id: Q14353
gene_symbol: GAMT
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GAMT encodes guanidinoacetate N-methyltransferase (EC 2.1.1.2), the second and terminal
  enzyme of endogenous creatine biosynthesis. It is a soluble cytosolic, S-adenosyl-L-methionine
  (SAM)-dependent methyltransferase of the class I-like SAM-binding superfamily (RMT2 family)
  that transfers a methyl group from SAM to guanidinoacetate, producing creatine and
  S-adenosyl-L-homocysteine. Guanidinoacetate is generated upstream by AGAT/GATM (largely in
  kidney); GAMT then methylates it, predominantly in liver, making creatine biosynthesis one of
  the body's largest single consumers of SAM-derived methyl groups and linking it to methionine
  and one-carbon metabolism. GAMT is most highly expressed in liver, with additional expression
  in skeletal muscle and brain (astrocytes and oligodendrocytes for local CNS creatine synthesis).
  Biallelic loss-of-function in GAMT causes cerebral creatine deficiency syndrome 2 (GAMT
  deficiency), an autosomal recessive disorder with brain creatine/phosphocreatine depletion,
  accumulation of neurotoxic guanidinoacetate, developmental delay, intellectual disability,
  intractable seizures and movement disturbance.
alternative_products:
- name: '1'
  id: Q14353-1
- name: '2'
  id: Q14353-2
  sequence_note: VSP_042722
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      GAMT is a soluble metabolic enzyme that acts in the cytoplasm; this localization is
      supportable but is broad context rather than the defining catalytic function. Kept as
      non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      Describes the cellular compartment in which GAMT acts rather than its core methyltransferase
      activity. Cytoplasmic localization is consistent with the cytosolic creatine-biosynthesis
      reaction; the more specific 'cytosol' term is also annotated.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Nucleus is an unsupported IBA pan-ancestor localization for GAMT. GAMT is a soluble
      cytosolic enzyme of creatine biosynthesis with no described nuclear pool or nuclear
      function; the human reaction is curated in the cytosol.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      No direct experimental support for a nuclear localization or nuclear role; the call derives
      solely from an IBA pan-ancestor inference and conflicts with the established cytosolic
      localization of this metabolic enzyme.
- term:
    id: GO:0006601
    label: creatine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Creatine biosynthetic process is a core biological process for GAMT, which catalyzes the
      terminal (step 2/2) reaction of the pathway.
    action: ACCEPT
    reason: >-
      Directly supported: GAMT methylates guanidinoacetate to creatine, completing endogenous
      creatine biosynthesis.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0030731
    label: guanidinoacetate N-methyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the defining catalytic activity of GAMT: SAM-dependent methylation of
      guanidinoacetate to creatine. Core molecular function.
    action: ACCEPT
    reason: >-
      Directly supported by the catalytic activity (EC 2.1.1.2; Rhea:10656) and corroborated by
      enzyme-deficiency evidence in patients.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0030731
    label: guanidinoacetate N-methyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core guanidinoacetate N-methyltransferase activity from
      EC 2.1.1.2 / Rhea:10656 / InterPro. Correct and concordant with experimental evidence.
    action: ACCEPT
    reason: >-
      The IEA mapping to the defining catalytic activity is correct for GAMT and matches the
      experimentally supported function.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from a high-throughput interactome (BioPlex) screen. The interaction
      is real but uninformative as a molecular function and no functional consequence is
      established for GAMT.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Per curation guidelines, generic protein binding does not describe an informative molecular
      function. The IPI interaction is retained as evidence (so not removed) but should not be
      treated as a function of GAMT.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from a binary interactome (HuRI) screen. Uninformative as a molecular
      function; no functional consequence established.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not an informative molecular function; high-throughput binary
      interaction without a characterized functional outcome for GAMT.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: >-
      Bare 'protein binding' from a proteome-scale interactome (BioPlex 3.0) screen. Uninformative
      as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding is not an informative molecular function; no functional consequence
      of the interaction is established for GAMT.
- term:
    id: GO:0006600
    label: creatine metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71288
  qualifier: involved_in
  review:
    summary: >-
      Creatine metabolic process is correct but is the broader parent of the more specific and
      better-supported 'creatine biosynthetic process'. Kept as non-core.
    action: KEEP_AS_NON_CORE
    reason: >-
      True for GAMT but less specific than creatine biosynthetic process, which captures the
      precise role of GAMT in the pathway.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0006601
    label: creatine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic assignment of creatine biosynthetic process (via UniPathway/ARBA). Concordant
      with the experimentally supported pathway role. Core process.
    action: ACCEPT
    reason: >-
      GAMT catalyzes step 2/2 of creatine biosynthesis; the IEA pathway assignment is correct.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0008168
    label: methyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71286
  qualifier: enables
  review:
    summary: >-
      Generic methyltransferase activity is correct but is a broad parent of the specific
      guanidinoacetate N-methyltransferase activity that is separately annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general: the specific child term GO:0030731 is the informative molecular function for
      GAMT and is already annotated.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-71286
  qualifier: located_in
  review:
    summary: >-
      Cytosol is the supported subcellular localization of this soluble metabolic enzyme; the
      creatine-synthesis reaction is curated in the cytosol. Kept as non-core localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Describes where GAMT acts rather than its catalytic function; cytosolic localization is
      consistent with biochemical fractionation of GAMT activity.
- term:
    id: GO:0006601
    label: creatine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8651275
  qualifier: involved_in
  review:
    summary: >-
      Direct assay evidence: patients with severe GAMT enzyme deficiency in liver accumulate
      guanidinoacetate and are creatine-deficient, demonstrating GAMT's role in creatine
      biosynthesis. Core process.
    action: ACCEPT
    reason: >-
      Supported by the demonstration that loss of GAMT activity blocks creatine synthesis and
      causes guanidinoacetate accumulation.
    supported_by:
    - reference_id: PMID:8651275
      supporting_text: >-
        In two children with an accumulation of guanidinoacetate in brain and a
        deficiency of creatine in blood, a severe deficiency of guanidinoacetate
        methyltransferase (GAMT) activity was detected in the liver.
- term:
    id: GO:0030731
    label: guanidinoacetate N-methyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:8651275
  qualifier: enables
  review:
    summary: >-
      Defining catalytic activity supported by mutational/enzyme-deficiency evidence: GAMT
      activity is severely reduced in patient liver carrying GAMT mutations. Core molecular
      function.
    action: ACCEPT
    reason: >-
      Loss of guanidinoacetate N-methyltransferase activity due to GAMT mutations establishes the
      enzyme's molecular function.
    supported_by:
    - reference_id: PMID:8651275
      supporting_text: >-
        a severe deficiency of guanidinoacetate
        methyltransferase (GAMT) activity was detected in the liver
- term:
    id: GO:0006601
    label: creatine biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:9325156
  qualifier: involved_in
  review:
    summary: >-
      Creatine biosynthetic process attributed via the GAMT gene-characterization paper. Concordant
      with the established core role. Core process.
    action: ACCEPT
    reason: >-
      Consistent with GAMT catalyzing the terminal step of creatine biosynthesis.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
- term:
    id: GO:0006936
    label: muscle contraction
  evidence_type: TAS
  original_reference_id: PMID:8547310
  qualifier: involved_in
  review:
    summary: >-
      GAMT is not a component of the muscle contraction apparatus. Any link to muscle contraction
      is an indirect, downstream physiological consequence of creatine availability (the
      creatine/phosphocreatine energy buffer), not a direct GAMT process.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Distal physiological consequence rather than a direct biological process of GAMT; GAMT acts
      as a metabolic enzyme producing creatine and has no direct role in contraction.
- term:
    id: GO:0008168
    label: methyltransferase activity
  evidence_type: TAS
  original_reference_id: PMID:9325156
  qualifier: enables
  review:
    summary: >-
      Generic methyltransferase activity, correct but a broad parent of the specific
      guanidinoacetate N-methyltransferase activity already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Over-general: superseded by the specific child term GO:0030731 for GAMT's informative
      molecular function.
    supported_by:
    - reference_id: UniProtKB:Q14353
      supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
core_functions:
- description: >-
    GAMT catalyzes the SAM-dependent methylation of guanidinoacetate to creatine, the terminal
    step of endogenous creatine biosynthesis, consuming S-adenosyl-L-methionine and releasing
    S-adenosyl-L-homocysteine.
  supported_by:
  - reference_id: UniProtKB:Q14353
    supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
  - reference_id: PMID:8651275
    supporting_text: >-
      a severe deficiency of guanidinoacetate
      methyltransferase (GAMT) activity was detected in the liver
  molecular_function:
    id: GO:0030731
    label: guanidinoacetate N-methyltransferase activity
  directly_involved_in:
  - id: GO:0006601
    label: creatine biosynthetic process
  - id: GO:0050843
    label: S-adenosylmethionine catabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  substrates:
  - id: CHEBI:57742
    label: guanidinoacetate
  - id: CHEBI:59789
    label: S-adenosyl-L-methionine
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: UniProtKB:Q14353
  title: Guanidinoacetate N-methyltransferase (GAMT), Homo sapiens - UniProtKB Q14353
  findings:
  - statement: >-
      GAMT converts guanidinoacetate to creatine using S-adenosylmethionine as the methyl donor;
      creatine biosynthesis step 2/2.
    supporting_text: Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      UniProt record for the gene under review; establishes the catalytic activity, pathway step,
      cytosolic reaction context and disease association.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput BioPlex interactome screen; source of a generic GAMT protein-binding (IPI)
      annotation with no characterized functional consequence.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI binary interactome screen; source of a generic GAMT protein-binding (IPI) annotation.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      BioPlex 3.0 proteome-scale interactome; source of a generic GAMT protein-binding (IPI)
      annotation.
- id: PMID:8547310
  title: Cloning and sequence analysis of human guanidinoacetate N-methyltransferase cDNA.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: >-
      Correctly identifies and clones human GAMT cDNA, but is used to support a 'muscle
      contraction' (GO:0006936) annotation, which is a distal physiological consequence rather
      than a direct GAMT process.
- id: PMID:8651275
  title: 'Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man.'
  findings:
  - statement: >-
      Severe deficiency of GAMT activity in liver causes guanidinoacetate accumulation in brain,
      creatine deficiency, and a treatable neurodevelopmental disorder.
    supporting_text: >-
      In two children with an accumulation of guanidinoacetate in brain and a
      deficiency of creatine in blood, a severe deficiency of guanidinoacetate
      methyltransferase (GAMT) activity was detected in the liver.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First report of GAMT deficiency; provides IDA/IMP support for GAMT activity and creatine
      biosynthesis and establishes the disease.
- id: PMID:9325156
  title: The human guanidinoacetate methyltransferase (GAMT) gene maps to a syntenic region on 19p13.3, homologous to band C of mouse chromosome 10, but GAMT is not mutated in jittery mice.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      GAMT gene mapping/characterization paper; consistent with the creatine biosynthetic role.
- id: Reactome:R-HSA-71286
  title: guanidinoacetate + S-adenosylmethionine => creatine + S-adenosylhomocysteine
  findings: []
- id: Reactome:R-HSA-71288
  title: Creatine metabolism
  findings: []
proposed_new_terms: []
suggested_questions:
- question: >-
    By what mechanism does guanidinoacetate (GAA) accumulation in GAMT deficiency drive
    neurotoxicity and epilepsy - direct GABA-A/glycine receptor effects, competition at the
    creatine transporter, or secondary metabolic disturbance - and how does it relate to the
    separate creatine-depletion component of the phenotype?
- question: >-
    What is GAMT's quantitative contribution to whole-body S-adenosyl-L-methionine (SAM)
    consumption and methyl-group demand, and how is hepatic GAMT flux coordinated with the
    methionine/one-carbon cycle?
- question: >-
    Is local CNS GAMT expression (vs. peripheral synthesis plus SLC6A8-mediated import)
    regulated, and does it matter for the brain creatine pool in health and disease?
- question: >-
    Does GAMT have any non-catalytic or moonlighting function beyond guanidinoacetate
    methylation?
suggested_experiments:
- description: >-
    Quantify SAM/SAH ratios and methylation flux in hepatocyte models with graded GAMT
    knockdown to measure GAMT's share of cellular methyl-group consumption.
- description: >-
    Dissect the GAA-toxicity vs. creatine-depletion contributions to the GAMT-deficiency
    phenotype using GAA-lowering (e.g. ornithine/arginine restriction) versus creatine
    supplementation in a GAMT-deficient model, with neurophysiological readouts.
- description: >-
    Map regulation of CNS GAMT expression across cell types and developmental stages, and test
    whether local synthesis or SLC6A8-mediated import dominates the brain creatine pool.