID:1218095, PMID:9630673, PMID:34428349). - #1099: the apo H protein is named as such (CHEBI:29969); the aminomethyl H protein has CHEBI:83143 and KEGG C01242 and records MAM02878m as retired; S-propanoyldihydrolipoamide loses the protein-bound ids; MAR20168 is named after LIPT1 and filed under lipoic acid metabolism. - TPO iodination (MAR06793/MAR06794) is tyrosine metabolism. - The 40 PXMP2 pore reactions note that Pxmp2 loss only partly restricts peroxisomal permeability (PMID:19352492). - MAR11476, MAR11479 and MAR05351 get every LDH with demonstrated activity (LDHA, LDHB, LDHC, LDHAL6A): LDH reduces the branched-chain 2-oxo acid (PMID:26014429) and 2-oxobutyrate (PMID:26059096); LDHAL6B has no demonstrated activity. * fix: remaining low-priority corrections from the curation review Diffusion and non-enzymatic reactions (#1101, #1103): - 14 missed diffusion transports (CO, ethanol, methanol, acetaldehyde, formaldehyde) flagged spontaneous; acetone diffuses mitochondria <=> cytosol <=> extracellular (MAR02222, MAR08364) and is not an MCT1 substrate (MAR08365 deprecated). - Plasma-membrane NH3 transport also by RHBG and RHCG (PMID:24077989); the NH4+ Rhea id is removed from NH3 transports. - Lipid nuclear transports named for what they move, with a note on lateral diffusion in the ER/nuclear envelope; flagged nuclear diffusions reversible. - MAM01739 is 5,6-dihydroxyindole (its ChEBI, KEGG and structure); the reactions that used it as aminochrome now use aminochrome (MAM02160); the two resulting duplicates are merged into the NQO1 and GSTM2 reactions, and the two glutathionyl-aminochrome ids into MAM01136. - MAR04840 (thiosulfate hydrolysis) has no chemical or enzymatic basis and is deprecated; H2S2O3 is merged into thiosulfate; mitochondrial TST transfers sulfur from GSSH to sulfite (MAR20203, RHEA:55976, PMID:25225291). - Further non-enzymatic reactions flagged (statin lactonisation, 1-pyrroline, aminochrome tautomerisation, mevalonolactone, PAH diols); Pictet-Spengler condensations are written as condensations. Annotations (#1084, #1086, #1087, #1090, #1033): - Deprecated MetaNetX reaction ids replaced by their matching successor or removed; R_-prefixed BiGG ids removed; KEGG ids of the lipoamide half-reactions and chloro-compound hydrolyses restored; ModelSEED ids that differ in proton coupling removed. - L-form PubChem/ChEBI ids for stereo-less amino-acid derivatives; iodide, ammonium and ascorbate ids of the ionic forms. - Chemically sensible protonation sites in 11 re-protonated SMILES; synaptamide structure; more precise names for kept ids of #1090 merges; (11Z)- and (7Z)-octadecenoylcarnitine and cis-vaccenoyl-CoA structures. - Gene rows of the Ca2+ channels, IPO4 and AQP11 completed; TRPV5 and TRPV6 added to MAR11311 (UniProt RHEA:29671, PMIDs 11097838, 19261737). - Genes without evidence removed from #1090 unions: CYP2J2 (MAR06700), ALDH3A1/ALDH9A1 (MAR01611); MAR04049 keeps CYP1A1 and CYP1B1. * chore: update model QC results [skip ci] * fix: pre-existing metabolite identity, structure and cross-reference errors - L-carnitine (MAM02348) had the D-carnitine structure and ids in every field but HMDB: now (R)-carnitine (CHEBI:16347, C00318, MNXM1105737, cpd00266, PubChem 10917); the carnitine-shuttle reactions carry the (R)-carnitine MetaNetX and ModelSEED ids. - Peptides: 221 peptide metabolites had D or undefined residues; they get all-L structures, and all-L PubChem/MetaNetX ids replace the D ones. - Statins: the rosuvastatin, pitavastatin, pravastatin, fluvastatin and cerivastatin metabolites were Ca/Na salt dimers (cerivastatin also one CH2 short); they are monomers at physiological charge, and their reactions are rewritten to stay balanced; statin acyl glucuronide lactonisation by UGT1A1/UGT1A3/UGT2B7 (PMID:26412035). - D-xylulose 1-phosphate, beta-GalNAc-globoside (penicillin G ids removed), 4-cis-decenoyl-CoA, (6Z,9Z)-octadecadienoyl-CoA, 10,11-dihydro-12-epi-LTB4, A2PE, lactosylceramide and alpha-/omega-muricholoyl-CoA get their own structures and cross-references; the reaction ids that followed the wrong compound are corrected or removed; KHK (MAR08772) has the D-xylulose MetaNetX id. - Shifted BiGG ids from the HMR/Recon mapping: 59 exchanges carry their own EX_ id, and 97 internal reactions the matching BiGG and MetaNetX ids. * fix: merge duplicate lactosylceramide and Leb glycolipid ids; linoleoyl-CoA, dihydro-LTB4 and peptide names - MAM03586 is merged into MAM02328 (lactosylceramide), which now carries lactosylceramide's BiGG/MetaNetX ids instead of digalactosylceramide's; the six Recon reactions that became identical to HMR ones are merged into them, and the GLA/PSAP globotriaosylceramide hydrolysis (MAR00804) gets its genes. - MAM01999 'glycolipid' is the Lewis b glycolipid (two fucoses, made by FUT3) and is merged into MAM03578; MAR08287 makes Lewis y (FUT9); duplicate reactions merged; MAR08271 is FUT3 or FUT5. - Linoleoyl-CoA has the (9Z,12Z) PubChem id; 10,11-dihydro-LTB4 and its CoA ester the 5S,12S structure and ids (CHEBI:133324); MAM00091m's metRetired is well formed. - Asp-Ala-Arg, Glu-Arg-Leu and Glu-Asn-Leu are named by their formula, BiGG ids and hydrolysis products. * fix: review corrections on the metabolite branch - MAR02660/MAR02662 unchanged (acyl-CoA reactions follow their own issues). - Cerivastatin M-22 and M-31 are the neutral lactones of M-1 and M-23, and the M-1/M-23 glucuronides are acyl glucuronides (only these lactonise); the lactonisation and hydrolysis reactions no longer use SAM/SAH to balance. - The fluvastatin acids have the 3R,5S configuration of fluvastatin and its lactone (PubChem 37888681). - MetaNetX ids of other isomers removed (MAR00150; the 10,11-dihydro-LTB4 reactions; two polyglutamyl-folates); MAR00766 duplicates MAR12035 in reverse and is merged into it; exchange names follow the renamed peptides; FUT5 evidence cited on MAR08271. * chore: update model QC results [skip ci] * chore: update model QC results [skip ci] * ci: relative links in the committed test-result reports model_qc_summary.md and gene-essential_summary.md sit in data/testResults next to the README and the CSVs they link to, so they now link relatively. The absolute links pinned the pull-request branch and broke once it was deleted after merging. The posted comments keep absolute links, which they need. * chore: relative links in the committed test-result reports * chore: add gene essentiality test result [skip ci]
Merged
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Follow-up to #1101. Flags 30 gene-less reactions as
spontaneousbecause they are non-enzymatic chemistry, so ftINIT always keeps them.Not in this PR: MAR03819 and MAR03820 (glutamate-5-semialdehyde ⇌ 1-pyrroline-5-carboxylate) and MAR08096 (4-hydroxyglutamate semialdehyde ⇌ 1-pyrroline-3-hydroxy-5-carboxylate) are also spontaneous ring closures, but they carry a GPR. That GPR should be removed when they are flagged.