MTRR encodes methionine synthase reductase (MSR), a cytosolic, NADPH-dependent diflavin oxidoreductase of the ferredoxin-NADP(+)-reductase (FNR)/dual-flavin family, closely related to the reductase domains of NADPH-cytochrome P450 reductase and nitric oxide synthase. Each polypeptide binds one FAD and one FMN and passes reducing equivalents from NADPH through its flavin centres. Its physiological role is to keep cobalamin-dependent methionine synthase (MTR/MS) catalytically active: during MTR turnover the enzyme-bound cob(I)alamin intermediate is occasionally oxidised to inactive cob(II)alamin, and MSR regenerates the active methylcob(III)alamin form by reductive methylation, using NADPH-derived electrons with S-adenosyl-L-methionine as the methyl donor. MSR also acts as an aquacobalamin reductase (reducing aquacob(III)alamin to cob(II)alamin) and as a molecular chaperone that stabilises apo-methionine synthase and promotes incorporation of cobalamin to form the holoenzyme. Cytosolic cobalamin processing occurs within a multiprotein complex that includes MTR, MTRR, MMACHC and MMADHC. Through the reactivation of methionine synthase, MTRR is essential for remethylation of homocysteine to methionine and for the linked folate and methylation (S-adenosylmethionine) cycles. Loss-of-function variants cause cblE-type homocystinuria with megaloblastic anaemia, and a common polymorphism (Ile22Met) is associated with neural tube defect susceptibility.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0050667 homocysteine metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation placing MTRR in homocysteine metabolism. MTRR reactivates methionine synthase, which remethylates homocysteine to methionine, so the protein is a bona fide participant in homocysteine metabolism. Supported by the disease phenotype (hyperhomocysteinaemia in cblE deficiency) and by direct biochemistry. Reason: Correct process-level annotation consistent with experimental evidence and the cblE disease phenotype. MTRR is required for the homocysteine-remethylating activity of methionine synthase. Supporting Evidence: PMID:9501215 Patients of the cblE complementation group of disorders of folate/cobalamin metabolism who are defective in reductive activation of methionine synthase exhibit megaloblastic anemia, developmental delay, hyperhomocysteinemia, and hypomethioninemia. |
| GO:0071265 L-methionine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation to L-methionine biosynthesis. By reactivating methionine synthase, MTRR is required for de novo remethylation of homocysteine to methionine; this is one of its core biological roles. Reason: Well supported: MTRR is necessary for methionine synthase activity, and its deficiency causes hypomethioninemia. This is a core process for MTRR. Supporting Evidence: PMID:16769880 Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR) |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA localisation to the cytosol. MTRR is a soluble cytosolic protein that acts on cytosolic methionine synthase; direct immunofluorescence and biochemical studies confirm cytosolic localisation and exclude a mitochondrial pool. Reason: Consistent with the experimental IDA localisation (PMID:18221906) and with the cytosolic location of its target methionine synthase. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0050660 flavin adenine dinucleotide binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for FAD binding. MTRR is a diflavin protein that binds one FAD per polypeptide; confirmed biochemically (equimolar FAD/FMN) and structurally (FAD in the FNR-like module crystal structure). Reason: Directly supported by experimental cofactor determination and crystallography. A core molecular function of this diflavin reductase. Supporting Evidence: PMID:11466310 is isolated with an equimolar concentration of FAD and FMN |
| GO:0010181 FMN binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for FMN binding. MTRR binds one FMN per polypeptide in its flavodoxin-like domain; the FMN domain is the module that docks onto methionine synthase for electron transfer. Reason: Supported by direct cofactor analysis; a core molecular function of this diflavin reductase. Supporting Evidence: PMID:11466310 is isolated with an equimolar concentration of FAD and FMN |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for the defining catalytic activity of MTRR, EC 1.16.1.8: NADPH-dependent reductive methylation of MTR-bound cob(II)alamin to regenerate active methylcob(III)alamin. This is the core molecular function of the gene. Reason: This is the precise, defining molecular function of MTRR, directly demonstrated biochemically and captured by IDA/EXP annotations to the same term. Core function. Supporting Evidence: PMID:11466310 we have cloned and expressed the cDNA encoding human methionine synthase reductase and demonstrate that it is sufficient for supporting NADPH-dependent activity of methionine synthase |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA localisation to cytoplasm from the UniProt Subcellular Location mapping. Consistent with, though less specific than, the experimentally supported cytosol annotations. Reason: Correct but broad; the more specific cytosol (GO:0005829) annotations are preferred. Retained as an accurate, if general, IEA localisation. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0009235 cobalamin metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) annotation placing MTRR in cobalamin metabolism. MTRR reduces and helps deliver the cobalamin cofactor of methionine synthase (and acts as an aquacobalamin reductase), so it is genuinely part of cytosolic cobalamin processing. Reason: Biologically correct: MTRR participates in the cytosolic cobalamin processing complex and reduces cobalamin cofactors. Duplicated by a Reactome TAS annotation. Supporting Evidence: PMID:27771510 the processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least MS, MSR, MMACHC and MMADHC |
| GO:0010181 FMN binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO IEA for FMN binding, from flavodoxin-like domain signatures. Correct and duplicates the IBA/IDA FMN binding annotations. Reason: Domain-based IEA consistent with experimental evidence for FMN binding. Supporting Evidence: PMID:11466310 is isolated with an equimolar concentration of FAD and FMN |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO IEA for the broad parent term oxidoreductase activity. MTRR is an oxidoreductase, but this term is far more general than the specific catalytic activity captured by GO:0030586 and by more specific redox terms. Reason: Not wrong, but uninformatively general given the specific [methionine synthase] reductase (NADPH) activity (GO:0030586) and NADPH-hemoprotein reductase activity annotations already present. Kept as a broad IEA but flagged as over-general. Supporting Evidence: PMID:17892308 functions in the sequential transfer of reducing equivalents from NADPH to MS via its flavin centers |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined-IEA annotation (EC 1.16.1.8 / RHEA mapping) to the defining catalytic activity. Correct and matches the curated experimental EC assignment. Reason: Accurate EC/RHEA-derived assignment of the core catalytic function; duplicates the IBA/EXP/IDA/TAS annotations to GO:0030586. Supporting Evidence: PMID:17892308 Human methionine synthase reductase (MSR) is a 78 kDa flavoprotein that regenerates the active form of cobalamin-dependent methionine synthase (MS) |
| GO:0046655 folic acid metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) annotation to folic acid metabolism. MTRR affects folate pool distribution because methionine synthase consumes 5-methyltetrahydrofolate; loss of MTRR causes accumulation of methyltetrahydrofolate (methyl-folate trap). Reason: Biologically supported: MTRR deficiency deranges folate metabolism via the methyl-folate trap. Duplicated by IDA and ISS annotations to the same term. Supporting Evidence: PMID:17369066 Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate |
| GO:0050667 homocysteine metabolic process | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) duplicate of the IBA homocysteine metabolic process annotation. Correct process-level annotation. Reason: Consistent with experimental and phylogenetic evidence; duplicates the IBA annotation to the same term. Supporting Evidence: PMID:9501215 Regeneration of functional enzyme requires reductive methylation via a reaction in which S-adenosylmethionine is utilized as a methyl donor. |
| GO:0170033 obsolete L-amino acid metabolic process | IEA GO_REF:0000117 | REMOVE | Summary: IEA (ARBA) annotation to an obsolete/very general amino-acid metabolism term. This adds no useful information beyond the specific methionine biosynthesis annotations. Reason: The term is obsolete and uninformatively broad; the specific L-methionine biosynthetic process (GO:0071265) and homocysteine annotations already capture the relevant biology. This over-propagated electronic annotation should be dropped. |
| GO:0009235 cobalamin metabolic process | TAS Reactome:R-HSA-9759218 | ACCEPT | Summary: Reactome TAS annotation to cobalamin metabolism (Cobalamin (Cbl) metabolism pathway). MTRR reduces the cobalamin cofactor and participates in the cytosolic cobalamin processing complex. Reason: Biologically correct and supported by the reactivation/aquacobalamin-reductase biochemistry and the MTR-MTRR-MMACHC-MMADHC complex. Duplicates the IEA cobalamin annotation. Supporting Evidence: PMID:16769880 MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence IDA localising MTRR to the cytosol, consistent with the MGI IDA and the antibody/immunofluorescence study demonstrating a cytosolic-only pool. Reason: Direct experimental localisation; core cellular location for this soluble cytosolic reductase. Supporting Evidence: PMID:18221906 antibodies to MSR protein localized MSR to the cytosol, but not to the mitochondria |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | EXP PMID:16769880 Human methionine synthase reductase is a molecular chaperone... | ACCEPT | Summary: Experimental annotation for the defining reductase activity, from the study demonstrating that recombinant human MSR maintains human MS activity in an NADPH-dependent manner and also reduces aquacobalamin. Reason: Directly experimentally demonstrated core catalytic function. Supporting Evidence: PMID:16769880 hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K(act) value of 71 nM |
| GO:0140104 molecular carrier activity | EXP PMID:21071249 Interaction between MMACHC and MMADHC, two human proteins pa... | MARK AS OVER ANNOTATED | Summary: Reactome-assigned EXP annotation to the very general term molecular carrier activity, cited to a paper on the MMACHC-MMADHC interaction. MTRR's demonstrated molecular function is that of a diflavin reductase/electron-transfer enzyme, not a substrate carrier; its role in the cobalamin-shuttling complex is better captured by its reductase activity and cobalamin-metabolism process annotations. The cited reference (PMID:21071249) characterises MMACHC and MMADHC and does not establish a carrier molecular function for MTRR. Reason: molecular carrier activity is an uninformative, non-core MF for MTRR and is not supported by the cited publication as a molecular function of MTRR. Its participation in cobalamin trafficking is more accurately represented by the reductase activity (GO:0030586) and cobalamin metabolic process (GO:0009235) annotations. Flagged as an over-annotation rather than removed, as it derives from a curated Reactome pathway model of the trafficking complex. Supporting Evidence: PMID:27771510 the processing of Cbl in cytoplasm occurs in a multiprotein complex composed of at least MS, MSR, MMACHC and MMADHC |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174374 | ACCEPT | Summary: Reactome TAS cytosol localisation (reaction: MTR transfers CH3 from MeCbl to HCYS). Correct compartment for the methionine synthase reaction that MTRR serves. Reason: Correct cytosolic localisation consistent with experimental IDA evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3149518 | ACCEPT | Summary: Reactome TAS cytosol localisation (reaction: MTRR reduces cob(II)alamin to meCbl), the reaction directly catalysed by MTRR, in the cytosol. Reason: Correct cytosolic localisation for the MTRR-catalysed reaction; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3149539 | ACCEPT | Summary: Reactome TAS cytosol localisation (reaction: MTR transfers CH3 from 5-methyl-THF to cob(I)alamin). Correct cytosolic compartment. Reason: Correct cytosolic localisation; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3204318 | ACCEPT | Summary: Reactome TAS cytosol localisation (reaction: cob(II)alamin transferred from MMACHC:MMADHC:cob(II)alamin to MTRR:MTR), reflecting the cytosolic cobalamin handoff complex. Reason: Correct cytosolic localisation for the trafficking complex; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3318563 | ACCEPT | Summary: Reactome TAS cytosol localisation (disease reaction: Defective MTRR does not convert cob(II)alamin to MeCbl). Correct cytosolic compartment. Reason: Correct cytosolic localisation; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3321918 | ACCEPT | Summary: Reactome TAS cytosol localisation (disease reaction: Defective MTR does not transfer CH3 group from MTHF to cob(I)alamin). Correct cytosolic compartment. Reason: Correct cytosolic localisation; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-3322140 | ACCEPT | Summary: Reactome TAS cytosol localisation (disease reaction: Defective MTR does not transfer CH3 group from MeCbl to HCYS). Correct cytosolic compartment. Reason: Correct cytosolic localisation; consistent with experimental evidence. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005829 cytosol | IDA PMID:18221906 Restricted role for methionine synthase reductase defined by... | ACCEPT | Summary: Direct experimental IDA localising MTRR to the cytosol by immunofluorescence and Western blot, explicitly excluding a mitochondrial pool despite an alternatively spliced isoform with a putative N-terminal extension. Reason: Strong, direct experimental localisation; the definitive study establishing that MTRR is a cytosol-restricted protein. Supporting Evidence: PMID:18221906 antibodies to MSR protein localized MSR to the cytosol, but not to the mitochondria of human fibroblasts or the human hepatoma line Huh-1 |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | IDA PMID:9501215 Cloning and mapping of a cDNA for methionine synthase reduct... | ACCEPT | Summary: IDA (MGI) for the defining reductase activity, tied to the cloning study that identified MTRR as the reducing system required to maintain methionine synthase in a functional state and confirmed by cblE mutations. Reason: Core catalytic function, established by cloning plus disease-causing mutations in cblE patients. Defer to the curator (full text read). Supporting Evidence: PMID:9501215 we have cloned a cDNA corresponding to the "methionine synthase reductase" reducing system required for maintenance of the methionine synthase in a functional state |
| GO:0005829 cytosol | IDA PMID:18221906 Restricted role for methionine synthase reductase defined by... | ACCEPT | Summary: Direct experimental IDA (is_active_in) for cytosolic localisation of MTRR, from the same subcellular localisation study. Reason: Direct experimental evidence that MTRR functions in the cytosol; core location. Supporting Evidence: PMID:18221906 These data confirm that MSR protein is restricted to the cytosol |
| GO:0005515 protein binding | IPI PMID:27771510 Methionine synthase and methionine synthase reductase intera... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the study demonstrating MTRR (MSR) interactions with MMACHC and MMADHC (and confirming the known MTR interaction) within the cytosolic cobalamin processing complex. The generic protein binding term is uninformative about the specific molecular function. Reason: Bare protein binding (GO:0005515) conveys no specific molecular function; per curation guidelines it is not a core function. The underlying interactions (MMACHC/MMADHC/MTR) are real and biologically informative, and are better captured by the cobalamin metabolic process and reductase-activity annotations. Retained (not removed) as an experimental IPI whose interaction data are valid. Supporting Evidence: PMID:27771510 we also observed novel interactions for MSR with MMACHC and with MMADHC |
| GO:0005515 protein binding | IPI PMID:17288554 Crystal structure and solution characterization of the activ... | MARK AS OVER ANNOTATED | Summary: IPI protein-binding annotation from the structural study showing that the human methionine synthase activation domain interacts with the FMN-binding domain of MTRR (MSR), an interaction enhanced by S-adenosylmethionine. This is the functionally critical MTR-MTRR docking interaction, but the generic protein binding term does not convey it. Reason: Bare protein binding is uninformative; the underlying MTR-MTRR interaction is genuine and central to reactivation, and is captured functionally by the reductase-activity and methionine-biosynthesis annotations. Retained as a valid experimental IPI. Supporting Evidence: PMID:17288554 human activation domain interacts with the FMN-binding domain of human methionine synthase reductase (hMSR) |
| GO:0033353 L-methionine cycle | ISS PMID:17369066 Metabolic derangement of methionine and folate metabolism in... | ACCEPT | Summary: ISS annotation (transferred from mouse Mtrr, UniProtKB:Q8C1A3) placing MTRR in the L-methionine cycle. The mouse knockdown study shows the expected methionine cycle derangement (elevated homocysteine, reduced methionine, folate changes). Reason: Correct pathway-level annotation supported by the mouse ortholog metabolic phenotype and by MTRR's essential role in the remethylation arm of the methionine cycle. Supporting Evidence: PMID:17369066 Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma methionine |
| GO:0003958 NADPH-hemoprotein reductase activity | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for NADPH-hemoprotein reductase activity, reflecting MSR's P450-reductase-like diflavin architecture and its NADPH-dependent cytochrome c reductase activity (a diagnostic assay for this enzyme family). MTRR is a P450-reductase-like dual flavoprotein. Reason: Supported by the demonstrated NADPH-dependent electron-transfer/cytochrome c reductase activity of MSR and its membership in the P450-reductase-like diflavin family. Reflects the generic diflavin electron-transfer chemistry; the MTRR-specific activity is GO:0030586. Supporting Evidence: PMID:11466310 It is a member of the family of dual flavoproteins |
| GO:0010181 FMN binding | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for FMN binding, from the biochemical characterisation showing MSR is isolated with equimolar FAD and FMN. Direct experimental support for the core cofactor-binding function. Reason: Direct experimental cofactor determination; core molecular function. Supporting Evidence: PMID:11466310 is isolated with an equimolar concentration of FAD and FMN |
| GO:0046655 folic acid metabolic process | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for folic acid metabolic process. MSR is required for methionine synthase activity, which consumes 5-methyltetrahydrofolate; loss of function traps folate as methyl-THF, connecting MTRR to folate metabolism. Reason: Supported by the enzyme's role in the folate/methionine one-carbon cycle; duplicated by IEA and ISS annotations to the same term. Full text read by curator. Supporting Evidence: PMID:17369066 increased tissue methyltetrahydrofolate |
| GO:0071949 FAD binding | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for FAD binding, from the biochemical characterisation showing equimolar FAD/FMN content. Direct experimental support for the core cofactor-binding function. Reason: Direct experimental cofactor determination; core molecular function. (GO:0071949 FAD binding and GO:0050660 flavin adenine dinucleotide binding both capture FAD binding.) Supporting Evidence: PMID:11466310 is isolated with an equimolar concentration of FAD and FMN |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for the defining reductase activity, from the study showing recombinant human MSR alone is sufficient to support NADPH-dependent methionine synthase activity. Direct evidence for the core catalytic function. Reason: Direct experimental demonstration of the core molecular function. Supporting Evidence: PMID:11466310 demonstrate that it is sufficient for supporting NADPH-dependent activity of methionine synthase |
| GO:0043418 L-homocysteine catabolic process | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) placing MTRR in homocysteine catabolism. By reactivating methionine synthase, MTRR enables the remethylation of homocysteine to methionine, i.e. consumption/catabolism of homocysteine. Reason: Consistent with MTRR's role in enabling homocysteine remethylation; supported by the cblE hyperhomocysteinaemia phenotype. Full text read by curator. Supporting Evidence: PMID:9501215 Methionine synthase catalyzes the remethylation of homocysteine to methionine |
| GO:0070402 NADPH binding | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for NADPH binding. MSR uses NADPH as its physiological electron donor (low-micromolar KM), and the NADP(H)-binding site is defined crystallographically. Direct experimental support. Reason: Supported by kinetic (KM for NADPH) and structural NADP(H)-binding data; a core cofactor/substrate-binding function of this NADPH-dependent reductase. Supporting Evidence: PMID:11466310 The K(m) for NADPH is 2.6 +/- 0.5 microm |
| GO:0071265 L-methionine biosynthetic process | IDA PMID:11466310 Human methionine synthase reductase, a soluble P-450 reducta... | ACCEPT | Summary: IDA (BHF-UCL) for L-methionine biosynthesis, reflecting that MSR is sufficient to support NADPH-dependent methionine synthase activity (the methionine-forming reaction). Duplicates the IBA annotation to the same term. Reason: Supported experimentally; core biological process for MTRR. Supporting Evidence: PMID:11466310 demonstrate that it is sufficient for supporting NADPH-dependent activity of methionine synthase |
| GO:0046655 folic acid metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation (transfer from mouse Mtrr, UniProtKB:Q8C1A3) to folic acid metabolism. Consistent with the IDA/IEA annotations and the folate derangement in the mouse model. Reason: Correct process-level annotation supported by ortholog data; duplicates IDA and IEA folic acid annotations. Supporting Evidence: PMID:17369066 increased tissue methyltetrahydrofolate |
| GO:0016723 oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor | IDA PMID:17892308 Mechanism of coenzyme binding to human methionine synthase r... | KEEP AS NON CORE | Summary: IDA for oxidoreductase activity acting on metal ions with NAD/NADP as acceptor. This class fits MTRR's chemistry: it transfers electrons from NADPH to the metal (cobalt) centre of cobalamin. It is a reasonable higher-level classification of the MTRR catalytic mechanism, though less specific than GO:0030586. Reason: Chemically accurate parent-class description of the electron transfer from NADPH to the cobalamin cobalt centre, but the specific MTRR activity is better captured by GO:0030586 (the core term). Retained as an accurate, non-core generalisation. Supporting Evidence: PMID:17892308 functions in the sequential transfer of reducing equivalents from NADPH to MS via its flavin centers |
| GO:0030586 [methionine synthase] reductase (NADPH) activity | TAS PMID:17892308 Mechanism of coenzyme binding to human methionine synthase r... | ACCEPT | Summary: TAS annotation to the defining reductase activity, from the crystallographic / ITC study of the FNR-like module that also confirmed EC 1.16.1.8 catalytic activity. Correct core function. Reason: Core catalytic function, well supported structurally and enzymatically; duplicates IBA/IDA/EXP/IEA annotations to GO:0030586. Supporting Evidence: PMID:17892308 regenerates the active form of cobalamin-dependent methionine synthase (MS) |
| GO:0050660 flavin adenine dinucleotide binding | IDA PMID:17892308 Mechanism of coenzyme binding to human methionine synthase r... | ACCEPT | Summary: IDA for FAD binding from the crystal structure of the FNR-like (FAD-binding) module of MSR with defined FAD-binding residues. Direct structural support. Reason: Direct structural evidence of FAD binding; core molecular function. Duplicates the IBA and GO:0071949 FAD-binding annotations. Supporting Evidence: PMID:17892308 MSR contains one FAD and one FMN cofactor per polypeptide |
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