Human 2.1.0

Erratum (added 2026-10)

Model files. Human-GEM.mat and Human-GEM.xml of this release are incomplete, as in v2.0.1. Use the files of v2.1.1, which has the same model and restores the missing content (#1145), or read model/Human-GEM.yml with raven-toolbox or RAVEN.

• Human-GEM.mat is a COBRA Toolbox structure with 23 fields instead of 33. It has no id, name, version, date, annotation, eccodes, rxnNotes, rxnReferences, rxnConfidenceScores, inchis, metFrom, rxnFrom or geneShortNames.
• Human-GEM.xml has no subsystems (no SBML groups). Reaction references and confidence scores are only in notes, which RAVEN's importModel does not read.

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Short summary:

This release contains three sets of changes:

• Structural model curation, most of it from a systematic review of reactions, metabolites and gene-reaction rules against literature and curated databases (UniProt, Rhea, ChEBI). Every change is documented with its evidence in the linked issues.
  • Energy metabolism and redox: #1028, #1081, #1094, #1099
  • Transport and compartments: #1039, #1041, #1047, #1095, #1100, #1116
  • Lipids, sterols and bile acids: #1040, #1088, #1096, #1105, #1106
  • Vitamins and cofactors: #1044, #1096, #1121
  • Carbohydrates, amino acids and other pathways: #1030, #1038, #1043, #1089, #1093
  • Metabolite identity, structure and duplicates: #1090, #1104, #1107
  • Earlier curation (#418) and outstanding gene associations: #1033, #1093
• Non-structural model changes:
  • Diffusion transports and non-enzymatic reactions are flagged as spontaneous, so that context-specific model extraction keeps them without a gene: #1101, #1103
  • ModelSEED reaction and compound cross-references, and corrected cross-references: #1086, #1087
  • Each metabolite's InChI is exported to the model files: #1084
• Improvements and maintenance of the Human-GEM repo:
  • Gene essentiality is scored per task category, with context-specific models built on Gurobi with a deterministic tie-break, run in parallel per cell line, and reported as a scoped diff in the pull request: #1077, #1079, #1080, #1082, #1091, #1092
  • Model QC checks growth on a capped Ham's medium, labels the MEMOTE score, and reports reactions whose chemistry is split across compartments: #1095, #1097, #1098
  • A human_gem Python package with load_model(): #1069
  • Clean-up of legacy code and task files: #1068, #1070
  • The release itself is automated, with an SBML round-trip gate, a naming check and unit tests for the QC code: #1078, #1122

	2.0.1	2.1.0
Reactions	12877	12748
Metabolites	8460	8374
Genes	2848	2870

Compared with 2.0.1, 26 reactions were added and 155 removed (duplicates, unsupported or chemically incorrect reactions), 211 reactions had their stoichiometry corrected, 130 their gene-reaction rule, and 257 metabolite entries (119 metabolites over all compartments) their formula or charge.

Longer details

Each reaction, metabolite and gene that differs between 2.0.1 and 2.1.0 is listed once, with its final change, under the last pull request that changed it; removed identifiers are kept in data/deprecatedIdentifiers/. Changes to names and annotations (cross-references, EC numbers, references, InChI, the spontaneous flag) are not listed per entity. Metabolite merges are written as base ids ("A → B" merges A into B in every compartment where it occurred).

• Fix (PR #1121)
  • Curate the vitamin D C-23 lactone and 24-oxo pathway, extracellular FAD hydrolysis and the 9-cis-retinol dehydrogenases, as discussed in #887
    • Assign the mitochondrial C-23 and 24-oxo steps to CYP24A1, and correct their cofactors, stoichiometry and direction (MAR02130, MAR02132, MAR02134, MAR02136, MAR02143, MAR02145)
    • Remove the cytosolic copies of the pathway, which lack evidence (MAR02129, MAR02131, MAR02133, MAR02135, MAR02137, MAR02139, MAR02142, MAR02144), and their cytosolic intermediates (MAM00607c, MAM00608c, MAM00611c, MAM00612c, MAM00621c, MAM00622c, MAM01416c)
    • Take the vitamin D catabolites of the biomass vitamin pool from the mitochondria, in the same total amount (MAR10065, MAR00033)
    • Replace ENPP1 with NT5E for extracellular FAD hydrolysis (MAR08968); remove SDR16C5 from the 9-cis-retinol dehydrogenases (MAR01690, MAR06644); add CYP4V2 to palmitate ω-hydroxylation (MAR08038)
• Fix (PR #1116)
  • Separate the Ca2+ ATPases by membrane and add Ca2+ release from the ER and Golgi, as discussed in #1000
    • Add the SERCA and SPCA Ca2+ ATPases into the ER and Golgi, and Ca2+ release from both (MAR20212–MAR20216)
    • Remove MAR07629 (merged into MAR00119, now the plasma-membrane PMCA)
    • Add Ca2+ in the ER and Golgi (MAM01413r, MAM01413g)
    • Add genes ITPR1, ITPR2, ITPR3, RYR1, RYR2, RYR3, TMCO1
• Fix (PR #1107)
  • Correct metabolite identity, structure and cross-reference errors that predate 2.0.1, as documented in #1113, #1114 and #1115
    • Merge the duplicate glycolipid MAM01999 → MAM03578, and "Galactosyl Glucosyl Ceramide" MAM03586 → LacCer pool MAM02328, in their reactions (MAR03253, MAR08271, MAR08272, MAR08273, MAR08287, MAR09320, MAR12035, MAR12048, MAR12049, MAR12064, MAR12070)
    • Remove reactions that became duplicates through these merges (MAR00595, MAR00766, MAR01076, MAR01078, MAR01118, MAR01141, MAR01348, MAR01349, MAR01351, MAR12053, MAR12065, MAR12132)
    • Assign globotriaosylceramide hydrolysis to GLA and PSAP (MAR00804); set the GPR of MAR08271 to FUT3 or FUT5
    • Represent statins and their metabolites as free acids instead of sodium or calcium salts, correcting formula and charge (MAM03198, MAM03235, MAM03236, MAM03237, MAM03238, MAM03241, MAM03279, MAM03280, MAM03285, MAM03286, MAM03294, MAM03305, MAM03306, MAM03312, MAM03514, MAM03515, MAM03516, MAM03517, MAM03518, MAM03519, MAM03523, MAM03524, MAM03546, MAM03547, MAM03566, MAM03579, MAM03580, MAM03581, MAM03582, MAM03583, MAM03780, MAM03892, MAM03893, MAM03911, MAM03912, MAM03913, MAM03914, MAM03915, MAM03916, MAM03917, MAM03918, MAM03919, MAM03920, MAM03985, MAM03998, MAM04007)
    • Rebalance the statin reactions for these structures, and write the cerivastatin lactone steps as hydrolysis or spontaneous lactonisation (MAR12360, MAR12538, MAR12540, MAR12542, MAR12544, MAR12549, MAR12557, MAR12558, MAR12561, MAR12720, MAR12724, MAR12792, MAR12809, MAR12812, MAR12813, MAR12815, MAR12817, MAR12818, MAR12829, MAR12830, MAR12832, MAR12833); add the GPR UGT1A1 or UGT1A3 or UGT2B7 to MAR12829
• Fix (PR #1106)
  • Correct reaction and GPR errors that predate 2.0.1, found in an evidence review, as documented in #1108–#1112
    • Separate D- and L-2-hydroxyglutarate: merge MAM00653 → (S)-2-hydroxyglutarate MAM03188, add (R)-2-hydroxyglutarate (MAM20012c, MAM20012e), add the D2HGDH, MDH and LDH reactions and their transport and exchange (MAR20204–MAR20211), and correct L2HGDH and D2HGDH (MAR00718, MAR00719); add gene D2HGDH
    • Remove reactions without evidence, or duplicates of other reactions (MAR00117, MAR00118, MAR01444 (into MAR08892), MAR01578, MAR01597, MAR01604 (into MAR01605), MAR01609 (into MAR01610), MAR01613 (into MAR01614), MAR01781, MAR01783, MAR01785, MAR01786 (into MAR01762), MAR01787, MAR02184, MAR02302, MAR02881, MAR02895, MAR03210 (into MAR01611), MAR03214 (into MAR01614), MAR03259, MAR04696, MAR04697, MAR04698, MAR06989 (into MAR08924), MAR08193, MAR08194, MAR08195, MAR08196, MAR08197, MAR08512, MAR08922, MAR10395, MAR20031 (into MAR08034))
    • Write hydrolysis and oxidation steps in their physiological direction and make them irreversible (MAR01332, MAR01333, MAR01334, MAR01335, MAR20018)
    • Correct stoichiometry and cofactors (MAR00035, MAR01453, MAR01500, MAR01610, MAR02301, MAR07029, MAR07092, MAR07093, MAR07097, MAR08201, MAR08671, MAR08892, MAR11733); merge hydrochloride MAM02144 → chloride MAM01442
    • Correct GPRs (MAR00115, MAR01453, MAR01608, MAR07796, MAR08780, MAR11731, MAR11733, MAR20018), and remove GPRs without evidence for the reaction (MAR01611, MAR03819, MAR03820, MAR04535, MAR07634, MAR08096, MAR08476); remove genes NUP210L, NUP62CL
    • Remove metabolites left unused (MAM00592m, MAM00592r, MAM01019r, MAM01182m, MAM01391c, MAM01391g, MAM01391l, MAM01394c, MAM02525g, MAM02754r)
• Fix (PR #1105)
  • Corrections to curation made since 2.0.1, from an evidence review against literature and curated databases; each correction is documented on its original pull request and issue
    • Remove the reactions that duplicate the vesicular neurotransmitter transports (MAR07633, MAR07634, MAR07635, MAR07636, MAR07637, MAR07681, MAR07736, MAR07737, MAR07738): MAR00052, MAR00058, MAR00065, MAR00087, MAR00334, MAR01314, MAR01396, MAR01442, MAR01555
    • Remove reactions without evidence, or duplicates (MAR00751 (into MAR06346), MAR01518, MAR01857, MAR01861, MAR03161, MAR03928 (into MAR06515), MAR04840, MAR06815 (into MAR12023), MAR06817 (into MAR12020), MAR08317 (into MAR00082), MAR08365)
    • Add sulfurtransferase TST acting on thiosulfate (MAR20203); merge H2S2O3 MAM02043 → thiosulfate MAM02991
    • Write reactions in their physiological direction and make them irreversible (MAR01310, MAR01315, MAR01318, MAR04554, MAR06712, MAR06742, MAR06807, MAR06877, MAR08024, MAR10406, MAR12022), or make them reversible (MAR02222, MAR07750, MAR07752, MAR08364, MAR09017, MAR09674, MAR11506, MAR12091, MAR12119)
    • Correct stoichiometry and cofactors (MAR00036, MAR01307, MAR01392, MAR01393, MAR06435, MAR06451, MAR06744, MAR09873, MAR09886)
    • Merge duplicate melanin intermediates: MAM03270 → MAM01136 and dopaminochrome MAM01739x → MAM01739c, in MAR06813, MAR06814, MAR12023, MAR12025, MAR12026; merge I-antigen MAM03584 → MAM02186, in MAR00082, MAR01083
    • Correct GPRs of the retinoic acid hydroxylases (MAR06664, MAR06665, MAR06681, MAR06682, MAR06700, MAR06701, MAR06702, MAR06703), the vitamin E β-oxidation reactions (MAR06434, MAR06435, MAR06436, MAR06450, MAR06451, MAR06453, MAR06472, MAR06473, MAR06486, MAR06488), the lactate dehydrogenases (MAR05351, MAR11476, MAR11479) and bile acid transport (MAR10101, MAR10103, MAR10119)
    • Add GPRs where the gene is known (MAR03946, MAR04049, MAR04873, MAR06346, MAR08024, MAR08034, MAR08408, MAR11311, MAR13002); add genes AQP11, CYP26C1, IPO4, TRPV5, TRPV6
    • Correct the formula and charge of MAM02599c
• Fix (PR #1104)
  • Curate metabolite structure, formula and identity inconsistencies, as discussed in #1085
    • Correct the formula or charge of 61 metabolites so that they match their structure (MAM01163, MAM01210, MAM02673, MAM02915, MAM02916, MAM03169, MAM03170, MAM03295, MAM03404, MAM03414, MAM03598, MAM03599, MAM03738, MAM03798, MAM03805–MAM03835, MAM03898, MAM03901, MAM03933, MAM03936–MAM03951, MAM04028, MAM04081)
    • Merge duplicates: MAM03652 → palmitoylethanolamide MAM03885, MAM20017 → MAM20015, MAM20077 → MAM20089; remove methylcobalamin MAM03322c
    • Rebalance reactions for these structures (MAR01070, MAR04599, MAR05427, MAR06350, MAR08993, MAR11099, MAR11142, MAR11188, MAR12993, MAR20019, MAR20093, MAR20173); remove MAR03138 (merged into MAR09550)
• Feat (PR #1100)
  • Associate small-solute peroxisomal transport with PXMP2
    • Set the GPR to PXMP2 (MAR00056, MAR01566, MAR01626, MAR03848, MAR03850, MAR03948, MAR04393, MAR04443, MAR04468, MAR04469, MAR04515, MAR04647, MAR04790, MAR05346, MAR05414, MAR06805, MAR06821, MAR06928, MAR06937, MAR06986, MAR06987, MAR07640, MAR07705, MAR07707, MAR07797, MAR08016, MAR08020, MAR08754, MAR08860, MAR08977, MAR08980, MAR09179, MAR09181, MAR09679, MAR09680, MAR11531, MAR11536, MAR11541, MAR11845, MAR11980); add gene PXMP2
• Fix (PR #1099)
  • Balance reactions that break stoichiometric consistency, as discussed in #837
    • Represent the glycine cleavage system H protein explicitly (MAR06402, MAR08433, MAR08434, MAR20168; add MAM20087m, merge MAM02878 → MAM20088), and balance MAR20189
    • Correct the formulas of thiamine-bound intermediates (MAM20078m, MAM20079m, MAM20080m, MAM20081m, MAM20082m)
• Fix (PR #1096)
  • Vitamin E side-chain β-oxidation, as discussed in #738
    • Assign ω-hydroxylation to CYP4F2 and remove its cytosolic duplicates (MAR06427, MAR06429, MAR06442, MAR06444, MAR06465, MAR06467, MAR06477, MAR06479; remove MAR06426, MAR06428, MAR06441, MAR06443, MAR06464, MAR06466, MAR06476, MAR06478); merge the cytosolic 13-hydroxy intermediates into the ER (MAM00356, MAM00357, MAM00360, MAM00361)
    • Use FAD instead of O2 as electron acceptor in the mitochondrial steps (MAR06433, MAR06436, MAR06448, MAR06453, MAR06470, MAR06471, MAR06472, MAR06473, MAR06482, MAR06484, MAR06486, MAR06488), and correct their GPRs (MAR06432, MAR06433, MAR06447, MAR06448, MAR06470, MAR06471, MAR06482, MAR06484)
• Fix (PR #1095)
  • Curate reactions whose chemistry was split across compartments, found by a new QC check, as discussed in #880
    • Merge MAM01915 → MAM01884 and MAM03231 → MAM03232 (MAR08298, MAR08299), correct MAR06779, and assign MAR00081 to B4GALT1–4
    • Remove the duplicates MAR01340 (into MAR08299), MAR08279 (into MAR00081), MAR08300 (into MAR09646), MAR09333 (into MAR09698), MAR10470 (into MAR10373), MAR10473 (into MAR10426); add MAM02186g
• Fix (PR #1094)
  • Use NADPH in the CYP2E1 fatty-acid ω-hydroxylations, as discussed in #992
    • Replace FMN/FMNH2 with NADP+/NADPH (MAR20021, MAR20023, MAR20025, MAR20027, MAR20029)
    • Remove the duplicates in the inner mitochondria compartment (MAR20022, MAR20024, MAR20026, MAR20028, MAR20030, MAR20032) and their metabolites (MAM01019i, MAM01689i, MAM01784i, MAM01828i, MAM02040i, MAM02344i, MAM02457i, MAM02494i, MAM02554i, MAM02555i, MAM02630i, MAM02754i, MAM20019i, MAM20021i, MAM20025i, MAM20027i, MAM20029i, MAM20031i), and FMN/FMNH2 in the ER (MAM01828r, MAM20019r)
• Fix (PR #1093)
  • Apply the remaining curations from #418
    • Move MAR03859 to the mitochondria; make MAR05113 reversible; remove MAR08514; remove gene CYB5D1
• Fix (PR #1090)
  • One base id per metabolite, and correct the cytochrome c and water MetaNetX ids, as discussed in #618, #626 and #1063
    • Merge duplicate metabolites: MAM00030 → MAM03388, MAM00382 → MAM00384, MAM00392 → MAM01892, MAM00435 → MAM03386, MAM00625 → MAM00623, MAM00678 → MAM03543, MAM00750 → MAM00751, MAM00942 → MAM03331, MAM01006 → MAM00993, MAM01067 → MAM04082, MAM01092 → MAM01090, MAM01392 → MAM03227, MAM02146 → MAM02174, MAM03032 → MAM03387, MAM03171 → MAM00074, MAM03276 → MAM01016, MAM03284 → MAM00103, MAM03353 → MAM00134, MAM03368 → MAM00748, MAM03553 → MAM03552, MAM03569 → MAM00008, MAM03571 → MAM01364, MAM03787 → MAM02387, MAM03790 → MAM02640, MAM03862 → MAM02723, MAM03971 → MAM03970, MAM03972 → MAM00118, MAM03978 → MAM01576, MAM04079 → MAM01468, MAM10026 → MAM03996, MAM10030 → MAM03685, MAM20005 → MAM20003, MAM20006 → MAM20004, MAM20009 → MAM20007, MAM20010 → MAM20008, MAM20016 → MAM20014, MAM20033 → MAM20032, MAM20035 → MAM20034, MAM20042 → MAM20041, MAM20044 → MAM20043, MAM20046 → MAM20045, MAM20048 → MAM20047, MAM20050 → MAM20049, MAM20052 → MAM20051, MAM20053 → MAM20013, MAM20055 → MAM20054, MAM20057 → MAM20056
    • Update the reactions that used them (MAR00729, MAR01328, MAR01455, MAR01505, MAR01509, MAR01539, MAR01540, MAR01608, MAR01611, MAR01614, MAR01762, MAR01764, MAR01765, MAR01804, MAR01805, MAR02818, MAR03294, MAR03321, MAR03412, MAR03758, MAR04003, MAR04039, MAR04043, MAR04970, MAR04974, MAR05111, MAR05120, MAR05175, MAR05188, MAR05193, MAR05373, MAR05374, MAR05376, MAR05378, MAR05379, MAR05383, MAR05402, MAR05403, MAR06598, MAR06599, MAR06600, MAR06793, MAR06794, MAR06924, MAR08607, MAR09656, MAR09713, MAR09953, MAR09954, MAR10023, MAR10024, MAR10083, MAR10087, MAR10101, MAR10103, MAR10105, MAR10106, MAR10107, MAR10119, MAR10161, MAR10224, MAR10228, MAR10353, MAR11230, MAR11285, MAR11752, MAR20006, MAR20008, MAR20010, MAR20034, MAR20036, MAR20047, MAR20050, MAR20054, MAR20056, MAR20058, MAR20060, MAR20061, MAR20063, MAR20065)
    • Remove the 34 reactions that became duplicates: MAR01338 (into MAR01334), MAR01784 (into MAR01762), MAR01797 (into MAR01765), MAR01802 (into MAR01605), MAR01803 (into MAR01608), MAR01806, MAR03209, MAR03420 (into MAR01540), MAR03766 (into MAR01804), MAR03768 (into MAR01805), MAR03815 (into MAR01611), MAR07052 (into MAR04039), MAR07055 (into MAR04043), MAR07056 (into MAR04049), MAR08543 (into MAR06794), MAR08544 (into MAR06793), MAR08700 (into MAR06700), MAR09934 (into MAR01328), MAR09941 (into MAR08796), MAR09945 (into MAR03577), MAR09948 (into MAR00430), MAR10166 (into MAR00431), MAR10167 (into MAR00428), MAR10423 (into MAR08798), MAR10424 (into MAR09449), MAR10455 (into MAR01764), MAR11527 (into MAR10161), MAR11528 (into MAR10224), MAR12221 (into MAR10087), MAR12230 (into MAR10083), MAR12262 (into MAR10103), MAR12264 (into MAR10119), MAR12294 (into MAR10101), MAR13041 (into MAR10228)
    • Carry over the GPRs of the removed duplicates (MAR01328, MAR04039, MAR04043, MAR08607)
• Fix (PR #1089)
  • Merge the duplicate galactose-1-phosphate and curate the galactose pathway GPRs, as discussed in #400
    • Merge MAM01911 → MAM01322; remove MAR04132 (into MAR04131), MAR04414 (into MAR04130); set the GPR of MAR08767 to UGP2; remove gene FAM227B
• Fix (PR #1088)
  • Correct two metabolite compartments and curate the NAAA ceramidase GPRs
    • Merge MAM20076n → MAM20076c (MAR20096); move MAM00208m to the mitochondria; set the GPR of MAR20096 and MAR20097 to ASAH1, ASAH2, ACER2 or NAAA
• Fix (PR #1081)
  • Route SQOR and CHDH through ubiquinone, and drop PRODH2 from the proline reactions, as discussed in #1015
    • Use ubiquinone instead of ETF (MAR08441, MAR20186); add PRODH2 on hydroxyproline (MAR20192); remove MAR08610
• Fix (PR #1047)
  • Add (S)-dihydroorotate transport and exchange, as discussed in #357
    • Add MAR20201, MAR20202 and MAM00180e
• Fix (PR #1044)
  • MAM01026 is 4-oxo-13-cis-retinoate: merge its duplicate and correct the CYP26 stoichiometry, as discussed in #375
    • Merge MAM00348 → MAM01026 and correct its formula; add MAM01031n
    • Add the 4-hydroxylation of 13-cis- and 9-cis-retinoate (MAR20197–MAR20200) with their products (MAM20090c, MAM20090r, MAM20091c, MAM20091r), and correct the CYP26 reactions that follow (MAR01563, MAR01564, MAR06664, MAR06665, MAR06681, MAR06682, MAR08704)
    • Remove MAR08703, MAR08706
• Feat (PR #1043)
  • Enable collagen secretion, as discussed in #335
    • Add procollagen export and exchange (MAR20195, MAR20196, MAM00232e); merge MAM02768 → MAM00204; remove MAR09553 (merged into MAR06983)
• Fix (PR #1041)
  • Correct the mechanism and stoichiometry of duplicate transport reactions, as discussed in #347
    • Remove duplicate transports: MAR00094 and MAR07667 (into MAR09609), MAR01636 and MAR08930 (into MAR09607), MAR02283 (into MAR01702), MAR02300 (into MAR00116), MAR09603 (into MAR09873), MAR09604 (into MAR09886), MAR02290, MAR02298
• Fix (PR #1040)
  • Remove charge-imbalanced duplicate lipoxygenase reactions, as discussed in #348
    • Remove MAR01355 (into MAR03882), MAR01358 (into MAR03878), MAR01361 (into MAR03884), MAR01364 (into MAR03880), MAR01405 (into MAR03261)
• Feat (PR #1039)
  • Add cellular succinate export via MCT proton symport (MAR20193), as discussed in #424
• Feat (PR #1033)
  • Associate the voltage-gated and store-operated Ca2+ channels with MAR11311, as discussed in #1001
    • Add genes CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, ORAI1, ORAI2, ORAI3
• Fix (PR #1030)
  • Remove the non-catalytic MAT2B from SAM synthesis (MAR03875, MAR07139), as discussed in #1013; remove gene MAT2B
• Fix (PR #1028)
  • Couple non-ETF flavoenzymes directly to ubiquinone, as discussed in #1015
    • Add ubiquinone-coupled GPD2 and PRODH (MAR00483, MAR03838) and remove the reactions they replace (MAR00449, MAR01169, MAR08611) and MAR08111; restrict the ETF:QO reaction MAR06911 to ETFA, ETFB and ETFDH; remove MAM01690m
• Feat (PR #1101, #1103)
  • Flag diffusion transports and non-enzymatic reactions as spontaneous (spontaneous column of reactions.tsv)
• Feat/fix (PR #1084, #1086, #1087)
  • Export each metabolite's InChI; add ModelSEED cross-references; add and correct reaction and metabolite cross-references
• Test and CI (PR #1068, #1069, #1070, #1077, #1078, #1079, #1080, #1082, #1091, #1092, #1097, #1098)
  • See the summary above