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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0006601 creatine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Creatine biosynthetic process is a core biological process for GAMT, which catalyzes the terminal (step 2/2) reaction of the pathway. Reason: Directly supported: GAMT methylates guanidinoacetate to creatine, completing endogenous creatine biosynthesis. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0030731 guanidinoacetate N-methyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the defining catalytic activity of GAMT: SAM-dependent methylation of guanidinoacetate to creatine. Core molecular function. Reason: Directly supported by the catalytic activity (EC 2.1.1.2; Rhea:10656) and corroborated by enzyme-deficiency evidence in patients. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0030731 guanidinoacetate N-methyltransferase activity | IEA GO_REF:0000120 | ACCEPT | 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. Reason: The IEA mapping to the defining catalytic activity is correct for GAMT and matches the experimentally supported function. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a binary interactome (HuRI) screen. Uninformative as a molecular function; no functional consequence established. Reason: Generic protein binding is not an informative molecular function; high-throughput binary interaction without a characterized functional outcome for GAMT. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Bare 'protein binding' from a proteome-scale interactome (BioPlex 3.0) screen. Uninformative as a molecular function. Reason: Generic protein binding is not an informative molecular function; no functional consequence of the interaction is established for GAMT. |
| GO:0006600 creatine metabolic process | TAS Reactome:R-HSA-71288 | KEEP AS NON CORE | 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. Reason: True for GAMT but less specific than creatine biosynthetic process, which captures the precise role of GAMT in the pathway. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0006601 creatine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of creatine biosynthetic process (via UniPathway/ARBA). Concordant with the experimentally supported pathway role. Core process. Reason: GAMT catalyzes step 2/2 of creatine biosynthesis; the IEA pathway assignment is correct. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0008168 methyltransferase activity | TAS Reactome:R-HSA-71286 | MARK AS OVER ANNOTATED | Summary: Generic methyltransferase activity is correct but is a broad parent of the specific guanidinoacetate N-methyltransferase activity that is separately annotated. Reason: Over-general: the specific child term GO:0030731 is the informative molecular function for GAMT and is already annotated. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0005829 cytosol | TAS Reactome:R-HSA-71286 | KEEP AS NON CORE | 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. Reason: Describes where GAMT acts rather than its catalytic function; cytosolic localization is consistent with biochemical fractionation of GAMT activity. |
| GO:0006601 creatine biosynthetic process | IDA PMID:8651275 Guanidinoacetate methyltransferase deficiency: the first inb... | ACCEPT | 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. Reason: Supported by the demonstration that loss of GAMT activity blocks creatine synthesis and causes guanidinoacetate accumulation. Supporting Evidence: PMID:8651275 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. |
| GO:0030731 guanidinoacetate N-methyltransferase activity | IMP PMID:8651275 Guanidinoacetate methyltransferase deficiency: the first inb... | ACCEPT | Summary: Defining catalytic activity supported by mutational/enzyme-deficiency evidence: GAMT activity is severely reduced in patient liver carrying GAMT mutations. Core molecular function. Reason: Loss of guanidinoacetate N-methyltransferase activity due to GAMT mutations establishes the enzyme's molecular function. Supporting Evidence: PMID:8651275 a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver |
| GO:0006601 creatine biosynthetic process | TAS PMID:9325156 The human guanidinoacetate methyltransferase (GAMT) gene map... | ACCEPT | Summary: Creatine biosynthetic process attributed via the GAMT gene-characterization paper. Concordant with the established core role. Core process. Reason: Consistent with GAMT catalyzing the terminal step of creatine biosynthesis. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
| GO:0006936 muscle contraction | TAS PMID:8547310 Cloning and sequence analysis of human guanidinoacetate N-me... | MARK AS OVER ANNOTATED | 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. 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. |
| GO:0008168 methyltransferase activity | TAS PMID:9325156 The human guanidinoacetate methyltransferase (GAMT) gene map... | MARK AS OVER ANNOTATED | Summary: Generic methyltransferase activity, correct but a broad parent of the specific guanidinoacetate N-methyltransferase activity already annotated. Reason: Over-general: superseded by the specific child term GO:0030731 for GAMT's informative molecular function. Supporting Evidence: UniProtKB:Q14353 Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Q: Does GAMT have any non-catalytic or moonlighting function beyond guanidinoacetate methylation?
Experiment: Quantify SAM/SAH ratios and methylation flux in hepatocyte models with graded GAMT knockdown to measure GAMT's share of cellular methyl-group consumption.
Experiment: 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.
Experiment: 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.
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