id: Q99707
gene_symbol: MTR
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  MTR encodes methionine synthase (5-methyltetrahydrofolate-homocysteine
  methyltransferase; EC 2.1.1.13), the cytosolic, methylcobalamin (vitamin
  B12)-dependent enzyme that catalyses the remethylation of homocysteine to
  methionine: (6S)-5-methyltetrahydrofolate + L-homocysteine -> (6S)-tetrahydrofolate
  + L-methionine. This single reaction links the folate cycle (regenerating
  tetrahydrofolate from 5-methyltetrahydrofolate) with the methionine cycle
  (regenerating methionine, and hence S-adenosylmethionine for cellular
  methylation). It is one of only two cobalamin-dependent enzymes in humans.
  The enzyme is modular, with a homocysteine-binding domain carrying a catalytic
  zinc ion that activates the homocysteine thiol, a pterin-binding domain that
  binds 5-methyltetrahydrofolate, two cobalamin-binding domains that hold the
  methylcobalamin cofactor, and a C-terminal S-adenosylmethionine-binding
  activation domain. Catalysis proceeds by shuttling the methyl group through the
  enzyme-bound cobalamin, which cycles between methylcob(III)alamin and
  cob(I)alamin. The reactive cob(I)alamin is periodically oxidised to inactive
  cob(II)alamin and must be reductively reactivated; methionine synthase reductase
  (MTRR) provides this reactivation and also acts as a chaperone promoting
  cobalamin loading of the apoenzyme. In the cytosol, cobalamin is handed to
  methionine synthase within a multiprotein complex that also includes MTRR,
  MMACHC and MMADHC. Loss-of-function mutations cause cblG homocystinuria with
  megaloblastic anemia, hyperhomocysteinemia and hypomethioninemia.
alternative_products:
- name: '1'
  id: Q99707-1
- name: '2'
  id: Q99707-2
  sequence_note: VSP_057283
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Methionine synthase is a cytosolic enzyme. This phylogenetic (IBA)
      cytosol annotation is consistent with the experimentally supported
      subcellular localization and with the cytosolic multiprotein cobalamin-processing
      complex it forms with MTRR, MMACHC and MMADHC.
    action: ACCEPT
    reason: >-
      Cytosol is the correct and precise compartment for the enzyme's catalytic
      activity. UniProt lists the subcellular location as cytoplasm, and the human
      cobalamin-processing complex operates in the cytosol.
    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
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0071265
    label: L-methionine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      MTR catalyses the terminal, committed step producing L-methionine from
      L-homocysteine, so participation in L-methionine biosynthesis is a core
      biological role. This IBA annotation is directly supported by experimental
      characterization of the human enzyme.
    action: ACCEPT
    reason: >-
      The de novo/remethylation route to methionine (MetH route) is a defined
      UniPathway step catalysed solely by MTR; this is a central function.
    supported_by:
    - reference_id: PMID:8968737
      supporting_text: >-
        Methionine synthase catalyzes the remethylation of homocysteine to methionine in
        a methylcobalamin-dependent reaction
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "L-methionine biosynthesis via de novo"
- term:
    id: GO:0046653
    label: tetrahydrofolate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      The MTR reaction consumes 5-methyltetrahydrofolate and regenerates
      tetrahydrofolate, coupling the methionine cycle to the folate cycle. MTR
      is therefore a genuine participant in tetrahydrofolate metabolism, although
      this facet is downstream of its methyltransferase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      The tetrahydrofolate metabolic aspect is a correct consequence of the
      catalysed reaction (THF is a product), but it describes a metabolic context
      rather than MTR's core molecular role, which is captured by methionine
      synthase activity and methionine biosynthesis.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: >-
        Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine =
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Methionine synthase activity (EC 2.1.1.13) is the defining molecular
      function of MTR and is supported by phylogenetic, experimental and
      structural evidence. This is the core molecular function.
    action: ACCEPT
    reason: >-
      Directly corresponds to the enzyme's catalytic activity, well supported at
      protein level and consistent across IBA, IDA, EXP, IEA and TAS annotations.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        catalyses the conversion of homocysteine to methionine by methyl group transfer
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Cytoplasm is the UniProt subcellular-location-derived compartment for MTR.
      It is correct but is the less precise parent of the cytosol annotation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct localization but superseded in specificity by the cytosol (GO:0005829)
      annotation; retain as a broader, non-core localization statement.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      MTR binds one catalytic zinc ion per subunit in its homocysteine-binding
      domain (Zn ligated by Cys/His at positions 260, 323 and 324); the zinc
      activates the homocysteine thiol for methyl transfer. This InterPro IEA
      is correct and functionally meaningful.
    action: ACCEPT
    reason: >-
      Zinc binding is an experimentally/structurally grounded catalytic cofactor
      requirement (UniProt COFACTOR Zn(2+); explicit Zn BINDING sites), not a
      spurious metal annotation.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "Note=Binds 1 zinc ion per subunit."
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated multi-method IEA (ARBA/InterPro/RHEA/EC 2.1.1.13) assignment of
      methionine synthase activity, redundant with and consistent with the
      experimental and IBA support for this molecular function.
    action: ACCEPT
    reason: >-
      Correct core molecular function inferred from family membership, EC and
      RHEA mappings that match the experimentally verified activity.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "EC=2.1.1.13"
- term:
    id: GO:0031419
    label: cobalamin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      MTR binds methylcob(III)alamin as its essential catalytic cofactor via its
      B12-binding domains (multiple methylcobalamin BINDING residues, including
      the axial cobalt coordination). This InterPro IEA captures a core
      cofactor-binding function.
    action: ACCEPT
    reason: >-
      Cobalamin binding is central to the enzyme mechanism (the methyl group is
      shuttled through enzyme-bound cobalamin); supported by UniProt cofactor and
      binding-site annotations.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;"
- term:
    id: GO:0042558
    label: pteridine-containing compound metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      The folate substrate (5-methyltetrahydrofolate) and product (tetrahydrofolate)
      are pteridine-containing compounds, so this InterPro IEA is true but very
      broad and non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct as a parent metabolic context (folate/THF is a pteridine derivative),
      but too general to represent the core function; the tetrahydrofolate
      metabolic process annotation is the more specific parent already captured.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: >-
        Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine =
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      Generic metal ion binding, subsumed by the more specific and accurate zinc
      ion binding annotation (MTR's catalytic Zn2+). Retained as a broad,
      non-informative parent term.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but uninformative; zinc ion binding (GO:0008270) is the specific,
      preferred molecular function. Cobalt is also present (in cobalamin) but is
      captured by cobalamin binding.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "Name=Zn(2+); Xref=ChEBI:CHEBI:29105;"
- term:
    id: GO:0071267
    label: L-methionine salvage
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: >-
      This IEA is an inter-ontology logical inference from methionine synthase
      activity (GO:0008705). L-methionine salvage refers to the methionine salvage
      (Yang) cycle that regenerates methionine from 5'-methylthioadenosine; MTR
      instead performs de novo remethylation of homocysteine, which is a distinct
      route. The inference is over-broad for MTR's biology.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The logically inferred salvage annotation conflates two different routes to
      methionine. MTR is the de novo homocysteine-remethylation (MetH) step, not a
      component of the methylthioadenosine-based methionine salvage pathway; better
      captured by L-methionine biosynthetic process.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "L-methionine biosynthesis via de novo"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23825108
  qualifier: enables
  review:
    summary: >-
      IntAct IPI recording a physical interaction between MTR and MMACHC (Q9Y4U1).
      The interaction is real and biologically meaningful (part of the cytosolic
      cobalamin-processing complex), but the bare "protein binding" term is
      uninformative about MTR's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation policy, an experimental IPI is retained rather than removed, but
      "protein binding" is too generic to convey function. The MTR-MMACHC interaction
      is better represented by the complex-assembly / cobalamin-processing context.
    supported_by:
    - reference_id: PMID:23825108
      supporting_text: >-
        the interaction of MS with MMACHC may
        play a role in the regulation of the cellular processing of Cbls that is
        required for Cbl cofactor synthesis
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      MTR is a cobalamin-dependent enzyme that both uses and cycles its cobalamin
      cofactor and, per biochemical evidence, is the only source of methylcobalamin
      in mammalian cells; it participates in cobalamin metabolism within the
      cytosolic Cbl-processing complex.
    action: ACCEPT
    reason: >-
      Correct participation in cobalamin metabolic process, supported by biochemical
      characterization of methylcobalamin generation and the Cbl-shuttling complex.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: "we believe that MS itself is the only source of MeCbl in mammalian cells"
- term:
    id: GO:0031103
    label: axon regeneration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara) from a rat ortholog. There is no
      human experimental support that methionine synthase acts directly in axon
      regeneration; this is a peripheral, weakly supported process attribution.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated ortholog-based process annotation not reflecting MTR's core
      metabolic role; any neuronal relevance is indirect (via methionine/SAM and
      methylation homeostasis) rather than a direct axon-regeneration function.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "FUNCTION: Catalyzes the transfer of a methyl group from"
- term:
    id: GO:0048678
    label: response to axon injury
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara) from a rat ortholog. Not supported by
      human experimental evidence for a direct role in the response to axon injury.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated ortholog-based process annotation; MTR's documented function
      is the folate/cobalamin-dependent remethylation of homocysteine, not a direct
      axon-injury response.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "FUNCTION: Catalyzes the transfer of a methyl group from"
- term:
    id: GO:0071265
    label: L-methionine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic (Ensembl Compara) transfer of L-methionine biosynthetic process,
      redundant with and consistent with the experimentally supported IBA/IMP
      annotations to the same term.
    action: ACCEPT
    reason: >-
      Correct core biological process; matches the experimentally validated role of
      MTR in producing methionine from homocysteine.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "L-methionine biosynthesis via de novo"
- term:
    id: GO:0071732
    label: cellular response to nitric oxide
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic transfer (Ensembl Compara) from a rat ortholog. Methionine
      synthase cobalamin can be inactivated by nitric oxide, giving some rationale,
      but a direct human "cellular response to nitric oxide" role is not
      experimentally established here and is peripheral.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-propagated ortholog-based process annotation; while cob(I)alamin is
      chemically NO-sensitive, this term overstates a dedicated NO-response function
      for MTR relative to its core metabolic role.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "Under aerobic\n"
- term:
    id: GO:0000096
    label: sulfur amino acid metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614635
  qualifier: involved_in
  review:
    summary: >-
      Homocysteine and methionine are sulfur amino acids, and the MTR reaction is
      part of sulfur amino acid metabolism. This Reactome TAS is correct but is a
      broad parent process.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but general; the more specific L-methionine biosynthetic process and
      homocysteine metabolic process better capture MTR's core role.
    supported_by:
    - reference_id: PMID:8968737
      supporting_text: >-
        Methionine synthase catalyzes the remethylation of homocysteine to methionine in
        a methylcobalamin-dependent reaction
- 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 placing MTR in cobalamin (Cbl) metabolism, consistent with its
      cobalamin-dependent mechanism and role in the cytosolic Cbl-processing complex.
    action: ACCEPT
    reason: >-
      Correct participation in cobalamin metabolic process; MTR both consumes and
      regenerates its cobalamin cofactor and generates methylcobalamin.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: "we believe that MS itself is the only source of MeCbl in mammalian cells"
- term:
    id: GO:0032259
    label: methylation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-156581
  qualifier: involved_in
  review:
    summary: >-
      MTR is a methyltransferase (transfers a methyl group from methylcobalamin/
      5-methyltetrahydrofolate to homocysteine), so participation in methylation is
      correct but is a very broad process term.
    action: KEEP_AS_NON_CORE
    reason: >-
      True but general; the specific molecular function (methionine synthase activity)
      and the methionine/homocysteine process terms are more informative.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        catalyses the conversion of homocysteine to methionine by methyl group transfer
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174374
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for methionine synthase activity, describing the half reaction in
      which the methyl group of methylcobalamin is transferred to homocysteine. Core
      molecular function.
    action: ACCEPT
    reason: >-
      Correct core molecular function, redundant with the IDA/EXP/IBA/IEA support.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        catalyses the conversion of homocysteine to methionine by methyl group transfer
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149539
  qualifier: enables
  review:
    summary: >-
      Reactome TAS for methionine synthase activity, describing the half reaction in
      which cob(I)alamin is re-methylated by 5-methyltetrahydrofolate. Core molecular
      function.
    action: ACCEPT
    reason: >-
      Correct core molecular function; complementary half-reaction of the same
      catalytic cycle.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        catalyses the conversion of homocysteine to methionine by methyl group transfer
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: EXP
  original_reference_id: PMID:17288554
  qualifier: enables
  review:
    summary: >-
      Experimental annotation of methionine synthase activity based on structural and
      solution characterization of the human enzyme's activation domain in the context
      of the catalytic homocysteine->methionine methyl-transfer reaction.
    action: ACCEPT
    reason: >-
      Directly supports the core molecular function with experimental evidence on the
      human protein.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        Human methionine synthase (hMS) is a multidomain cobalamin-dependent enzyme that
        catalyses the conversion of homocysteine to methionine by methyl group transfer
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27771510
  qualifier: enables
  review:
    summary: >-
      IPI recording physical interactions of MTR with MMADHC (Q9H3L0), MTRR (Q9UBK8)
      and MMACHC (Q9Y4U1), placing MTR in the cytosolic cobalamin-processing
      interactome. The interactions are real and functionally relevant, but the bare
      "protein binding" term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation policy the experimental IPI is retained rather than removed, but
      "protein binding" does not convey MTR's molecular function; the assembly into
      the MTR-MTRR-MMACHC-MMADHC complex is the biologically meaningful description.
    supported_by:
    - reference_id: PMID:27771510
      supporting_text: >-
        we also observed novel interactions for MSR with MMACHC and with MMADHC and
        MS with MMADHC
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17288554
  qualifier: enables
  review:
    summary: >-
      IPI recording interaction of MTR with MTRR (Q9UBK8); the activation domain of
      human methionine synthase interacts with the FMN-binding domain of MTRR, an
      interaction enhanced by S-adenosylmethionine. Real and functionally important
      (reductive reactivation), but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Experimental IPI retained rather than removed, but "protein binding" is too
      generic; the MTR activation-domain / MTRR FMN-domain interaction underpins
      reductive reactivation of the cobalamin cofactor.
    supported_by:
    - reference_id: PMID:17288554
      supporting_text: >-
        Fluorescence studies show that human activation
        domain interacts with the FMN-binding domain of human methionine synthase
        reductase (hMSR)
- term:
    id: GO:0031103
    label: axon regeneration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity (ISS) transfer from a rat ortholog. As with the
      IEA counterpart, there is no human experimental support for a direct role of
      methionine synthase in axon regeneration.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog-based process transfer that does not reflect MTR's documented core
      metabolic function; any neuronal effect is indirect via methionine/SAM
      homeostasis.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "FUNCTION: Catalyzes the transfer of a methyl group from"
- term:
    id: GO:0048678
    label: response to axon injury
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity (ISS) transfer from a rat ortholog; not supported
      by human experimental evidence for a direct response-to-axon-injury role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog-based process transfer not reflecting MTR's core function.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "FUNCTION: Catalyzes the transfer of a methyl group from"
- term:
    id: GO:0071732
    label: cellular response to nitric oxide
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Curator sequence-similarity (ISS) transfer from a rat ortholog. Although
      methionine synthase cobalamin is chemically sensitive to nitric oxide, a
      dedicated human NO-response function is not experimentally established and is
      peripheral to the core catalytic role.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Ortholog-based process transfer that overstates a dedicated NO-response role;
      MTR's core function is folate/cobalamin-dependent homocysteine remethylation.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "Under aerobic\n"
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: IMP
  original_reference_id: PMID:23825108
  qualifier: enables
  review:
    summary: >-
      IMP annotation of methionine synthase activity: cblG mutations in MTR decrease
      the cobalamin-dependent conversion, and cblG-variant cells expressing only a
      truncated MTR isoform have undetectable methionine synthase activity, tying the
      activity to the gene.
    action: ACCEPT
    reason: >-
      Loss of MTR function (mutation) abolishing methionine synthase activity provides
      genetic support for the core molecular function.
    supported_by:
    - reference_id: PMID:23825108
      supporting_text: >-
        In cblG, mutations in methionine synthase (MTR)
        decrease conversion of hydroxocobalamin
- term:
    id: GO:0009235
    label: cobalamin metabolic process
  evidence_type: IMP
  original_reference_id: PMID:23825108
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to cobalamin metabolic process: cblG mutations in MTR decrease
      the conversion of hydroxocobalamin to methylcobalamin, demonstrating MTR's role
      in cellular cobalamin processing.
    action: ACCEPT
    reason: >-
      Genetic (mutation) evidence that MTR function is required for normal cobalamin
      (methylcobalamin) handling supports participation in cobalamin metabolism.
    supported_by:
    - reference_id: PMID:23825108
      supporting_text: >-
        In cblG, mutations in methionine synthase (MTR)
        decrease conversion of hydroxocobalamin
- term:
    id: GO:0071265
    label: L-methionine biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:23825108
  qualifier: involved_in
  review:
    summary: >-
      IMP annotation to L-methionine biosynthetic process: MTR mutations in cblG
      impair the homocysteine-to-methionine remethylation, linking the gene to
      methionine biosynthesis by mutant phenotype.
    action: ACCEPT
    reason: >-
      Genetic loss-of-function evidence supporting the core biological process of
      methionine biosynthesis.
    supported_by:
    - reference_id: PMID:23825108
      supporting_text: >-
        In cblG, mutations in methionine synthase (MTR)
        decrease conversion of hydroxocobalamin
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3321918
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (in the context of a defective-MTR
      reaction). Consistent with the established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3322140
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (defective-MTR reaction context).
      Consistent with the established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0008705
    label: methionine synthase activity
  evidence_type: IDA
  original_reference_id: PMID:16769880
  qualifier: enables
  review:
    summary: >-
      IDA for methionine synthase activity: recombinant purified human MS was shown to
      be an active EC 2.1.1.13 enzyme whose sustained activity requires MSR. This is
      direct experimental support for the core molecular function.
    action: ACCEPT
    reason: >-
      Direct assay of purified human methionine synthase activity; strongest evidence
      class for the core molecular function.
    supported_by:
    - reference_id: PMID:16769880
      supporting_text: "Sustained activity of mammalian methionine synthase (MS) requires MS reductase"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174374
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (methyl-transfer half reaction).
      Consistent with established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149518
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (MTRR reductive-reactivation
      reaction context). Consistent with established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3149539
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (cob(I)alamin re-methylation half
      reaction). Consistent with established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3204318
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (cobalamin transfer from
      MMACHC:MMADHC complex to MTRR:MTR). Consistent with established cytosolic
      localization and the cytosolic Cbl-processing complex.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    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-3318563
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing MTR to the cytosol (defective-MTRR reaction context).
      Consistent with established cytosolic localization.
    action: ACCEPT
    reason: >-
      Correct, specific cytosolic localization.
    supported_by:
    - reference_id: file:human/MTR/MTR-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:8968737
  qualifier: involved_in
  review:
    summary: >-
      Legacy TAS to nervous system development citing the MTR cloning/cblG-mutation
      paper. That paper reports cloning and disease mutations and the neurological
      phenotype of deficiency, but does not establish a direct developmental role for
      MTR; the neurological consequences arise from impaired methionine/SAM and
      folate metabolism.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-broad process attribution. The cited paper does not demonstrate MTR acting
      directly in nervous system development; developmental delay in cblG is a
      downstream consequence of the metabolic defect rather than a direct
      developmental function.
    supported_by:
    - reference_id: PMID:8968737
      supporting_text: >-
        Methionine synthase catalyzes the remethylation of homocysteine to methionine in
        a methylcobalamin-dependent reaction
- term:
    id: GO:0050667
    label: homocysteine metabolic process
  evidence_type: IMP
  original_reference_id: PMID:23825108
  qualifier: involved_in
  review:
    summary: >-
      MTR directly consumes L-homocysteine, remethylating it to L-methionine, so it
      is a central participant in homocysteine metabolism. This term is not present in
      the current GOA set but is well supported and captures a core biological process
      of the gene (loss of MTR function causes homocystinuria).
    action: NEW
    reason: >-
      Proposed new annotation. Homocysteine metabolic process is a specific,
      informative process term directly reflecting MTR's substrate; its clinical
      hallmark on loss of function is homocystinuria/hyperhomocysteinemia. Added to
      reflect the core_functions homocysteine-metabolism role.
    supported_by:
    - reference_id: PMID:8968737
      supporting_text: >-
        Methionine synthase catalyzes the remethylation of homocysteine to methionine in
        a methylcobalamin-dependent reaction
    - reference_id: PMID:23825108
      supporting_text: >-
        In cblG, mutations in methionine synthase (MTR)
        decrease conversion of hydroxocobalamin
core_functions:
- description: >-
    Cobalamin (methylcobalamin)-dependent methionine synthase catalysing the
    folate-dependent remethylation of L-homocysteine to L-methionine
    (5-methyltetrahydrofolate + L-homocysteine -> tetrahydrofolate + L-methionine),
    the committed step linking the folate and methionine cycles.
  molecular_function:
    id: GO:0008705
    label: methionine synthase activity
  directly_involved_in:
  - id: GO:0071265
    label: L-methionine biosynthetic process
  supported_by:
  - reference_id: PMID:16769880
    supporting_text: "Sustained activity of mammalian methionine synthase (MS) requires MS reductase"
  - reference_id: PMID:8968737
    supporting_text: >-
      Methionine synthase catalyzes the remethylation of homocysteine to methionine in
      a methylcobalamin-dependent reaction
- description: >-
    Methyl transfer during catalysis is mediated by an essential enzyme-bound
    cobalamin cofactor (methylcob(III)alamin), cycling between methylcobalamin and
    cob(I)alamin; MTR binds cobalamin via its dedicated B12-binding domains.
  molecular_function:
    id: GO:0031419
    label: cobalamin binding
  directly_involved_in:
  - id: GO:0009235
    label: cobalamin metabolic process
  supported_by:
  - reference_id: file:human/MTR/MTR-uniprot.txt
    supporting_text: "Name=methylcob(III)alamin; Xref=ChEBI:CHEBI:28115;"
  - reference_id: PMID:16769880
    supporting_text: "we believe that MS itself is the only source of MeCbl in mammalian cells"
- description: >-
    The homocysteine remethylation reaction consumes 5-methyltetrahydrofolate and
    regenerates tetrahydrofolate, so MTR functions in homocysteine metabolism at the
    junction of the methionine and folate cycles, in the cytosol.
  molecular_function:
    id: GO:0008705
    label: methionine synthase activity
  directly_involved_in:
  - id: GO:0050667
    label: homocysteine metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:8968737
    supporting_text: >-
      Methionine synthase catalyzes the remethylation of homocysteine to methionine in
      a methylcobalamin-dependent reaction
  - 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
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- 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: >-
      Full text available. Directly characterizes purified human methionine synthase
      (EC 2.1.1.13) activity and its dependence on MSR (chaperone / aquacobalamin
      reductase); supports both the methionine synthase activity (IDA) and cobalamin
      metabolic process annotations.
- 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: >-
      Abstract only in cache. Establishes the human enzyme as a multidomain
      cobalamin-dependent methionine synthase converting homocysteine to methionine
      by methyl transfer, and characterizes the activation-domain/MTRR interaction;
      supports the EXP methionine synthase activity and MTRR-interaction annotations.
- id: PMID:23825108
  title: 'Interaction between methionine synthase isoforms and MMACHC: characterization
    in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract only in cache. cblG mutations in MTR decrease cobalamin conversion and
      cblG-variant cells have undetectable MS activity; MTR interacts with MMACHC.
      Supports the IMP activity/process annotations and the MMACHC interaction (IPI).
- 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: >-
      Abstract only in cache. Demonstrates the cytosolic multiprotein cobalamin-processing
      complex (MS, MSR, MMACHC, MMADHC) and MTR interactions with MMACHC/MMADHC/MTRR;
      supports the cytosolic localization and protein-interaction annotations.
- id: PMID:8968737
  title: 'Human methionine synthase: cDNA cloning and identification of mutations
    in patients of the cblG complementation group of folate/cobalamin disorders.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract only in cache. Original human MTR cDNA cloning; defines the enzyme as
      catalysing methylcobalamin-dependent remethylation of homocysteine to methionine
      and identifies cblG mutations. The TAS nervous-system-development annotation it
      supports is over-broad relative to what the paper shows.
- id: Reactome:R-HSA-156581
  title: Methylation
  findings: []
- id: Reactome:R-HSA-1614635
  title: Sulfur amino acid metabolism
  findings: []
- 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: []