id: Q14749
gene_symbol: GNMT
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Glycine N-methyltransferase (EC 2.1.1.20) is an abundant, predominantly hepatic
  cytosolic enzyme that transfers a methyl group from S-adenosyl-L-methionine
  (SAM/AdoMet) to glycine, forming sarcosine (N-methylglycine) and
  S-adenosyl-L-homocysteine (SAH/AdoHcy). Its major physiological role is not
  biosynthetic but regulatory; by disposing of excess SAM it controls the cellular
  SAM:SAH ratio (methylation capacity), thereby integrating one-carbon and folate
  metabolism. Consistent with this role it is feedback-inhibited by
  5-methyltetrahydrofolate, coupling folate status to methyl-group disposal. It is a
  homotetramer of a class I-like SAM-dependent methyltransferase fold. Loss-of-function
  variants cause glycine N-methyltransferase deficiency (hypermethioninemia), with
  elevated plasma methionine and SAM alongside mild hepatopathy.
existing_annotations:
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred glycine N-methyltransferase activity. This is
      the correct and central molecular function of GNMT, supported by direct experimental
      assays of the human enzyme.
    action: ACCEPT
    reason: The IBA inference agrees with direct experimental measurement of glycine
      N-methyltransferase activity for the human enzyme and with the UniProt-annotated
      catalytic activity (EC 2.1.1.20, RHEA:19937). This is the core function.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L-"
- term:
    id: GO:0046500
    label: S-adenosylmethionine metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement in S-adenosylmethionine metabolism.
      GNMT consumes SAM to methylate glycine and is a principal route for disposal
      of excess SAM, regulating the SAM:SAH ratio.
    action: ACCEPT
    reason: Directly supported by the UniProt function statement that GNMT regulates
      the ratio between SAM and SAH, and by the catalytic consumption of SAM. Core
      process context for the enzyme.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred cytosolic localization, consistent with the
      cytoplasmic/cytosolic localization of the human enzyme.
    action: ACCEPT
    reason: Agrees with experimental IDA cytosol localization (HPA) and with Reactome
      annotation of cytosolic GNMT; GNMT is a soluble cytosolic enzyme with no membrane
      or targeting features.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0006111
    label: regulation of gluconeogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred role in regulation of gluconeogenesis, largely
      transferred from mouse Gnmt phenotypes. This is at best an indirect, downstream
      metabolic consequence of altered one-carbon/methylation flux rather than a direct
      function of the enzyme.
    action: KEEP_AS_NON_CORE
    reason: GNMT's direct biochemical function is methyl-group disposal; any effect
      on gluconeogenesis is a secondary systemic-metabolic consequence observed in
      knockout/overexpression models. Retain as a non-core process rather than a core
      function.
- term:
    id: GO:0006730
    label: one-carbon metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement in one-carbon metabolism. GNMT is
      a key node in one-carbon/methyl-group metabolism, disposing of excess methyl
      groups from SAM and integrating folate status via 5-methyl-THF inhibition.
    action: ACCEPT
    reason: Consistent with GNMT's established role in methyl-group metabolism and
      its feedback inhibition by 5-methyltetrahydrofolate, which couples the enzyme
      to folate/one-carbon status.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: Plays an
- term:
    id: GO:0016594
    label: glycine binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred glycine binding, corresponding to binding of
      the methyl-acceptor substrate. Directly supported experimentally for the human
      enzyme.
    action: ACCEPT
    reason: Glycine is the methyl-acceptor substrate; binding is a mechanistic component
      of the glycine N-methyltransferase activity and is directly observed (IDA) in
      the human crystal/kinetic studies.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L-"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred self-association, consistent with GNMT being
      an obligate homotetramer.
    action: KEEP_AS_NON_CORE
    reason: GNMT is a well-established homotetramer; identical protein binding (self-interaction)
      is the molecular basis of its quaternary structure, but the biologically informative
      term is protein homotetramerization, so this is retained as non-core.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred homotetramerization. GNMT assembles into a homotetramer,
      which is the active quaternary form and is required for full activity/stability.
    action: ACCEPT
    reason: The homotetramer is directly demonstrated by crystallography and biophysical
      studies of the human enzyme; the disease variant H176N destabilizes the tetramer.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
    - reference_id: PMID:8281755
      supporting_text: all tetramers and exhibit
- term:
    id: GO:1904047
    label: S-adenosyl-L-methionine binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically inferred SAM binding, corresponding to binding of the
      methyl-donor cofactor/substrate. Multiple SAM-binding residues are annotated
      in the human structure.
    action: ACCEPT
    reason: SAM is the methyl donor; its binding is an intrinsic mechanistic component
      of glycine N-methyltransferase activity, with numerous SAM-binding residues mapped
      in the human enzyme structure.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: ligand="S-adenosyl-L-methionine"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of cytoplasmic localization from the UniProt Subcellular
      Location vocabulary. Consistent with the known cytosolic localization of GNMT.
    action: ACCEPT
    reason: Matches the UniProt SUBCELLULAR LOCATION (Cytoplasm) and experimental cytosol
      localization; correct though less specific than the cytosol annotation.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of glycine N-methyltransferase activity via automated
      pipelines (ARBA/InterPro/RHEA/EC mapping). Correct core molecular function.
    action: ACCEPT
    reason: The electronic mapping (EC 2.1.1.20, RHEA:19937, InterPro IPR014369) correctly
      recapitulates the experimentally established core function.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: EC=2.1.1.20
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: High-throughput yeast two-hybrid interaction (CCSB-HI1) reporting GNMT
      binding to a partner. The bare protein binding term is uninformative about GNMT's
      molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation policy, bare protein binding (GO:0005515) from a proteome-scale
      interactome screen does not convey a specific molecular function and is retained
      only as an over-annotation; the interaction is not established as biologically
      meaningful for GNMT.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: an initial version of a proteome-scale map of
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: Interaction reported in a human liver protein interaction network study.
      Bare protein binding is uninformative about GNMT's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Large-scale interactome hit yielding only the generic protein binding term;
      no specific, functionally interpretable GNMT molecular function is implied.
    supported_by:
    - reference_id: PMID:21988832
      supporting_text: protein interaction network of the human liver
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: Interaction reported in a large-scale alternative-splicing interactome
      study. Bare protein binding is uninformative about GNMT's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome hit yielding only generic protein binding;
      no specific GNMT molecular function is implied.
    supported_by:
    - reference_id: PMID:26871637
      supporting_text: Widespread Expansion of Protein Interaction Capabilities by Alternative
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Interaction reported in a population-scale variant/interaction-disruption
      study. Bare protein binding is uninformative about GNMT's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome hit yielding only generic protein binding;
      no specific GNMT molecular function is implied.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: disruption of protein interactions by genetic variants
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Multiple interactions reported in the HuRI reference human binary interactome.
      Bare protein binding is uninformative about GNMT's molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteome-scale binary interactome hits yielding only the generic protein
      binding term; individual partners are not established as biologically meaningful
      for GNMT and no specific molecular function is implied.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference interactome map of human binary protein interactions
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: Self-interaction of GNMT detected in a proteome-scale two-hybrid screen
      (partner UniProtKB:Q14749), consistent with the homotetramer.
    action: KEEP_AS_NON_CORE
    reason: The self-interaction reflects GNMT's homotetrameric assembly. It is biologically
      real (GNMT is an obligate homotetramer) but is a structural property better captured
      by protein homotetramerization; keep as non-core molecular detail.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25502805
  qualifier: enables
  review:
    summary: GNMT self-interaction assayed in the Clone-seq/Y2H interactome-scanning
      pipeline (partner UniProtKB:Q14749), consistent with homotetramer formation.
    action: KEEP_AS_NON_CORE
    reason: Reflects the known self-association of the homotetrameric enzyme; retained
      as a non-core structural attribute.
    supported_by:
    - reference_id: PMID:25502805
      supporting_text: Hprt1, Pnp, Tpk1, Gnmt, Gale
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:26871637
  qualifier: enables
  review:
    summary: GNMT self-interaction reported (partner UniProtKB:Q14749), consistent
      with the homotetramer.
    action: KEEP_AS_NON_CORE
    reason: Reflects GNMT's homotetrameric self-association; non-core structural detail.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: GNMT self-interaction reported (partner UniProtKB:Q14749), consistent
      with the homotetramer.
    action: KEEP_AS_NON_CORE
    reason: Reflects GNMT's homotetrameric self-association; non-core structural detail.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0016594
    label: glycine binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation of glycine binding (methyl-acceptor substrate) via
      automated pipelines. Correct mechanistic component of the enzyme's function.
    action: ACCEPT
    reason: Consistent with the experimentally observed glycine binding and with the
      glycine N-methyltransferase reaction.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: KM=12.2 uM for glycine
- term:
    id: GO:0046500
    label: S-adenosylmethionine metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation of involvement in SAM metabolism via automated pipelines.
      Correct process context (GNMT consumes SAM and regulates the SAM:SAH ratio).
    action: ACCEPT
    reason: Agrees with the manually and phylogenetically supported SAM-metabolic role
      of GNMT.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation of homotetramerization via automated pipelines.
      Correct; GNMT is a homotetramer.
    action: ACCEPT
    reason: Consistent with crystallographic and biophysical evidence that human GNMT
      is a homotetramer.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (immunofluorescence, Human Protein Atlas) evidence of cytosolic
      localization of GNMT.
    action: ACCEPT
    reason: Experimental localization consistent with GNMT being a soluble cytosolic
      enzyme; this is the most specific and best-supported localization term.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based cytoplasmic localization transferred from the
      rat ortholog (UniProtKB:P13255). Consistent with the known cytosolic localization.
    action: ACCEPT
    reason: The ISS transfer from the well-characterized rat ortholog matches the human
      enzyme's cytosolic localization; correct though less specific than cytosol.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:14651980
  qualifier: enables
  review:
    summary: Direct experimental characterization of recombinant wild-type and mutant
      human GNMT activity toward glycine and SAM, establishing glycine N-methyltransferase
      activity for the human enzyme.
    action: ACCEPT
    reason: Kinetic assays of the purified human enzyme directly demonstrate glycine
      N-methyltransferase activity; the core molecular function.
    supported_by:
    - reference_id: PMID:14651980
      supporting_text: toward both substrates, S-adenosylmethionine
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:14739680
  qualifier: enables
  review:
    summary: Case study of GNMT deficiency in which the patient's GNMT variant, on
      expression, retained only barely detectable catalytic activity, confirming glycine
      N-methyltransferase activity of the human enzyme and its loss in disease.
    action: ACCEPT
    reason: Demonstrates human GNMT catalytic activity and its abolition by a disease
      variant (N140S), with the metabolic phenotype (elevated methionine/SAM, normal
      sarcosine) diagnostic of GNMT deficiency.
    supported_by:
    - reference_id: PMID:14739680
      supporting_text: retained only
    - reference_id: PMID:14739680
      supporting_text: strongly suggested GNMT
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:17660255
  qualifier: enables
  review:
    summary: Structural/biophysical study of human GNMT (including the H176N disease
      variant) measuring enzyme activity, confirming glycine N-methyltransferase activity.
    action: ACCEPT
    reason: Direct activity measurement on the human tetrameric enzyme; supports the
      core molecular function and links tetramer stability to activity.
    supported_by:
    - reference_id: PMID:17660255
      supporting_text: the tetrameric enzyme,
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:8281755
  qualifier: enables
  review:
    summary: Comparative kinetic/structural characterization of mammalian GNMTs including
      the human liver enzyme, establishing glycine N-methyltransferase catalytic activity.
    action: ACCEPT
    reason: Direct kinetic characterization of the human liver enzyme; confirms the
      core molecular function and its homotetrameric, cooperative behavior toward SAM.
    supported_by:
    - reference_id: PMID:8281755
      supporting_text: Human liver contains a rather high level of glycine N-methyltransferase
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798317
  qualifier: located_in
  review:
    summary: Reactome-asserted cytosolic localization of the GNMT tetramer catalyzing
      the AdoMet-to-glycine methyl transfer.
    action: ACCEPT
    reason: Consistent with experimental cytosol localization and the enzyme's soluble
      cytosolic nature.
    supported_by:
    - reference_id: Reactome:R-HSA-6798317
      supporting_text: Cytosolic glycine N-methyltransferase (GNMT) catalyses the transfer
        of a methyl group from S-adenosylmethionine
- term:
    id: GO:0016594
    label: glycine binding
  evidence_type: IDA
  original_reference_id: PMID:15340920
  qualifier: enables
  review:
    summary: Crystal structures and kinetic analysis of recombinant human (and mouse/rat)
      GNMT, providing direct evidence for glycine binding at the active site.
    action: ACCEPT
    reason: Structural/kinetic characterization of the human enzyme directly supports
      binding of the glycine substrate.
    supported_by:
    - reference_id: PMID:15340920
      supporting_text: Human and mouse GNMT were
- term:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:15340920
  qualifier: enables
  review:
    summary: Direct structural and kinetic characterization of recombinant human GNMT,
      confirming glycine N-methyltransferase activity.
    action: ACCEPT
    reason: The comparison of crystal structures and kinetic properties of the recombinant
      human enzyme directly establishes the core catalytic function.
    supported_by:
    - reference_id: PMID:15340920
      supporting_text: crystal structures and kinetic
- term:
    id: GO:0046500
    label: S-adenosylmethionine metabolic process
  evidence_type: IDA
  original_reference_id: PMID:15340920
  qualifier: involved_in
  review:
    summary: The kinetic characterization of human GNMT (consuming SAM to methylate
      glycine) supports its participation in S-adenosylmethionine metabolism.
    action: ACCEPT
    reason: GNMT catalytically consumes SAM; direct kinetic study of the human enzyme
      supports its role in SAM metabolism (methyl-group disposal / SAM:SAH regulation).
    supported_by:
    - reference_id: PMID:15340920
      supporting_text: kinetic properties of recombinant human
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IPI
  original_reference_id: PMID:15340920
  qualifier: involved_in
  review:
    summary: The crystal structures of recombinant human GNMT demonstrate the homotetrameric
      (subunit) assembly of the enzyme.
    action: ACCEPT
    reason: Crystallographic determination of subunit organization directly supports
      homotetramerization of the human enzyme.
    supported_by:
    - reference_id: PMID:8281755
      supporting_text: all tetramers and exhibit
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "SUBUNIT: Homotetramer"
- term:
    id: GO:0032259
    label: methylation
  evidence_type: IDA
  original_reference_id: PMID:8281755
  qualifier: involved_in
  review:
    summary: GNMT is a methyltransferase that carries out methylation (transfer of
      a methyl group from SAM to glycine). Methylation is the general biological process
      corresponding to its catalytic activity.
    action: NEW
    reason: The methylation process (GO:0032259) is annotated by UniProt via keyword
      mapping and directly reflects GNMT's demonstrated methyltransferase activity;
      added here as it complements the more specific SAM/one-carbon process annotations.
    supported_by:
    - reference_id: file:human/GNMT/GNMT-uniprot.txt
      supporting_text: "Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L-"
    - reference_id: PMID:8281755
      supporting_text: Human liver contains a rather high level of glycine N-methyltransferase
core_functions:
- description: Glycine N-methyltransferase catalytic activity - transfers a methyl
    group from S-adenosyl-L-methionine to glycine, producing sarcosine (N-methylglycine)
    and S-adenosyl-L-homocysteine (EC 2.1.1.20).
  molecular_function:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  directly_involved_in:
  - id: GO:0046500
    label: S-adenosylmethionine metabolic process
  supported_by:
  - reference_id: file:human/GNMT/GNMT-uniprot.txt
    supporting_text: "Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L-"
  - reference_id: PMID:8281755
    supporting_text: Human liver contains a rather high level of glycine N-methyltransferase
- description: By consuming excess S-adenosyl-L-methionine to methylate glycine, GNMT
    regulates the cellular SAM:SAH ratio (methylation capacity) and participates in
    one-carbon/methyl-group metabolism; it is feedback-inhibited by 5-methyltetrahydrofolate,
    integrating folate status.
  molecular_function:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  directly_involved_in:
  - id: GO:0006730
    label: one-carbon metabolic process
  supported_by:
  - reference_id: file:human/GNMT/GNMT-uniprot.txt
    supporting_text: regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L-
- description: GNMT assembles as a homotetramer, the active/stable quaternary form
    of the class I-like SAM-dependent methyltransferase; SAM (methyl donor) and glycine
    (methyl acceptor) binding are intrinsic mechanistic components, and the enzyme
    acts in the cytosol.
  molecular_function:
    id: GO:0017174
    label: glycine N-methyltransferase activity
  directly_involved_in:
  - id: GO:0032259
    label: methylation
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:8281755
    supporting_text: all tetramers and exhibit
  - reference_id: file:human/GNMT/GNMT-uniprot.txt
    supporting_text: "SUBUNIT: Homotetramer"
proposed_new_terms: []
suggested_questions:
- question: Beyond systemic effects seen in mouse models, does human GNMT directly
    participate in regulation of gluconeogenesis, or is that solely a downstream consequence
    of altered methylation/one-carbon flux?
- question: Are any of the high-throughput binary interactors (e.g. ARRB1, NTAQ1, SNRNP200)
    physiologically meaningful, or are they screen artifacts?
suggested_experiments:
- description: Structure-guided kinetic dissection of 5-methyltetrahydrofolate feedback
    inhibition to quantify how folate status tunes the SAM:SAH ratio in hepatocytes.
- description: Metabolic flux analysis in GNMT-deficient vs wild-type hepatocytes to
    directly measure the contribution of GNMT to SAM disposal and methylation capacity.
references:
- 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:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/GNMT/GNMT-uniprot.txt
  title: UniProtKB entry GNMT_HUMAN (Q14749)
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary source for catalytic activity (EC 2.1.1.20, RHEA:19937),
      SAM:SAH regulatory function, homotetramer, cytoplasmic localization, kinetics,
      and disease variants.
- id: PMID:14651980
  title: Effect of naturally occurring mutations in human glycine N-methyltransferase
    on activity and conformation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Kinetic/conformational characterization of recombinant WT and disease-mutant
      human GNMT; supports the enzyme activity annotation and KM values.
- id: PMID:14739680
  title: 'Glycine N -methyltransferase deficiency: a new patient with a novel mutation.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Case report of GNMT deficiency; diagnostic metabolite pattern (elevated
      methionine/AdoMet, normal N-methylglycine) and near-abolished activity of the
      N140S variant.
- id: PMID:15340920
  title: 'Glycine N-methyltransferases: a comparison of the crystal structures and
    kinetic properties of recombinant human, mouse and rat enzymes.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Crystal structures and kinetics of recombinant human GNMT; supports
      activity, glycine binding, SAM metabolism, and homotetramer.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale Y2H screen (CCSB-HI1); source of a generic protein-binding
      IPI, not functionally specific for GNMT.
- id: PMID:17660255
  title: Destabilization of human glycine N-methyltransferase by H176N mutation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Biophysical/structural study of human GNMT tetramer and the destabilizing
      H176N disease variant; supports activity and homotetramerization.
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Human liver interactome screen; source of a generic protein-binding
      IPI, not functionally specific for GNMT.
- id: PMID:25502805
  title: A massively parallel pipeline to clone DNA variants and examine molecular
    phenotypes of human disease mutations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Clone-seq/Y2H interactome-scanning pipeline; GNMT (Gnmt) appears
      in a self-interaction/stability panel, consistent with homotetramer.
- id: PMID:26871637
  title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Alternative-splicing interactome study; source of generic protein-binding
      and self-interaction IPIs for GNMT.
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Population-scale interaction-disruption study; source of generic
      protein-binding and self-interaction IPIs for GNMT.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: HuRI reference binary interactome; multiple generic protein-binding
      IPIs for GNMT, not individually functionally validated.
- id: PMID:8281755
  title: Mammalian glycine N-methyltransferases. Comparative kinetic and structural
    properties of the enzymes from human, rat, rabbit and pig livers.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Comparative kinetic/structural study establishing human liver GNMT
      as an abundant homotetramer with cooperative SAM kinetics.
- id: Reactome:R-HSA-6798317
  title: GNMT tetramer transfers methyl group from AdoMet to Gly to form AdoHyc and
    SARC
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction for cytosolic GNMT tetramer catalyzing AdoMet-to-glycine
      methyl transfer; supports catalytic function and cytosol localization.