Gamt

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: nucleus is an unsupported IBA pan-ancestor localization call for Gamt. GAMT is a soluble cytosolic metabolic enzyme; rat liver subcellular fractionation localizes GAMT activity to the cytosolic fraction, and there is no experimental evidence for a nuclear pool or nuclear function. Downgraded from non-core to over-annotated. Reason: This compartment is not supported by the rat evidence, which places GAMT in the cytosolic fraction of liver; the nucleus call derives solely from an IBA pan-ancestor inference with no direct support. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN001282244 · PANTHER:PTN001282244 SUPPORTS SOURCE BUT NOT TARGET Current PTHR32379 PAINT slice confirms the nucleus IBD at this deep eukaryote node (taxon 2759, 2017-02-28), seeded by the S. cerevisiae family member (SGD:S000002873). Nuclear localization may be genuine for the yeast seed, but it does not transfer across this node - direct rat data place GAMT in the liver cytosolic fraction (nucleus and cytosol are mutually exclusive compartments), and the same node separately asserts cytoplasm (IBD seeded by S. pombe and S. cerevisiae members), which is the compartment the target evidence supports. No IRD prunes the mammalian branch, so the leak is a node-placement issue, not a withdrawn assertion. Supporting Evidence: file:rat/Gamt/Gamt-deep-research-falcon.md In rat liver, GAMT is primarily localized to the cytosolic fraction.
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: cytoplasm is retained for Gamt as supported contextual biology, but it is not the defining core function (IBA, GO_REF:0000033). Rat liver subcellular fractionation localizes GAMT enzymatic activity to the cytosolic fraction, corroborating cytoplasmic localization for this soluble metabolic enzyme. Reason: This term describes localization or oligomeric/interaction context rather than the defining catalytic role. Supporting Evidence: file:rat/Gamt/Gamt-deep-research-falcon.md the authors report that GAMT is primarily localized to the cytosolic fraction in rat liver. file:rat/Gamt/Gamt-deep-research-falcon.md In rat liver, GAMT is primarily localized to the cytosolic fraction.
GO:0006601 creatine biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: creatine biosynthetic process is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IBA, GO_REF:0000033). GAMT catalyzes the second/terminal step of the two-step endogenous creatine biosynthetic pathway. Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2. file:rat/Gamt/Gamt-deep-research-falcon.md GAMT is the second/terminal enzyme in the 2-step endogenous creatine pathway.
GO:0030731 guanidinoacetate N-methyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: guanidinoacetate N-methyltransferase activity is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IBA, GO_REF:0000033). This is the defining catalytic activity of GAMT, transferring a methyl group from SAM to guanidinoacetate to yield creatine. Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2. file:rat/Gamt/Gamt-deep-research-falcon.md GAMT transfers a methyl group from S-adenosylmethionine (SAM/AdoMet) to guanidinoacetate (GAA), yielding creatine.
GO:0030731 guanidinoacetate N-methyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: guanidinoacetate N-methyltransferase activity is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IEA, GO_REF:0000120). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2.
GO:0006601 creatine biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: creatine biosynthetic process is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IEA, GO_REF:0000120). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2.
GO:1990402 embryonic liver development	IEP PMID:15918910 Creatine synthesis and transport during rat embryogenesis: s...	MARK AS OVER ANNOTATED	Summary: The cited study maps where Gamt mRNA and protein appear during rat embryogenesis and finds expression in the hepatic primordium from day 12.5; this is an expression pattern, not evidence that Gamt shapes liver development (IEP, PMID:15918910). Reason: The evidence is spatiotemporal expression only. Being transcribed in a developing organ does not make a metabolic enzyme a participant in that organ's development, and nothing in the study perturbs Gamt or assays a hepatic developmental outcome. The appropriate reading is that the embryonic liver is a site of creatine synthesis from mid-gestation, which the accepted creatine biosynthetic process annotations already capture; the liver-development term over-reaches. Supporting Evidence: PMID:15918910 AGAT and GAMT are expressed in hepatic primordium as soon as 12.5 days UniProtKB:P10868 TISSUE SPECIFICITY: Expressed in hepatic primordium in the embryo as soon as 12.5 days.
GO:0006601 creatine biosynthetic process	ISO GO_REF:0000121	ACCEPT	Summary: creatine biosynthetic process is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (ISO, GO_REF:0000121). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2.
GO:0030731 guanidinoacetate N-methyltransferase activity	ISS GO_REF:0000024	ACCEPT	Summary: guanidinoacetate N-methyltransferase activity is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (ISS, GO_REF:0000024). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 CATALYTIC ACTIVITY: Reaction=guanidinoacetate + S-adenosyl-L-methionine = creatine
GO:0030731 guanidinoacetate N-methyltransferase activity	ISO GO_REF:0000121	ACCEPT	Summary: guanidinoacetate N-methyltransferase activity is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (ISO, GO_REF:0000121). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: UniProtKB:P10868 CATALYTIC ACTIVITY: Reaction=guanidinoacetate + S-adenosyl-L-methionine = creatine
GO:0006601 creatine biosynthetic process	TAS PMID:12079381 Crystal structure of guanidinoacetate methyltransferase from...	ACCEPT	Summary: creatine biosynthetic process is the gene's core process; the cited structural paper states it as the established role of the enzyme it solved (TAS, PMID:12079381). Reason: GAMT catalyses the terminal, committed step of creatine synthesis, converting guanidinoacetate to creatine with SAM as methyl donor, and the rat liver enzyme studied here is that enzyme. The author statement is consistent with the direct evidence on the same gene. Supporting Evidence: PMID:12079381 Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis. UniProtKB:P10868 CATALYTIC ACTIVITY: Reaction=guanidinoacetate + S-adenosyl-L-methionine = creatine
GO:0042802 identical protein binding	IPI PMID:12079381 Crystal structure of guanidinoacetate methyltransferase from...	KEEP AS NON CORE	Summary: Self-association was observed directly in the rat liver GAMT crystal structure, where the protein that had lost its N-terminal 36 residues during purification formed a dimer with an inter-subunit contact at the guanidinoacetate site; retained as oligomeric context, not as the defining activity (IPI, PMID:12079381). Reason: The interaction is real and structurally resolved, and the partner subunit even contributes a residue to the substrate site, so the annotation is not an inference. Two caveats keep it non-core. First, it is an oligomeric-state observation rather than a molecular activity. Second, the dimer was formed by the N-terminally truncated protein, and UniProt records the physiological species as a monomer that only may dimerise after that cleavage, which itself abolishes activity - so the self-association should not be read as the functional state of the enzyme in the cell. Supporting Evidence: PMID:12079381 The truncated enzyme forms a dimer, and each subunit contains one SAH molecule in the active site. Arg220 of the partner subunit forms a pair of hydrogen bonds with Asp134 at the guanidinoacetate-binding site. UniProtKB:P10868 SUBUNIT: Monomer. May form homodimers upon proteolytic removal of the first 36 amino acid residues.
GO:0006601 creatine biosynthetic process	IDA PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: c...	ACCEPT	Summary: creatine biosynthetic process is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IDA, PMID:15533043). Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: crystal structures of guanidinoacetate methyltransferase ternary complexes.
GO:0008757 S-adenosylmethionine-dependent methyltransferase activity	IDA PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: c...	ACCEPT	Summary: The ternary-complex structures of rat GAMT resolve the bound adenosyl cofactor and the methyl-transfer geometry, establishing SAM-dependent methyltransferase activity; this is the parent of the specific guanidinoacetate term the gene also carries (IDA, PMID:15533043). Reason: The cofactor is directly visualised in the active site and the proposed mechanism has the SAM methyl carbon approaching the guanidinoacetate nitrogen at bonding distance, so SAM dependence is demonstrated rather than assumed. The term is broader than GO:0030731 but correct, and a parent alongside the specific child is not a problem. Supporting Evidence: PMID:15533043 SAH has extensive interactions with GAMT through H-bonds and hydrophobic interactions. PMID:15533043 O(D1) of D134 and C(E) of SAM approach N(E) of GAA from the tetrahedral directions. file:rat/Gamt/Gamt-deep-research-falcon.md Required methyl donor/cofactor: SAM; acceptor substrate: guanidinoacetate.
GO:0030731 guanidinoacetate N-methyltransferase activity	IDA PMID:12069495 Myocellular creatine and creatine transporter serine phospho...	ACCEPT	Summary: guanidinoacetate N-methyltransferase activity is retained for Gamt, but PMID:12069495 only measured GAMT activity as a secondary starvation-study assay. Reason: The term is correct for Gamt; however, this particular PMID is marginal support because it reports that GAMT activity was not significantly changed in starved gastrocnemius muscle, rather than directly characterizing the enzyme. Supporting Evidence: PMID:12069495 Myocellular creatine and creatine transporter serine phosphorylation after starvation.
GO:0030731 guanidinoacetate N-methyltransferase activity	IDA PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: c...	ACCEPT	Summary: Ternary complexes of the intact rat enzyme with SAH plus guanidinoacetate (or the guanidine analogue) resolve the substrate in the active site and the mechanism of methyl transfer to its guanidino nitrogen, directly establishing guanidinoacetate N-methyltransferase activity (IDA, PMID:15533043). Reason: This is the gene's defining activity and the cited structures are of the rat enzyme with its own substrate bound, with the specific recognition contacts identified; the evidence is as direct as it gets for a transferase. Supporting Evidence: PMID:15533043 The guanidino groups of GAA and GUN form two pairs of H-bonds with E45 and D134, respectively. PMID:15533043 Guanidinoacetate methyltransferase (GAMT) is the enzyme that catalyzes the last step of creatine biosynthesis.
GO:0050843 S-adenosylmethionine catabolic process	IDA PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: c...	ACCEPT	Summary: S-adenosylmethionine catabolic process is retained for Gamt because it matches the documented core molecular role or a direct pathway consequence (IDA, PMID:15533043). The methyl-transfer reaction consumes SAM and releases S-adenosylhomocysteine (SAH) as the coproduct. Reason: This term is directly supported by Gamt conversion of guanidinoacetate to creatine using SAM as methyl donor. Supporting Evidence: PMID:15533043 Catalytic mechanism of guanidinoacetate methyltransferase: crystal structures of guanidinoacetate methyltransferase ternary complexes. file:rat/Gamt/Gamt-deep-research-falcon.md Coproduct is S-adenosylhomocysteine (SAH/AdoHcy).
GO:0030731 guanidinoacetate N-methyltransferase activity	NAS PMID:3277179 Molecular cloning, sequence analysis, and expression in Esch...	ACCEPT	Summary: The rat liver cDNA was cloned and expressed in E. coli, and the recombinant protein had guanidinoacetate methyltransferase activity with kinetics matching the purified liver enzyme - which ties this gene's sequence to the activity (NAS, PMID:3277179). Reason: Although recorded as an author statement, the cited work is the experiment that identified P10868 as the gene encoding the rat liver enzyme, by heterologous expression and kinetic comparison. The activity assignment for this gene product is therefore well grounded. Supporting Evidence: PMID:3277179 This protein represented as much as 5% of the bacterial soluble protein and showed the guanidinoacetate methyltransferase activity. PMID:3277179 Also, the enzyme showed kinetic properties indistinguishable from those of the liver enzyme.
GO:0007283 spermatogenesis	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: spermatogenesis is marked as over-annotated for Gamt; the evidence supports the gene's core activity or context, not this broader process claim (ISO, GO_REF:0000121). Reason: The available evidence supports creatine biosynthesis and expression in relevant tissues, not a direct role in this broad developmental or organismal-growth process. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:1098221 · mouse Gamt SUPPORTS SOURCE BUT NOT TARGET Mouse donor annotation reflects organism-level consequences of creatine deficiency rather than a direct Gamt role in spermatogenesis; the transfer propagates phenotype as function. Supporting Evidence: UniProtKB:P10868 FUNCTION: Converts guanidinoacetate to creatine
GO:0009887 animal organ morphogenesis	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: animal organ morphogenesis is marked as over-annotated for Gamt; the evidence supports the gene's core activity or context, not this broader process claim (ISO, GO_REF:0000121). Reason: The available evidence supports creatine biosynthesis and expression in relevant tissues, not a direct role in this broad developmental or organismal-growth process. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:1098221 · mouse Gamt SUPPORTS SOURCE BUT NOT TARGET Mouse donor annotation reflects organism-level consequences of creatine deficiency rather than a direct Gamt role in organ morphogenesis; the transfer propagates phenotype as function. Supporting Evidence: UniProtKB:P10868 FUNCTION: Converts guanidinoacetate to creatine
GO:0040014 regulation of multicellular organism growth	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: regulation of multicellular organism growth is marked as over-annotated for Gamt; the evidence supports the gene's core activity or context, not this broader process claim (ISO, GO_REF:0000121). Reason: The available evidence supports creatine biosynthesis and expression in relevant tissues, not a direct role in this broad developmental or organismal-growth process. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:1098221 · mouse Gamt SUPPORTS SOURCE BUT NOT TARGET Mouse donor annotation reflects growth impairment downstream of creatine deficiency, not a direct Gamt role in growth regulation; the transfer propagates phenotype as function. Supporting Evidence: UniProtKB:P10868 FUNCTION: Converts guanidinoacetate to creatine
GO:0006601 creatine biosynthetic process	ISO GO_REF:0000121	ACCEPT	Summary: Second ortholog transfer of creatine biosynthetic process, this one from human GAMT (UniProtKB:Q14353) rather than from the mouse gene; the rat enzyme independently has direct evidence for the same process, so the transfer is correct but adds nothing beyond it (ISO, GO_REF:0000121). Reason: Human GAMT is the orthologous terminal enzyme of creatine biosynthesis and is the donor UniProt itself uses for the rat FUNCTION statement, so the process transfers without reservation. Rat Gamt also carries direct evidence for the same term (IDA from the ternary-complex structures and from the rat liver enzyme), which makes this row redundant rather than wrong; it is accepted because the term is the gene's core process and duplicate rows with different evidence codes are not a problem in themselves. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q14353 SUPPORTS TRANSFER Human GAMT is the one-to-one ortholog and the source UniProt cites for the rat FUNCTION statement (ECO:0000250\|UniProtKB:Q14353); creatine biosynthesis is the shared core process, so the transfer is sound. It duplicates the rat gene's own direct evidence for the term rather than extending it. Supporting Evidence: UniProtKB:P10868 PATHWAY: Amine and polyamine biosynthesis; creatine biosynthesis; creatine from L-arginine and glycine: step 2/2. file:rat/Gamt/Gamt-deep-research-falcon.md GAMT is the second/terminal enzyme in the 2-step endogenous creatine pathway.

Gene Description

Existing Annotations Review

Core Functions

Gamt catalyzes the SAM-dependent methylation of guanidinoacetate to creatine, completing creatine biosynthesis.

References

Deep Research

Falcon

📚 Additional Documentation

Notes

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