MTRR

id: Q9UBK8
gene_symbol: MTRR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: B
  id: Q9UBK8-2
- name: A
  id: Q9UBK8-1
  sequence_note: VSP_060027
existing_annotations:
- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9501215
      supporting_text: >-
        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.
- term:
    id: GO:0071265
    label: L-methionine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Well supported: MTRR is necessary for methionine synthase activity, and its
      deficiency causes hypomethioninemia. This is a core process for MTRR.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: >-
        Sustained activity of mammalian methionine synthase (MS) requires MS reductase
        (MSR)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with the experimental IDA localisation (PMID:18221906) and with the
      cytosolic location of its target methionine synthase.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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).
    action: ACCEPT
    reason: >-
      Directly supported by experimental cofactor determination and crystallography.
      A core molecular function of this diflavin reductase.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        is isolated with an equimolar concentration of FAD and FMN
- term:
    id: GO:0010181
    label: FMN binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Supported by direct cofactor analysis; a core molecular function of this
      diflavin reductase.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        is isolated with an equimolar concentration of FAD and FMN
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        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
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      IEA localisation to cytoplasm from the UniProt Subcellular Location mapping.
      Consistent with, though less specific than, the experimentally supported cytosol
      annotations.
    action: ACCEPT
    reason: >-
      Correct but broad; the more specific cytosol (GO:0005829) annotations are
      preferred. Retained as an accurate, if general, IEA localisation.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Biologically correct: MTRR participates in the cytosolic cobalamin processing
      complex and reduces cobalamin cofactors. Duplicated by a Reactome TAS annotation.
    supported_by:
    - reference_id: PMID:27771510
      supporting_text: >-
        the processing of Cbl in cytoplasm occurs in a multiprotein complex composed
        of at least MS, MSR, MMACHC and MMADHC
- term:
    id: GO:0010181
    label: FMN binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO IEA for FMN binding, from flavodoxin-like domain signatures. Correct
      and duplicates the IBA/IDA FMN binding annotations.
    action: ACCEPT
    reason: >-
      Domain-based IEA consistent with experimental evidence for FMN binding.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        is isolated with an equimolar concentration of FAD and FMN
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17892308
      supporting_text: >-
        functions in the sequential transfer of reducing equivalents from NADPH to
        MS via its flavin centers
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Combined-IEA annotation (EC 1.16.1.8 / RHEA mapping) to the defining catalytic
      activity. Correct and matches the curated experimental EC assignment.
    action: ACCEPT
    reason: >-
      Accurate EC/RHEA-derived assignment of the core catalytic function; duplicates
      the IBA/EXP/IDA/TAS annotations to GO:0030586.
    supported_by:
    - reference_id: PMID:17892308
      supporting_text: >-
        Human methionine synthase reductase (MSR) is a 78 kDa flavoprotein that
        regenerates the active form of cobalamin-dependent methionine synthase (MS)
- term:
    id: GO:0046655
    label: folic acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    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).
    action: ACCEPT
    reason: >-
      Biologically supported: MTRR deficiency deranges folate metabolism via the
      methyl-folate trap. Duplicated by IDA and ISS annotations to the same term.
    supported_by:
    - reference_id: PMID:17369066
      supporting_text: >-
        Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma
        methionine, and increased tissue methyltetrahydrofolate
- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      IEA (ARBA) duplicate of the IBA homocysteine metabolic process annotation.
      Correct process-level annotation.
    action: ACCEPT
    reason: >-
      Consistent with experimental and phylogenetic evidence; duplicates the IBA
      annotation to the same term.
    supported_by:
    - reference_id: PMID:9501215
      supporting_text: >-
        Regeneration of functional enzyme requires reductive methylation via a reaction
        in which S-adenosylmethionine is utilized as a methyl donor.
- term:
    id: GO:0170033
    label: obsolete L-amino acid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      IEA (ARBA) annotation to an obsolete/very general amino-acid metabolism term.
      This adds no useful information beyond the specific methionine biosynthesis
      annotations.
    action: REMOVE
    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.
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9759218
  qualifier: involved_in
  review:
    summary: >-
      Reactome TAS annotation to cobalamin metabolism (Cobalamin (Cbl) metabolism
      pathway). MTRR reduces the cobalamin cofactor and participates in the cytosolic
      cobalamin processing complex.
    action: ACCEPT
    reason: >-
      Biologically correct and supported by the reactivation/aquacobalamin-reductase
      biochemistry and the MTR-MTRR-MMACHC-MMADHC complex. Duplicates the IEA cobalamin
      annotation.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: >-
        MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of
        NADPH
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      HPA immunofluorescence IDA localising MTRR to the cytosol, consistent with the
      MGI IDA and the antibody/immunofluorescence study demonstrating a cytosolic-only
      pool.
    action: ACCEPT
    reason: >-
      Direct experimental localisation; core cellular location for this soluble
      cytosolic reductase.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        antibodies to MSR protein localized MSR to the cytosol, but not to the
        mitochondria
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: EXP
  original_reference_id: PMID:16769880
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Directly experimentally demonstrated core catalytic function.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: >-
        hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K(act) value
        of 71 nM
- term:
    id: GO:0140104
    label: molecular carrier activity
  evidence_type: EXP
  original_reference_id: PMID:21071249
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27771510
      supporting_text: >-
        the processing of Cbl in cytoplasm occurs in a multiprotein complex composed
        of at least MS, MSR, MMACHC and MMADHC
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174374
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (reaction: MTR transfers CH3 from MeCbl to
      HCYS). Correct compartment for the methionine synthase reaction that MTRR serves.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation consistent with experimental IDA evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149518
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (reaction: MTRR reduces cob(II)alamin to
      meCbl), the reaction directly catalysed by MTRR, in the cytosol.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation for the MTRR-catalysed reaction; consistent with
      experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149539
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (reaction: MTR transfers CH3 from
      5-methyl-THF to cob(I)alamin). Correct cytosolic compartment.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3204318
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation for the trafficking complex; consistent with
      experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3318563
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (disease reaction: Defective MTRR does not
      convert cob(II)alamin to MeCbl). Correct cytosolic compartment.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3321918
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (disease reaction: Defective MTR does not
      transfer CH3 group from MTHF to cob(I)alamin). Correct cytosolic compartment.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322140
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS cytosol localisation (disease reaction: Defective MTR does not
      transfer CH3 group from MeCbl to HCYS). Correct cytosolic compartment.
    action: ACCEPT
    reason: >-
      Correct cytosolic localisation; consistent with experimental evidence.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18221906
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Strong, direct experimental localisation; the definitive study establishing that
      MTRR is a cytosol-restricted protein.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        antibodies to MSR protein localized MSR to the cytosol, but not to the
        mitochondria of human fibroblasts or the human hepatoma line Huh-1
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: IDA
  original_reference_id: PMID:9501215
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Core catalytic function, established by cloning plus disease-causing mutations
      in cblE patients. Defer to the curator (full text read).
    supported_by:
    - reference_id: PMID:9501215
      supporting_text: >-
        we have cloned a cDNA corresponding to the "methionine synthase reductase"
        reducing system required for maintenance of the methionine synthase in a
        functional state
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:18221906
  qualifier: is_active_in
  review:
    summary: >-
      Direct experimental IDA (is_active_in) for cytosolic localisation of MTRR,
      from the same subcellular localisation study.
    action: ACCEPT
    reason: >-
      Direct experimental evidence that MTRR functions in the cytosol; core location.
    supported_by:
    - reference_id: PMID:18221906
      supporting_text: >-
        These data confirm that MSR protein is restricted to the cytosol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27771510
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:27771510
      supporting_text: >-
        we also observed novel interactions for MSR with MMACHC and with MMADHC
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17288554
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        human activation domain interacts with the FMN-binding domain of human
        methionine synthase reductase (hMSR)
- term:
    id: GO:0033353
    label: L-methionine cycle
  evidence_type: ISS
  original_reference_id: PMID:17369066
  qualifier: involved_in
  review:
    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).
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17369066
      supporting_text: >-
        Mtrr(gt/gt) mice have increased plasma homocyst(e)ine, decreased plasma
        methionine
- term:
    id: GO:0003958
    label: NADPH-hemoprotein reductase activity
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        It is a member of the family of dual flavoproteins
- term:
    id: GO:0010181
    label: FMN binding
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental cofactor determination; core molecular function.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        is isolated with an equimolar concentration of FAD and FMN
- term:
    id: GO:0046655
    label: folic acid metabolic process
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:17369066
      supporting_text: >-
        increased tissue methyltetrahydrofolate
- term:
    id: GO:0071949
    label: FAD binding
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental cofactor determination; core molecular function.
      (GO:0071949 FAD binding and GO:0050660 flavin adenine dinucleotide binding both
      capture FAD binding.)
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        is isolated with an equimolar concentration of FAD and FMN
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental demonstration of the core molecular function.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        demonstrate that it is sufficient for supporting NADPH-dependent activity of
        methionine synthase
- term:
    id: GO:0043418
    label: L-homocysteine catabolic process
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with MTRR's role in enabling homocysteine remethylation; supported by
      the cblE hyperhomocysteinaemia phenotype. Full text read by curator.
    supported_by:
    - reference_id: PMID:9501215
      supporting_text: >-
        Methionine synthase catalyzes the remethylation of homocysteine to methionine
- term:
    id: GO:0070402
    label: NADPH binding
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Supported by kinetic (KM for NADPH) and structural NADP(H)-binding data; a core
      cofactor/substrate-binding function of this NADPH-dependent reductase.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        The K(m) for NADPH is 2.6 +/- 0.5 microm
- term:
    id: GO:0071265
    label: L-methionine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:11466310
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Supported experimentally; core biological process for MTRR.
    supported_by:
    - reference_id: PMID:11466310
      supporting_text: >-
        demonstrate that it is sufficient for supporting NADPH-dependent activity of
        methionine synthase
- term:
    id: GO:0046655
    label: folic acid metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct process-level annotation supported by ortholog data; duplicates IDA and
      IEA folic acid annotations.
    supported_by:
    - reference_id: PMID:17369066
      supporting_text: >-
        increased tissue methyltetrahydrofolate
- term:
    id: GO:0016723
    label: oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor
  evidence_type: IDA
  original_reference_id: PMID:17892308
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17892308
      supporting_text: >-
        functions in the sequential transfer of reducing equivalents from NADPH to
        MS via its flavin centers
- term:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  evidence_type: TAS
  original_reference_id: PMID:17892308
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Core catalytic function, well supported structurally and enzymatically;
      duplicates IBA/IDA/EXP/IEA annotations to GO:0030586.
    supported_by:
    - reference_id: PMID:17892308
      supporting_text: >-
        regenerates the active form of cobalamin-dependent methionine synthase (MS)
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: IDA
  original_reference_id: PMID:17892308
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct structural evidence of FAD binding; core molecular function. Duplicates
      the IBA and GO:0071949 FAD-binding annotations.
    supported_by:
    - reference_id: PMID:17892308
      supporting_text: >-
        MSR contains one FAD and one FMN cofactor per polypeptide
core_functions:
- description: >-
    Methionine synthase reductase catalytic activity: as an NADPH-dependent diflavin
    (FAD + FMN) oxidoreductase, MTRR passes electrons from NADPH through its flavin
    centres to reductively methylate the cob(II)alamin cofactor of methionine synthase
    (MTR), regenerating active methylcob(III)alamin (EC 1.16.1.8) and thereby restoring
    MTR's homocysteine-remethylating activity.
  molecular_function:
    id: GO:0030586
    label: '[methionine synthase] reductase (NADPH) activity'
  directly_involved_in:
  - id: GO:0071265
    label: L-methionine biosynthetic process
  - id: GO:0050667
    label: homocysteine metabolic process
  - id: GO:0009235
    label: cobalamin metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11466310
    supporting_text: >-
      demonstrate that it is sufficient for supporting NADPH-dependent activity of
      methionine synthase
  - reference_id: PMID:17892308
    supporting_text: >-
      regenerates the active form of cobalamin-dependent methionine synthase (MS)
- description: >-
    FAD cofactor binding: MTRR binds one FAD per polypeptide in its FNR-like
    FAD-binding module, the entry point for NADPH-derived electrons into the diflavin
    electron-transfer chain.
  molecular_function:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11466310
    supporting_text: >-
      is isolated with an equimolar concentration of FAD and FMN
  - reference_id: PMID:17892308
    supporting_text: >-
      MSR contains one FAD and one FMN cofactor per polypeptide
- description: >-
    FMN cofactor binding: MTRR binds one FMN per polypeptide in its flavodoxin-like
    domain, which relays electrons to and docks onto the activation domain of
    methionine synthase.
  molecular_function:
    id: GO:0010181
    label: FMN binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:11466310
    supporting_text: >-
      is isolated with an equimolar concentration of FAD and FMN
  - reference_id: PMID:17288554
    supporting_text: >-
      human activation domain interacts with the FMN-binding domain of human
      methionine synthase reductase (hMSR)
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11466310
  title: Human methionine synthase reductase, a soluble P-450 reductase-like dual
    flavoprotein, is sufficient for NADPH-dependent methionine synthase activation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes MSR as a soluble P450-reductase-like diflavin
      protein (equimolar FAD/FMN) sufficient for NADPH-dependent methionine synthase
      activation. Abstract-only in cache but supports the core reductase/cofactor
      annotations; BHF-UCL curators (2015) used the full text.
- id: PMID:16769880
  title: Human methionine synthase reductase is a molecular chaperone for human methionine
    synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified, full text available. Shows MSR maintains hMS activity (Kact 71
      nM), reduces aquacobalamin to cob(II)alamin, and acts as a chaperone stabilising
      apoMS. Supports the reductase, aquacobalamin-reductase and cobalamin-metabolism
      biology.
- id: PMID:17288554
  title: Crystal structure and solution characterization of the activation domain
    of human methionine synthase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Demonstrates that the human MS activation domain interacts with
      the FMN-binding domain of MSR, enhanced by S-adenosylmethionine; supports the
      MTR-MTRR docking interaction underlying the protein-binding IPI.
- id: PMID:17369066
  title: Metabolic derangement of methionine and folate metabolism in mice deficient
    in methionine synthase reductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Mouse Mtrr hypomorph shows elevated homocysteine, reduced
      methionine and increased tissue methyltetrahydrofolate; underpins the ISS
      transfers for methionine cycle and folate metabolism.
- id: PMID:17892308
  title: Mechanism of coenzyme binding to human methionine synthase reductase revealed
    through the crystal structure of the FNR-like module and isothermal titration
    calorimetry.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Crystal structure of the NADP+-bound FNR-like module; confirms
      one FAD and one FMN per polypeptide, NADP(H) binding, diflavin architecture and
      EC 1.16.1.8. Supports the catalytic and cofactor core functions.
- id: PMID:18221906
  title: Restricted role for methionine synthase reductase defined by subcellular
    localization.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Antibody/immunofluorescence and GFP-fusion evidence that MSR is
      restricted to the cytosol and not mitochondria; definitive support for the
      cytosol localisation annotations.
- id: PMID:21071249
  title: Interaction between MMACHC and MMADHC, two human proteins participating in
    intracellular vitamin B₁₂ metabolism.
  findings: []
  reference_review:
    relevance: LOW
    correctness: MISCITED
    review_notes: >-
      PubMed-verified paper, but it characterises the MMACHC-MMADHC interaction and
      does not establish a molecular carrier function for MTRR. Cited by Reactome for
      the GO:0140104 molecular carrier activity annotation on MTRR, which it does not
      support; the MTRR molecular carrier annotation is flagged as over-annotated.
- id: PMID:27771510
  title: Methionine synthase and methionine synthase reductase interact with MMACHC
    and with MMADHC.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes MSR interactions with MMACHC and MMADHC and the
      cytosolic multiprotein Cbl-processing complex (MS, MSR, MMACHC, MMADHC);
      supports the protein-binding IPI and cobalamin-metabolism annotations.
- id: PMID:9501215
  title: Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein
    defective in patients with homocystinuria.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified, full text available. Cloning of MTRR as the reducing system
      maintaining methionine synthase; cblE mutations confirm identity; FNR-family
      membership; cytosolic targeting predicted. Foundational reference.
- id: Reactome:R-HSA-174374
  title: MTR transfers CH3 from MeCbl to HCYS
  findings: []
- id: Reactome:R-HSA-3149518
  title: MTRR reduces cob(II)alamin to meCbl
  findings: []
- id: Reactome:R-HSA-3149539
  title: MTR transfers CH3 group from 5-methyl-THF to cob(I)alamin
  findings: []
- id: Reactome:R-HSA-3204318
  title: cob(II)alamin is transferred from MMACHC:MMADHC:cob(II)alamin to MTRR:MTR
  findings: []
- id: Reactome:R-HSA-3318563
  title: Defective MTRR does not convert cob(II)alamin to MeCbl
  findings: []
- id: Reactome:R-HSA-3321918
  title: Defective MTR does not transfer CH3 group from MTHF to cob(I)alamin
  findings: []
- id: Reactome:R-HSA-3322140
  title: Defective MTR does not transfer CH3 group from MeCbl to HCYS
  findings: []
- id: Reactome:R-HSA-9759218
  title: Cobalamin (Cbl) metabolism
  findings: []