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fix: vitamin E beta-oxidation GPRs and electron acceptor, CYP4F2 for omega-hydroxylation - #1096
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…for its omega-hydroxylation
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✅ unchanged · ✨ improved vs Full workflow run · this comment is edited as results come in |
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/run gene-essentiality |
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Gene essentiality was run on this pull request via GH Actions. Gene essentiality: effect of this changeChecked 35 gene(s) directly affected plus 729 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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The genes flagged in the gene-essentiality run (CYP4F2, AMACR, ACADSB, HADHA, HADHB, ECHS1, and ETFA, ETFB, ETFDH in 3/5 lines) are an effect of the biomass definition, not of the curation in this PR. The cofactor and vitamin pool MAR10065 requires two vitamin E catabolites, 3-carboxy-alpha-chromanol and gamma-CEHC-glucuronide (0.0345 each), which are made only by tocopherol omega-hydroxylation followed by beta-oxidation. With the corrected GPRs, the genes on that route become growth-essential; before this PR the same requirement made CYP4F11 essential. In the full model, all of them become dispensable (growth ratio 1.00) when these two metabolites are removed from MAR10065. Redefining the biomass is described in #1118. |
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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.
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Corrections in #1105 after an evidence review:
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This was referenced Sep 28, 2026
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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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Closes #738
Closes #888
Vitamin E side-chain β-oxidation stays in the mitochondria: α-CEHC, the end product, is found almost only in mitochondria (PMID:19819327).
β-oxidation GPRs (MAR06432–MAR06488): the 24–28-gene lists of peroxisomal, cytosolic and mitochondrial enzymes are replaced by mitochondrial ones, following #738:
Differences from #738:
Electron acceptor: these mitochondrial reactions reduced O2 to H2O2, as in peroxisomes. They now reduce FAD to FADH2, like other mitochondrial acyl-CoA dehydrogenases (#791, for these 14 reactions).
ω-hydroxylation: the GPR is CYP4F2 only. It is the only human enzyme shown to ω-hydroxylate tocopherols (PMID:15753130). CYP4F22 acts on fatty acids of C28 and longer in skin (PMID:26056268), and there is no tocopherol evidence for CYP4F3, CYP4F8 or CYP4F11. The cytosolic copies of these ER reactions (MAR06426, MAR06428, MAR06441, MAR06443, MAR06464, MAR06466, MAR06476, MAR06478) and their four cytosolic 13′-hydroxy intermediates are deprecated. The ER route already takes tocopherols in and moves the 13′-carboxy products out.
Growth is unchanged. Every β-oxidation reaction still carries flux from tocopherol to CEHC, as on develop.