MAT1A encodes the alpha-1 catalytic subunit of the liver-specific methionine adenosyltransferase (S-adenosylmethionine synthase isoform type-1; EC 2.5.1.6), which assembles into the MAT I homotetramer and the MAT III homodimer. The enzyme catalyses S-adenosyl-L-methionine (SAM/AdoMet) synthesis from L-methionine and ATP (L-methionine + ATP + H2O -> S-adenosyl-L-methionine + phosphate + diphosphate) in an unusual two-step reaction that cleaves both ends of the ATP triphosphate chain, requiring Mg2+ and K+. SAM is the universal methyl donor for most cellular transmethylation reactions and the committed entry point of the methionine/SAM cycle. MAT1A is a cytosolic enzyme expressed predominantly in adult liver, where the bulk of SAM is produced. Loss-of-function variants cause methionine adenosyltransferase I/III deficiency (MATD; isolated persistent hypermethioninemia): usually clinically benign, but severe biallelic forms produce hepatic SAM deficiency and central-nervous-system demyelination.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004478 methionine adenosyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) call of the core catalytic molecular function. MAT1A is the liver alpha-1 subunit of methionine adenosyltransferase and directly synthesizes SAM from L-methionine and ATP. This is the defining activity of the gene and is corroborated by direct enzyme assays and structural work. Reason: Correct and central molecular function, consistent across the AdoMet synthase family and confirmed experimentally for human MAT1A. Supporting Evidence: file:human/MAT1A/MAT1A-uniprot.txt Reaction=L-methionine + ATP + H2O = S-adenosyl-L-methionine + phosphate PMID:23425511 MAT catalyses the transfer of the adenosyl group from ATP to the sulfur atom of Met (L-methionine), in an unusual two-step reaction cleaving at both ends of the ATP triphosphate chain |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) localization to the cytosol. MAT1A is a soluble cytosolic enzyme; SAM synthesis occurs in the cytoplasm and there are no membrane, signal, or organellar targeting features in the UniProt record. Reason: Correct subcellular location, consistent with the family and with Reactome TAS annotations to the same term. Supporting Evidence: PMID:10677294 The MAT1A gene is expressed primarily in the liver, the organ in which synthesis of the predominant portion of AdoMet occurs |
| GO:0006556 S-adenosylmethionine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) call of the core biological process: SAM biosynthesis. This is the process directly executed by the MAT catalytic activity and is the single-step pathway "S-adenosyl-L-methionine from L-methionine" in UniProt. Reason: Directly reflects the enzyme's committed catalytic role in producing the universal methyl donor; well supported experimentally. Supporting Evidence: PMID:23425511 MAT constitutes the first reaction step of the essential βmethionine cycleβ |
| GO:0004478 methionine adenosyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro, mapped to RHEA:21080 / EC 2.5.1.6) assignment of the core methionine adenosyltransferase activity. Duplicates the IBA and IDA calls for the same correct molecular function. Reason: Correct catalytic function; the InterPro/RHEA/EC mapping matches the experimentally demonstrated activity. Supporting Evidence: file:human/MAT1A/MAT1A-uniprot.txt EC=2.5.1.6 {ECO:0000269|PubMed:10677294} |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based electronic annotation of ATP binding. ATP is a co-substrate of the MAT reaction and the crystal structures resolve multiple ATP-binding residues, so the term is correct, though it is a sub-feature of the catalytic activity rather than a distinct core function. Reason: True molecular activity (ATP is a substrate; UniProt lists numerous ATP-binding residues), but non-core: it is subsumed by the methionine adenosyltransferase activity. Supporting Evidence: file:human/MAT1A/MAT1A-uniprot.txt Reaction=L-methionine + ATP + H2O = S-adenosyl-L-methionine + phosphate |
| GO:0006556 S-adenosylmethionine biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro/UniPathway) assignment of the SAM biosynthetic process, duplicating the IBA and IDA annotations for this core process. Reason: Correct process, matching the UniPathway "S-adenosyl-L-methionine from L-methionine" pathway and the experimental IDA/IMP evidence. Supporting Evidence: PMID:25075345 which is synthesized by methionine adenosyltransferase (MAT), is the main source of methyl groups |
| GO:0051259 protein complex oligomerization | IEA GO_REF:0000117 | MODIFY | Summary: Electronic (ARBA) annotation of generic protein complex oligomerization. MAT1A does oligomerize (MAT I homotetramer, MAT III homodimer), but a more specific and experimentally supported term, protein homotetramerization (GO:0051289), is already annotated by IDA. Reason: The essence is correct but the term is too general; the specific homo-oligomerization of identical subunits is better captured by GO:0051289 protein homotetramerization, which is directly supported by the crystal structure. Proposed replacements: protein homotetramerization Supporting Evidence: file:human/MAT1A/MAT1A-uniprot.txt Homotetramer (MAT-I); dimer of dimers (PubMed:23425511) |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IntAct/BioPlex 2.0 high-throughput affinity-purification mass-spectrometry interactome screen; the WITH/FROM records the MAT1A-MAT2A (P31153) association. The bare "protein binding" term is uninformative about the molecular function of MAT1A. Reason: Uninformative generic protein-binding term derived from a proteome-scale screen; per curation guidelines bare "protein binding" is not retained as a core function. Kept (not removed) because it is an experimental IPI. Supporting Evidence: PMID:28514442 uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IntAct/HuRI binary (yeast two-hybrid) interactome map; WITH/FROM records the MAT1A-MAT2A (P31153) interaction. Bare "protein binding" is uninformative. Reason: Generic protein-binding term from a proteome-scale binary interactome; not retained as a core molecular function per curation guidelines. Kept as an experimental IPI. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IntAct neurodegenerative-disease interactome screen; WITH/FROM records interactions with APP (P05067) and HTT (P42858). These are screen-derived associations, not an informative molecular function of MAT1A. Reason: Bare "protein binding" from a high-throughput interactome study; uninformative as a molecular function. Kept as an experimental IPI rather than removed. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IntAct/BioPlex 3.0 affinity-purification mass-spectrometry interactome; WITH/FROM records the MAT1A-MAT2A (P31153) association. Bare "protein binding" is uninformative. Reason: Generic protein-binding term from a proteome-scale AP-MS network; not a core molecular function per curation guidelines. Kept as an experimental IPI. Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IntAct multimodal cell-map (AP-MS/imaging) study; WITH/FROM records the MAT1A-MAT2A (P31153) association. Bare "protein binding" is uninformative. Reason: Generic protein-binding term from a systems-scale interactome/cell-map study; not retained as a core molecular function. Kept as an experimental IPI. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: IntAct/CCSB interactome mapping; WITH/FROM records a MAT1A-MAT1A (Q00266) self interaction. This self-association reflects the genuine biology of the enzyme, which forms the MAT I homotetramer and MAT III homodimer of identical alpha-1 subunits. Reason: Unlike bare "protein binding", identical protein binding is informative here: MAT1A is an obligate homo-oligomer (homotetramer/homodimer), so self-association is a real functional property. The self-interaction WITH/FROM (Q00266) is consistent with the crystal structure and UniProt SUBUNIT annotation. Supporting Evidence: PMID:10677294 MAT I and MAT III are homotetramers and homodimers of the file:human/MAT1A/MAT1A-uniprot.txt Homotetramer (MAT-I); dimer of dimers (PubMed:23425511) |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | ACCEPT | Summary: IntAct/HuRI binary interactome; self (Q00266) interaction. Reflects MAT1A homo-oligomerization into MAT I (tetramer) and MAT III (dimer). Reason: Informative and biologically correct: MAT1A self-association underlies the functional MAT I/III oligomers, consistent with structural and enzymatic evidence. Supporting Evidence: file:human/MAT1A/MAT1A-uniprot.txt Homotetramer (MAT-I); dimer of dimers (PubMed:23425511) |
| GO:0048269 methionine adenosyltransferase complex | IPI PMID:37917677 Formaldehyde regulates S-adenosylmethionine biosynthesis and... | ACCEPT | Summary: ComplexPortal assignment of MAT1A as a subunit of the methionine adenosyltransferase complex (the homomeric MAT I/III complex, CPX-3168/CPX-3169). The functional MAT1A enzyme is an oligomeric complex of alpha-1 subunits. Reason: MAT1A is only catalytically functional as an oligomeric MAT complex (homotetramer MAT I / homodimer MAT III), so part_of the methionine adenosyltransferase complex is correct. PMID:37917677 studies the MAT1A enzyme (the terminal enzyme of SAM biosynthesis) and its isoform-specific Cys120. Supporting Evidence: PMID:37917677 S-adenosylmethionine synthase isoform type-1 (MAT1A), the terminal enzyme in SAM biosynthesis, at a privileged, isoform-specific Cys120 file:human/MAT1A/MAT1A-uniprot.txt Homotetramer (MAT-I); dimer of dimers (PubMed:23425511) |
| GO:0006556 S-adenosylmethionine biosynthetic process | IDA PMID:25075345 Structure and function study of the complex that synthesizes... | ACCEPT | Summary: ComplexPortal IDA (direct assay) for the SAM biosynthetic process. This structure/ function study characterizes the ATP-driven synthesis of SAM by methionine adenosyltransferase enzymes, including demonstration that a MAT1A-containing complex (MAT(alpha1)4(betaV1)2) is stable in vitro. Reason: Directly supports the core SAM-biosynthesis process for the MAT enzymes; MAT1A is the liver catalytic subunit executing this reaction. Supporting Evidence: PMID:25075345 S-adenosylmethionine (SAMe) is the principal methyl donor of the cell and is PMID:25075345 the complex MAT(Ξ±1)4(Ξ²V1)2 is stable in vitro |
| GO:0048269 methionine adenosyltransferase complex | IPI PMID:25075345 Structure and function study of the complex that synthesizes... | ACCEPT | Summary: ComplexPortal assignment of MAT1A to the methionine adenosyltransferase complex, based on the structural characterization of MAT complexes. MAT1A (alpha-1) forms the homo-oligomeric MAT I/III complex and, in vitro, a MAT(alpha1)4(betaV1)2 assembly. Reason: Correct: MAT1A functions as part of an oligomeric methionine adenosyltransferase complex. This paper explicitly shows the MAT1A (alpha1)-containing complex is stable. Supporting Evidence: PMID:25075345 the complex MAT(Ξ±1)4(Ξ²V1)2 is stable in vitro |
| GO:0004478 methionine adenosyltransferase activity | IDA PMID:10677294 Methionine adenosyltransferase I/III deficiency: novel mutat... | ACCEPT | Summary: Direct assay (IDA) of methionine adenosyltransferase activity. Chamberlin et al. characterized MATD missense variants by transient-expression enzyme assays, measuring residual MAT activity relative to wild type (e.g. R264C has virtually no activity, G336R retains 23%), directly demonstrating the catalytic function of MAT1A. Reason: Experimental demonstration of the core catalytic activity in human MAT1A; the enzyme catalyses the two-step transfer of the adenosyl moiety of ATP to methionine to form AdoMet. Supporting Evidence: PMID:10677294 catalyzes an unusual two-step reaction that involves the transfer of the adenosyl moiety of ATP to methionine to form PMID:10677294 R264C has virtually no enzymatic activity |
| GO:0006556 S-adenosylmethionine biosynthetic process | IMP PMID:10677294 Methionine adenosyltransferase I/III deficiency: novel mutat... | ACCEPT | Summary: Mutant-phenotype (IMP) evidence for involvement in SAM biosynthesis: loss-of-function MAT1A variants abolish or greatly reduce MAT I/III activity and cause hepatic AdoMet synthesis deficiency (isolated hypermethioninemia), establishing the gene's role in the SAM biosynthetic process. Reason: Human genetic (variant) evidence directly ties MAT1A to SAM biosynthesis, the core process for this gene. Supporting Evidence: PMID:10677294 The MAT1A gene is expressed primarily in the liver, the organ in which synthesis of the predominant portion of AdoMet occurs |
| GO:0009087 L-methionine catabolic process | IMP PMID:10677294 Methionine adenosyltransferase I/III deficiency: novel mutat... | KEEP AS NON CORE | Summary: Mutant-phenotype (IMP) evidence: deleterious MAT1A variants cause abnormal accumulation of methionine (hypermethioninemia), because the SAM-synthesis reaction is the principal route of methionine consumption in the liver. In this sense MAT1A contributes to L-methionine catabolism/disposal via SAM formation. Reason: Defensible: the MAT reaction consumes L-methionine, and its loss causes methionine to accumulate, so MAT1A participates in methionine catabolism. However, the gene's core framing is SAM biosynthesis (methionine is the substrate), so methionine catabolism is a downstream/related process rather than the primary function. Supporting Evidence: PMID:10677294 is characterized by persistent hypermethioninemia without PMID:10677294 Current evidence establishes that deleterious MAT1A mutations cause abnormal accumulation of methionine |
| GO:0051289 protein homotetramerization | IDA PMID:23425511 Insight into S-adenosylmethionine biosynthesis from the crys... | ACCEPT | Summary: Direct (crystallographic) evidence that MAT1A assembles as a homotetramer (MAT I), described as a dimer of dimers, with the SAM-bound human MAT1A structure (PDB 2OBV). Reason: Experimentally demonstrated homo-oligomerization; MAT I is a homotetramer of the MAT1A alpha-1 subunit, and MAT III a homodimer. This is the specific, well-supported oligomerization term. Supporting Evidence: PMID:23425511 organizes into tetramer (isoform I) or dimer (isoform III) file:human/MAT1A/MAT1A-uniprot.txt Homotetramer (MAT-I); dimer of dimers (PubMed:23425511) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5603087 | ACCEPT | Summary: Reactome traceable-author-statement localization to the cytosol (reaction: defective MAT1A does not transfer Ado from ATP to L-Met). Consistent with the cytosolic IBA annotation. Reason: Correct cytosolic localization; MAT1A is a soluble cytoplasmic enzyme. Supporting Evidence: PMID:10677294 The MAT1A gene is expressed primarily in the liver, the organ in which synthesis of the predominant portion of AdoMet occurs |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174391 | ACCEPT | Summary: Reactome TAS localization to the cytosol (reaction: MAT1A multimers transfer Ado from ATP to L-Met). Duplicates the cytosol annotation for the SAM-synthesis reaction. Reason: Correct cytosolic localization of the SAM-synthesis reaction catalysed by MAT1A multimers. Supporting Evidence: PMID:23425511 organizes into tetramer (isoform I) or dimer (isoform III) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2408551 | ACCEPT | Summary: Reactome TAS localization to the cytosol (reaction: SeMet is converted to AdoSeMet by MAT). Reflects the cytosolic MAT activity acting on the selenomethionine analogue. Reason: Correct cytosolic localization; MAT can also adenosylate selenomethionine in the cytosol. Supporting Evidence: PMID:10677294 The MAT1A gene is expressed primarily in the liver, the organ in which synthesis of the predominant portion of AdoMet occurs |
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Download this section (compressed HTML)Q: Beyond forming the catalytic MAT I/III oligomers, does MAT1A have any physiologically relevant heteromeric partners in adult hepatocytes, or are its reported protein-binding interactions (e.g. with MAT2A, APP, HTT) artefacts of proteome-scale screens?
Q: How does isoform-specific regulation of the MAT1A Cys120 gating-loop residue (S-nitrosylation and formaldehyde adduction) modulate hepatic SAM levels in vivo?
Experiment: Quantitative in vitro kinetics (Km, Vmax) of recombinant human MAT I vs MAT III on L-methionine and ATP, with Mg2+/K+ dependence, to define the catalytic parameters distinct from the ubiquitous MAT2A isoform.
Experiment: Targeted metabolomics of hepatic SAM, SAH, and methionine in MAT1A-variant hepatocytes to correlate residual enzyme activity with methylation-potential (SAM/SAH ratio) and the clinical spectrum of MATD.
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