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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0017174 glycine N-methyltransferase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L- |
| GO:0046500 S-adenosylmethionine metabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L- |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred cytosolic localization, consistent with the cytoplasmic/cytosolic localization of the human enzyme. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0006111 regulation of gluconeogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. |
| GO:0006730 one-carbon metabolic process | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt Plays an |
| GO:0016594 glycine binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred glycine binding, corresponding to binding of the methyl-acceptor substrate. Directly supported experimentally for the human enzyme. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L- |
| GO:0042802 identical protein binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred self-association, consistent with GNMT being an obligate homotetramer. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0051289 protein homotetramerization | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred homotetramerization. GNMT assembles into a homotetramer, which is the active quaternary form and is required for full activity/stability. Reason: The homotetramer is directly demonstrated by crystallography and biophysical studies of the human enzyme; the disease variant H176N destabilizes the tetramer. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer PMID:8281755 all tetramers and exhibit |
| GO:1904047 S-adenosyl-L-methionine binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred SAM binding, corresponding to binding of the methyl-donor cofactor/substrate. Multiple SAM-binding residues are annotated in the human structure. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt ligand="S-adenosyl-L-methionine" |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization from the UniProt Subcellular Location vocabulary. Consistent with the known cytosolic localization of GNMT. Reason: Matches the UniProt SUBCELLULAR LOCATION (Cytoplasm) and experimental cytosol localization; correct though less specific than the cytosol annotation. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0017174 glycine N-methyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of glycine N-methyltransferase activity via automated pipelines (ARBA/InterPro/RHEA/EC mapping). Correct core molecular function. Reason: The electronic mapping (EC 2.1.1.20, RHEA:19937, InterPro IPR014369) correctly recapitulates the experimentally established core function. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt EC=2.1.1.20 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:16189514 an initial version of a proteome-scale map of |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: Interaction reported in a human liver protein interaction network study. Bare protein binding is uninformative about GNMT's molecular function. Reason: Large-scale interactome hit yielding only the generic protein binding term; no specific, functionally interpretable GNMT molecular function is implied. Supporting Evidence: PMID:21988832 protein interaction network of the human liver |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MARK AS OVER ANNOTATED | Summary: Interaction reported in a large-scale alternative-splicing interactome study. Bare protein binding is uninformative about GNMT's molecular function. Reason: High-throughput interactome hit yielding only generic protein binding; no specific GNMT molecular function is implied. Supporting Evidence: PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by Alternative |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Interaction reported in a population-scale variant/interaction-disruption study. Bare protein binding is uninformative about GNMT's molecular function. Reason: High-throughput interactome hit yielding only generic protein binding; no specific GNMT molecular function is implied. Supporting Evidence: PMID:31515488 disruption of protein interactions by genetic variants |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Multiple interactions reported in the HuRI reference human binary interactome. Bare protein binding is uninformative about GNMT's molecular function. 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. Supporting Evidence: PMID:32296183 reference interactome map of human binary protein interactions |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: Self-interaction of GNMT detected in a proteome-scale two-hybrid screen (partner UniProtKB:Q14749), consistent with the homotetramer. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0042802 identical protein binding | IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam... | KEEP AS NON CORE | Summary: GNMT self-interaction assayed in the Clone-seq/Y2H interactome-scanning pipeline (partner UniProtKB:Q14749), consistent with homotetramer formation. Reason: Reflects the known self-association of the homotetrameric enzyme; retained as a non-core structural attribute. Supporting Evidence: PMID:25502805 Hprt1, Pnp, Tpk1, Gnmt, Gale |
| GO:0042802 identical protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | KEEP AS NON CORE | Summary: GNMT self-interaction reported (partner UniProtKB:Q14749), consistent with the homotetramer. Reason: Reflects GNMT's homotetrameric self-association; non-core structural detail. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0042802 identical protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: GNMT self-interaction reported (partner UniProtKB:Q14749), consistent with the homotetramer. Reason: Reflects GNMT's homotetrameric self-association; non-core structural detail. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0016594 glycine binding | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of glycine binding (methyl-acceptor substrate) via automated pipelines. Correct mechanistic component of the enzyme's function. Reason: Consistent with the experimentally observed glycine binding and with the glycine N-methyltransferase reaction. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt KM=12.2 uM for glycine |
| GO:0046500 S-adenosylmethionine metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of involvement in SAM metabolism via automated pipelines. Correct process context (GNMT consumes SAM and regulates the SAM:SAH ratio). Reason: Agrees with the manually and phylogenetically supported SAM-metabolic role of GNMT. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt regulating the ratio between S-adenosyl-L-methionine and S-adenosyl-L- |
| GO:0051289 protein homotetramerization | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of homotetramerization via automated pipelines. Correct; GNMT is a homotetramer. Reason: Consistent with crystallographic and biophysical evidence that human GNMT is a homotetramer. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct (immunofluorescence, Human Protein Atlas) evidence of cytosolic localization of GNMT. Reason: Experimental localization consistent with GNMT being a soluble cytosolic enzyme; this is the most specific and best-supported localization term. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based cytoplasmic localization transferred from the rat ortholog (UniProtKB:P13255). Consistent with the known cytosolic localization. Reason: The ISS transfer from the well-characterized rat ortholog matches the human enzyme's cytosolic localization; correct though less specific than cytosol. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0017174 glycine N-methyltransferase activity | EXP PMID:14651980 Effect of naturally occurring mutations in human glycine N-m... | ACCEPT | 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. Reason: Kinetic assays of the purified human enzyme directly demonstrate glycine N-methyltransferase activity; the core molecular function. Supporting Evidence: PMID:14651980 toward both substrates, S-adenosylmethionine |
| GO:0017174 glycine N-methyltransferase activity | EXP PMID:14739680 Glycine N -methyltransferase deficiency: a new patient with ... | ACCEPT | 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. 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. |
| GO:0017174 glycine N-methyltransferase activity | EXP PMID:17660255 Destabilization of human glycine N-methyltransferase by H176... | ACCEPT | Summary: Structural/biophysical study of human GNMT (including the H176N disease variant) measuring enzyme activity, confirming glycine N-methyltransferase activity. Reason: Direct activity measurement on the human tetrameric enzyme; supports the core molecular function and links tetramer stability to activity. Supporting Evidence: PMID:17660255 the tetrameric enzyme, |
| GO:0017174 glycine N-methyltransferase activity | EXP PMID:8281755 Mammalian glycine N-methyltransferases. Comparative kinetic ... | ACCEPT | Summary: Comparative kinetic/structural characterization of mammalian GNMTs including the human liver enzyme, establishing glycine N-methyltransferase catalytic activity. Reason: Direct kinetic characterization of the human liver enzyme; confirms the core molecular function and its homotetrameric, cooperative behavior toward SAM. Supporting Evidence: PMID:8281755 Human liver contains a rather high level of glycine N-methyltransferase |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6798317 | ACCEPT | Summary: Reactome-asserted cytosolic localization of the GNMT tetramer catalyzing the AdoMet-to-glycine methyl transfer. Reason: Consistent with experimental cytosol localization and the enzyme's soluble cytosolic nature. Supporting Evidence: Reactome:R-HSA-6798317 Cytosolic glycine N-methyltransferase (GNMT) catalyses the transfer of a methyl group from S-adenosylmethionine |
| GO:0016594 glycine binding | IDA PMID:15340920 Glycine N-methyltransferases: a comparison of the crystal st... | ACCEPT | Summary: Crystal structures and kinetic analysis of recombinant human (and mouse/rat) GNMT, providing direct evidence for glycine binding at the active site. Reason: Structural/kinetic characterization of the human enzyme directly supports binding of the glycine substrate. Supporting Evidence: PMID:15340920 Human and mouse GNMT were |
| GO:0017174 glycine N-methyltransferase activity | IDA PMID:15340920 Glycine N-methyltransferases: a comparison of the crystal st... | ACCEPT | Summary: Direct structural and kinetic characterization of recombinant human GNMT, confirming glycine N-methyltransferase activity. Reason: The comparison of crystal structures and kinetic properties of the recombinant human enzyme directly establishes the core catalytic function. Supporting Evidence: PMID:15340920 crystal structures and kinetic |
| GO:0046500 S-adenosylmethionine metabolic process | IDA PMID:15340920 Glycine N-methyltransferases: a comparison of the crystal st... | ACCEPT | Summary: The kinetic characterization of human GNMT (consuming SAM to methylate glycine) supports its participation in S-adenosylmethionine metabolism. Reason: GNMT catalytically consumes SAM; direct kinetic study of the human enzyme supports its role in SAM metabolism (methyl-group disposal / SAM:SAH regulation). Supporting Evidence: PMID:15340920 kinetic properties of recombinant human |
| GO:0051289 protein homotetramerization | IPI PMID:15340920 Glycine N-methyltransferases: a comparison of the crystal st... | ACCEPT | Summary: The crystal structures of recombinant human GNMT demonstrate the homotetrameric (subunit) assembly of the enzyme. Reason: Crystallographic determination of subunit organization directly supports homotetramerization of the human enzyme. Supporting Evidence: PMID:8281755 all tetramers and exhibit file:human/GNMT/GNMT-uniprot.txt SUBUNIT: Homotetramer |
| GO:0032259 methylation | IDA PMID:8281755 Mammalian glycine N-methyltransferases. Comparative kinetic ... | NEW | 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. 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. Supporting Evidence: file:human/GNMT/GNMT-uniprot.txt Reaction=glycine + S-adenosyl-L-methionine = sarcosine + S-adenosyl-L- PMID:8281755 Human liver contains a rather high level of glycine N-methyltransferase |
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Download this section (compressed HTML)Q: 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?
Q: Are any of the high-throughput binary interactors (e.g. ARRB1, NTAQ1, SNRNP200) physiologically meaningful, or are they screen artifacts?
Experiment: Structure-guided kinetic dissection of 5-methyltetrahydrofolate feedback inhibition to quantify how folate status tunes the SAM:SAH ratio in hepatocytes.
Experiment: Metabolic flux analysis in GNMT-deficient vs wild-type hepatocytes to directly measure the contribution of GNMT to SAM disposal and methylation capacity.
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