{"gene":"MAT1A","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1993,"finding":"MAT1A (liver S-adenosylmethionine synthetase) is encoded by a single-copy gene expressed exclusively in the liver, producing a single mRNA species encoding a 395-amino-acid protein with a calculated molecular mass of ~43.6 kDa. The gene structure and tissue-specific expression were characterized by Southern, Northern, and primer extension analyses.","method":"cDNA cloning, Southern blotting, Northern blotting, primer extension","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1 — full-length cDNA characterization with multiple orthogonal molecular methods; foundational paper","pmids":["8393662"],"is_preprint":false},{"year":1993,"finding":"The murine MAT1A ortholog (adult liver S-adenosylmethionine synthetase) spans ~18 kb with nine exons, contains a TATA box at -28 to -23 bp, and the -365 to -2 bp region drives liver-specific expression. The enzyme shares 96% amino acid identity with the human enzyme and contains the conserved ATP-binding motif Gly-X-Gly-X-X-Gly.","method":"cDNA/genomic cloning, transient expression assays in hepatocytes, primer extension, RACE","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — structural and functional characterization with multiple methods including promoter dissection","pmids":["8314764"],"is_preprint":false},{"year":1981,"finding":"Rat liver contains two species of S-adenosylmethionine synthetase (MAT I/III): synthetase alpha (apparent MW ~210 kDa, 9S, tetramer) exhibits negative cooperativity with low S0.5 for methionine (~17 µM) and ATP (~0.5 mM), while synthetase beta (apparent MW ~160 kDa, 5.5S, dimer) shows positive cooperativity with higher S0.5 values. Both require Mg²⁺ and K⁺ and are inhibited by p-chloromercuribenzoate, indicating essential thiols.","method":"Partial purification (~200-1000-fold), gel filtration, sedimentation analysis, kinetic studies","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic characterization with kinetic analysis; foundational biochemical paper replicated across labs","pmids":["7213623"],"is_preprint":false},{"year":1997,"finding":"Mammalian liver MAT (encoded by MAT1A) exists as two oligomeric forms: a homodimer (MAT III) and a homotetramer (MAT I) of the same catalytic subunit. Both isoenzymes are inhibited in human liver cirrhosis, explaining abnormal methionine metabolism in cirrhotic patients.","method":"Biochemical fractionation, molecular characterization, clinical liver biopsy analysis","journal":"Pharmacology & Therapeutics","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical characterization of oligomeric forms replicated across multiple studies; review synthesizing foundational work","pmids":["9175157"],"is_preprint":false},{"year":1995,"finding":"Mutations in the MAT1A gene cause partial inactivation of methionine adenosyltransferase activity, leading to isolated persistent hypermethioninemia. Site-directed mutagenesis of identified patient mutations and transient expression assays established that these mutations reduce but do not abolish MAT catalytic activity.","method":"Gene characterization, site-directed mutagenesis, transient expression assays","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis with functional assay; establishes structure-function relationship","pmids":["7560086"],"is_preprint":false},{"year":1996,"finding":"Complete loss of MAT1A activity (homozygous truncating mutations) causes brain demyelination, while missense mutations that partially retain activity do not. Mutations in the MATA1 gene that alter the reading frame produce truncated, enzymatically inactive MATα1 subunits, and the resulting loss of S-adenosylmethionine impairs synthesis of myelin phospholipids (phosphatidylcholine and sphingomyelin).","method":"Patient MATA1 gene sequencing, mutation characterization, correlation of genotype with neurological phenotype","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — genotype-phenotype correlation with molecular characterization across multiple patients; replicated in subsequent clinical studies","pmids":["8770875"],"is_preprint":false},{"year":2000,"finding":"Six novel MAT1A mutations were identified; compound heterozygotes and homozygotes for truncating/severely inactivating mutations develop very high plasma methionine (1226-1870 µM) and manifest brain gray matter abnormalities or demyelination, while patients with inactivating missense mutations or the dominant R264H mutation show lower methionine (105-467 µM) and are clinically unaffected, establishing a genotype-phenotype correlation.","method":"MAT1A sequencing in hypermethioninemic patients, plasma methionine measurement, brain MRI","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple patients with molecular characterization; genotype-phenotype correlation replicated across studies","pmids":["10677294"],"is_preprint":false},{"year":2001,"finding":"The R264H (R265H in rat) mutation produces a monomeric MAT with only 0.37% of AdoMet synthetic activity but retains tripolyphosphatase activity similar to wild-type. The R265H mutant subunit associates with wild-type subunit to form a heterodimer that cannot synthesize AdoMet; tripolyphosphatase activity is maintained in this hybrid but is not stimulated by methionine and ATP, indicating substrate binding is disrupted. This explains dominant inheritance of hypermethioninemia by dominant-negative subunit poisoning.","method":"Site-directed mutagenesis, in vivo expression, kinetic assays, activity measurements","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted mutant enzymes with in vitro activity assays and mutagenesis; explains dominant inheritance mechanism","pmids":["11278456"],"is_preprint":false},{"year":2010,"finding":"AUF1 binds the 3'-UTR of MAT1A mRNA and destabilizes it, while HuR stabilizes MAT2A mRNA. During hepatic de-differentiation and in HCC, increased AUF1 and HuR expression drives the MAT1A→MAT2A switch. S-adenosylmethionine treatment shifts the balance toward methyl-HuR (an inhibitor of MAT2A mRNA stability), restoring MAT1A expression. Both RNA-binding proteins regulate the MAT switch during fetal liver development and HCC progression.","method":"RNA-binding protein pulldown, mRNA stability assays, immunofluorescence, RNP complex analysis, in vitro and in vivo studies","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal RNP analyses with multiple cell models and in vivo validation; multiple orthogonal methods","pmids":["20102719"],"is_preprint":false},{"year":2012,"finding":"Three microRNAs — miR-664, miR-485-3p, and miR-495 — are upregulated in HCC and directly repress MAT1A expression. Knockdown of each miRNA individually or in combination induces MAT1A expression, reduces HCC cell growth, and increases apoptosis. Maintaining MAT1A expression significantly blocked the antitumorigenic effect of miRNA knockdown. Mechanistically, miRNA-mediated MAT1A repression reduces global CpG methylation and increases LIN28B expression.","method":"miRNA knockdown, stable overexpression, orthotopic liver cancer xenograft models, luciferase reporter assays","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple miRNAs validated with knockdown/OE, in vivo xenograft models, mechanistic rescue experiments","pmids":["23241961"],"is_preprint":false},{"year":2012,"finding":"MAT1A promoter undergoes CpG hypermethylation and histone H4 deacetylation in fast-growing HCC, while MAT2A promoter shows hypomethylation and H4 acetylation, driving the MAT1A:MAT2A switch. AUF1 protein destabilizes MAT1A mRNA and HuR stabilizes MAT2A mRNA in HCC. Forced MAT1A overexpression in HCC cells raises SAM levels, decreases cell proliferation, increases apoptosis, downregulates Cyclin D1, E2F1, IKK, NF-κB, and antiapoptotic BCL2/XIAP, and upregulates proapoptotic BAX/BAK.","method":"Promoter methylation analysis (bisulfite sequencing), histone acetylation assays, RNP complex analysis, forced overexpression with proliferation and apoptosis readouts","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 — epigenetic mechanism plus functional overexpression with multiple downstream pathway readouts","pmids":["22318685"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of human MAT1A and MAT2A in binary complexes with their product SAM were determined, revealing a compact active site with a gating loop that accommodates different substrate/product conformations during catalysis. Comparison with E. coli and rat structures shows the structural basis for catalysis. MAT2B has an SDR core with an NADP/H cofactor specificity and the SDR catalytic triad (YxxxKS).","method":"X-ray crystallography, ligand-bound complex structures","journal":"The Biochemical Journal","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with product-bound complexes, providing direct structural mechanism for catalysis","pmids":["23425511"],"is_preprint":false},{"year":2023,"finding":"Formaldehyde (FA) inhibits MAT1A by reacting with a hyperreactive cysteine residue (Cys120) in the active site, reducing SAM production in a MAT-isoform-specific manner. A genetic mouse model of chronic FA overload showed decreased SAM and reduced methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a serve as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle.","method":"Chemoproteomics (cysteine reactivity profiling), in vitro MAT1A activity assays, genetic mouse model, histone methylation analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — chemical biology with site-specific cysteine identification, in vitro activity assay, and in vivo mouse model validation","pmids":["37917677"],"is_preprint":false},{"year":2023,"finding":"A CTBP1/HDAC1/HDAC2 transcriptional repressor complex directly suppresses MAT1A transcription in HCC cells. Silencing HDAC1 or HDAC2, or overexpressing MAT1A, inhibited cancer cell malignancy. MAT1A overexpression increased intracellular SAM levels, which promoted ferroptosis of HCC cells and enhanced CD8+ T-cell cytotoxicity and IFN-γ production. In vivo, MAT1A overexpression suppressed CTBP1-induced xenograft tumor growth, and ferroptosis inhibitor ferrostatin-1 blocked these tumor-suppressive effects.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, MAT1A overexpression, xenograft mouse models, ferroptosis assays, CD8+ T-cell cytotoxicity assays","journal":"Laboratory Investigation","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying the repressor complex, functional rescue experiments, and in vivo xenograft validation with mechanistic pathway dissection","pmids":["37230466"],"is_preprint":false},{"year":2022,"finding":"miR-143 targets MAT1a mRNA in liver, and betaine supplementation downregulates miR-143 expression, which in turn increases SAM levels by de-repressing MAT1a. This regulatory axis controls hepatic lipogenesis and gluconeogenesis, with miR-143 KO promoting lipolysis and glucose utilization through repression of GPNMB and targeting MAPK11.","method":"miR-143 knockout mouse model, betaine supplementation experiments, luciferase reporter assays for MAT1a 3'-UTR targeting, metabolic phenotyping","journal":"Journal of Agricultural and Food Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with metabolic readouts and reporter validation, but MAT1a role is partially indirect","pmids":["35734958"],"is_preprint":false},{"year":2019,"finding":"MAT1A overexpression in bladder cancer cells (5637 line) increased tolerance to gemcitabine and stalled cell proliferation, suggesting MAT1A upregulation allows cancer cells to persist in a quiescent state to evade chemotherapy. MAT1A was identified as significantly upregulated in patient-derived xenograft tumors following cisplatin/gemcitabine treatment.","method":"PDX transcriptomic profiling (RNA-seq), MAT1A overexpression in cell lines, proliferation and drug tolerance assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 3 — overexpression with cell proliferation phenotype, supported by PDX data, but limited mechanistic pathway placement","pmids":["31600961"],"is_preprint":false}],"current_model":"MAT1A encodes the liver-specific catalytic subunit of methionine adenosyltransferase (MAT I/III), which exists as a homodimer (MAT III) or homotetramer (MAT I) and catalyzes S-adenosylmethionine (SAM) synthesis from methionine and ATP; its activity is inhibited by formaldehyde at Cys120, its expression is repressed by a CTBP1/HDAC1/HDAC2 complex and by miR-664/485-3p/495/143, and its mRNA is destabilized by AUF1 during HCC progression, with loss of MAT1A reducing hepatic SAM, impairing methylation reactions (including myelin phospholipid synthesis), and promoting HCC through NF-κB activation and reduced ferroptosis."},"narrative":{"teleology":[{"year":1981,"claim":"Establishing that liver SAM synthesis is catalyzed by two kinetically distinct oligomeric enzyme species answered the question of why hepatic methionine metabolism shows complex cooperativity: a high-affinity tetramer (MAT I) and a lower-affinity dimer (MAT III) partition methionine flux across physiological concentration ranges.","evidence":"Partial purification, gel filtration, sedimentation, and kinetic analysis of rat liver MAT species","pmids":["7213623"],"confidence":"High","gaps":["Subunit composition not yet linked to a specific gene","Regulatory mechanisms controlling interconversion between dimer and tetramer unknown","No structural information available"]},{"year":1993,"claim":"Cloning the human and murine MAT1A genes established that a single liver-specific gene encodes the catalytic subunit of both MAT I and MAT III, resolving the molecular identity of the liver-type SAM synthetase and revealing its tissue-restricted promoter.","evidence":"cDNA cloning, Northern blotting, Southern blotting, primer extension, and promoter-reporter assays in hepatocytes","pmids":["8393662","8314764"],"confidence":"High","gaps":["Transcription factor network driving liver-specific expression not defined","No disease mutations yet identified"]},{"year":1996,"claim":"Identification of patient mutations established that MAT1A deficiency causes isolated persistent hypermethioninemia and revealed a dose-dependent genotype–phenotype correlation: complete loss of activity causes brain demyelination via impaired myelin phospholipid synthesis, while partial loss is clinically benign.","evidence":"Patient MAT1A sequencing, site-directed mutagenesis with transient expression, plasma methionine measurement, and brain MRI across multiple families","pmids":["7560086","8770875","10677294"],"confidence":"High","gaps":["Precise threshold of residual activity that protects against neurological damage undefined","Mechanism linking SAM depletion to demyelination only inferred from lipid composition"]},{"year":2001,"claim":"Biochemical dissection of the R264H dominant mutation revealed a dominant-negative mechanism: the mutant subunit forms heterodimers with wild-type subunits that retain tripolyphosphatase activity but cannot synthesize SAM, explaining autosomal dominant hypermethioninemia.","evidence":"Site-directed mutagenesis, heterodimer reconstitution, kinetic assays for SAM synthesis and tripolyphosphatase activity","pmids":["11278456"],"confidence":"High","gaps":["Structural basis for disrupted substrate binding in heterodimer not resolved","Whether other dominant mutations share the same mechanism unknown"]},{"year":2012,"claim":"Multi-layered silencing of MAT1A in hepatocellular carcinoma was established: promoter CpG hypermethylation and histone deacetylation suppress transcription, AUF1 destabilizes MAT1A mRNA, and miR-664/miR-485-3p/miR-495 directly repress translation, while forced MAT1A re-expression raises SAM, reduces proliferation, and downregulates NF-κB and Cyclin D1 signaling.","evidence":"Bisulfite sequencing, histone acetylation assays, RNP pulldown, miRNA knockdown/overexpression, luciferase reporters, orthotopic xenograft models","pmids":["20102719","22318685","23241961"],"confidence":"High","gaps":["Relative contribution of each silencing layer to the MAT1A→MAT2A switch not quantified","Whether SAM-dependent tumor suppression operates identically across HCC subtypes untested"]},{"year":2013,"claim":"Crystal structures of human MAT1A in complex with SAM revealed the active-site architecture and gating loop dynamics underlying catalysis, providing the first structural framework for understanding isoform-specific kinetics and mutational effects.","evidence":"X-ray crystallography of human MAT1A–SAM binary complex","pmids":["23425511"],"confidence":"High","gaps":["No substrate (methionine + ATP) ternary complex captured","Structural basis for tetramer vs. dimer assembly not resolved at atomic level"]},{"year":2023,"claim":"Two new regulatory axes were identified: formaldehyde inhibits MAT1A by reacting with the hyperreactive Cys120 in the active site, coupling one-carbon metabolism to epigenetic output, while a CTBP1/HDAC1/HDAC2 repressor complex directly silences MAT1A transcription in HCC, with MAT1A re-expression promoting ferroptosis and enhancing anti-tumor CD8+ T-cell immunity.","evidence":"Chemoproteomics with cysteine profiling, genetic FA-overload mouse model, histone methylation analysis; Co-IP, ChIP, xenograft models, ferroptosis assays, CD8+ T-cell cytotoxicity assays","pmids":["37917677","37230466"],"confidence":"High","gaps":["Whether Cys120 modification is reversible in vivo and the identity of the repair pathway unknown","How SAM mechanistically triggers ferroptosis (lipid peroxidation substrate or iron regulation) not delineated","Interaction between formaldehyde sensing and HCC-associated MAT1A silencing unexplored"]},{"year":null,"claim":"Key unresolved questions include the structural basis for MAT I tetramer versus MAT III dimer equilibrium, the identity of factors that govern oligomeric interconversion in vivo, whether formaldehyde-Cys120 modification is enzymatically reversible, and the precise SAM-dependent mechanism by which MAT1A promotes ferroptosis.","evidence":"","pmids":[],"confidence":"High","gaps":["No ternary substrate complex structure","Dimer-tetramer interconversion mechanism unknown","Ferroptosis pathway downstream of SAM not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,7,11]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,7,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,8,10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,13]}],"complexes":["MAT I (homotetramer)","MAT III (homodimer)"],"partners":["AUF1","CTBP1","HDAC1","HDAC2"],"other_free_text":[]},"mechanistic_narrative":"MAT1A encodes the liver-specific catalytic subunit of methionine adenosyltransferase (MAT), which catalyzes S-adenosylmethionine (SAM) synthesis from methionine and ATP and assembles into kinetically distinct homodimeric (MAT III) and homotetrameric (MAT I) forms with differing methionine affinities [PMID:7213623, PMID:9175157]. Crystal structures reveal a compact active site with a gating loop that accommodates substrate and product conformations during catalysis, and the active-site Cys120 is a target for formaldehyde-mediated inhibition that reduces SAM production and downstream histone methylation in vivo [PMID:23425511, PMID:37917677]. MAT1A expression is silenced during hepatocarcinogenesis through CpG promoter hypermethylation, CTBP1/HDAC1/HDAC2 transcriptional repression, AUF1-mediated mRNA destabilization, and targeting by miR-664/miR-485-3p/miR-495/miR-143, and its restoration raises intracellular SAM, suppresses NF-κB signaling, and promotes ferroptosis in hepatocellular carcinoma cells [PMID:22318685, PMID:37230466, PMID:20102719, PMID:23241961]. Loss-of-function mutations in MAT1A cause autosomal recessive isolated persistent hypermethioninemia, with complete loss of activity leading to brain demyelination through impaired myelin phospholipid synthesis, while the dominant-negative R264H mutation poisons wild-type subunits within heterodimers [PMID:7560086, PMID:8770875, PMID:11278456]."},"prefetch_data":{"uniprot":{"accession":"Q00266","full_name":"S-adenosylmethionine synthase isoform type-1","aliases":["Methionine adenosyltransferase 1","MAT 1","Methionine adenosyltransferase I/III","MAT-I/III"],"length_aa":395,"mass_kda":43.6,"function":"Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q00266/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAT1A","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAT1A","total_profiled":1310},"omim":[{"mim_id":"610550","title":"METHIONINE ADENOSYLTRANSFERASE I, ALPHA; MAT1A","url":"https://www.omim.org/entry/610550"},{"mim_id":"607608","title":"SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1","url":"https://www.omim.org/entry/607608"},{"mim_id":"601468","title":"METHIONINE ADENOSYLTRANSFERASE II, ALPHA; MAT2A","url":"https://www.omim.org/entry/601468"},{"mim_id":"250850","title":"METHIONINE ADENOSYLTRANSFERASE I/III DEFICIENCY","url":"https://www.omim.org/entry/250850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":1259.5}],"url":"https://www.proteinatlas.org/search/MAT1A"},"hgnc":{"alias_symbol":["MAT","SAMS","MATA1","SAMS1","MAT-I/III"],"prev_symbol":[]},"alphafold":{"accession":"Q00266","domains":[{"cath_id":"3.30.300.10","chopping":"16-25_151-254","consensus_level":"medium","plddt":98.2749,"start":16,"end":254},{"cath_id":"3.30.300.10","chopping":"29-125","consensus_level":"medium","plddt":98.5703,"start":29,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00266","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00266-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00266-F1-predicted_aligned_error_v6.png","plddt_mean":96.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAT1A","jax_strain_url":"https://www.jax.org/strain/search?query=MAT1A"},"sequence":{"accession":"Q00266","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00266.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00266/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00266"}},"corpus_meta":[{"pmid":"22555442","id":"PMC_22555442","title":"Mating-type 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networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22939629","id":"PMC_22939629","title":"A census of human soluble protein complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33361760","citation_count":366,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1683972","id":"PMC_1683972","title":"Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway.","date":"1991","source":"Lancet (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/1683972","citation_count":202,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19913121","id":"PMC_19913121","title":"Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.","date":"2009","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19913121","citation_count":164,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16385451","id":"PMC_16385451","title":"A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.","date":"2005","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16385451","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23241961","id":"PMC_23241961","title":"MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma.","date":"2012","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23241961","citation_count":130,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7213623","id":"PMC_7213623","title":"Multiple species of mammalian S-adenosylmethionine synthetase. Partial purification and characterization.","date":"1981","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7213623","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35013218","id":"PMC_35013218","title":"EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35013218","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8770875","id":"PMC_8770875","title":"Demyelination of the brain is associated with methionine adenosyltransferase I/III deficiency.","date":"1996","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8770875","citation_count":91,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22318685","id":"PMC_22318685","title":"Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression.","date":"2012","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/22318685","citation_count":79,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32814053","id":"PMC_32814053","title":"Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32814053","citation_count":79,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20201926","id":"PMC_20201926","title":"Human variation in alcohol response is influenced by variation in neuronal signaling genes.","date":"2010","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/20201926","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8393662","id":"PMC_8393662","title":"Characterization of a full-length cDNA encoding human liver S-adenosylmethionine synthetase: tissue-specific gene expression and mRNA levels in hepatopathies.","date":"1993","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/8393662","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28700943","id":"PMC_28700943","title":"A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28700943","citation_count":64,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10677294","id":"PMC_10677294","title":"Methionine adenosyltransferase I/III deficiency: novel mutations and clinical variations.","date":"2000","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10677294","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8314764","id":"PMC_8314764","title":"Cloning and expression of murine S-adenosylmethionine synthetase.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8314764","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19161160","id":"PMC_19161160","title":"An association study of 45 folate-related genes in spina bifida: Involvement of cubilin (CUBN) and tRNA aspartic acid methyltransferase 1 (TRDMT1).","date":"2009","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/19161160","citation_count":61,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23425511","id":"PMC_23425511","title":"Insight into S-adenosylmethionine biosynthesis from the crystal structures of the human methionine adenosyltransferase catalytic and regulatory subunits.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23425511","citation_count":57,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37917677","id":"PMC_37917677","title":"Formaldehyde regulates S-adenosylmethionine biosynthesis and one-carbon metabolism.","date":"2023","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37917677","citation_count":57,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7560086","id":"PMC_7560086","title":"Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency.","date":"1995","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/7560086","citation_count":54,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46459,"output_tokens":2956,"usd":0.091858},"stage2":{"model":"claude-opus-4-6","input_tokens":6145,"output_tokens":2329,"usd":0.133425},"total_usd":0.499636,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60017,"output_tokens":4759,"usd":0.125718},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7868,"output_tokens":2390,"usd":0.148635}},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian gene MAT1A (methionine adenosyltransferase 1A, the liver-specific isoform encoding the catalytic subunit of MAT I/III). Most papers in this corpus are about unrelated topics (yeast mating type MAT locus, microbial mats, SAMs=self-assembled monolayers, etc.). I'll focus on papers relevant to the mammalian MAT1A gene.\n\nRelevant papers: PMIDs 20102719, 11278456, 25925782, 35729157, 37230466, 35734958, 7894257, 10644686, 15498786, 31600961, 16435220, 27816361\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The R264H mutation in MAT1A (equivalent to R265H in rat) produces a monomeric MAT enzyme with only 0.37% of normal AdoMet synthetic activity but retains tripolyphosphatase activity. The mutant subunit associates with wild-type MAT I/III subunits to form a catalytically inactive heterodimer, explaining the dominant inheritance of hypermethioninemia associated with this mutation.\",\n      \"method\": \"In vitro enzymatic assays (AdoMet synthesis and tripolyphosphatase activity), mutagenesis, in vivo co-expression studies demonstrating subunit association and dominant-negative effect\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis and in vitro enzyme assays, multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"11278456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAT1A mRNA stability is post-transcriptionally regulated by the RNA-binding protein AUF1, which binds to the 3' UTR of MAT1A and destabilizes its mRNA. S-adenosylmethionine treatment shifts the balance between AUF1 and methyl-HuR, altering MAT1A expression. This mechanism governs the MAT1A/MAT2A switch during hepatic de-differentiation, liver development, and hepatocellular carcinoma progression.\",\n      \"method\": \"In silico 3' UTR analysis, RNA-binding protein functional assays, immunofluorescence, mRNA stability measurements, SAM treatment experiments in cell culture and liver tissue\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (binding assays, mRNA stability, in vivo tissue analysis) from single lab\",\n      \"pmids\": [\"20102719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Methionine adenosyltransferase (MAT) activity is measurable in multiple human brain regions, with the highest activity in nucleus caudatus and putamen. Kinetic parameters (Km for methionine ~11 μM, Vmax ~25.7 nmol/mg protein/h) were established for the parietal cortex enzyme, and MAT activity in frontal cortex increases significantly with age.\",\n      \"method\": \"Enzymatic activity assays in human postmortem brain tissue with kinetic characterization\",\n      \"journal\": \"European neuropsychopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single enzymatic characterization in postmortem tissue, no mechanistic pathway placement\",\n      \"pmids\": [\"7894257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The beta regulatory subunit of human MAT II (encoded by a distinct gene from MAT1A) associates with both E. coli and human MAT alpha subunits (including MAT1A-encoded subunits), and this association lowers the Km for L-methionine, confirming the beta subunit's regulatory function in modulating MAT enzymatic activity.\",\n      \"method\": \"Recombinant protein expression in E. coli, co-association assays, kinetic characterization of Km for methionine\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — recombinant reconstitution with kinetic measurements, but primarily about MAT II beta subunit interacting with MAT alpha subunits generally\",\n      \"pmids\": [\"10644686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAT IIα (encoded by MAT2A, not MAT1A) is acetylated at lysine 81 by P300, which promotes its ubiquitylation and proteasomal degradation; HDAC3 deacetylates and stabilizes MAT IIα. This finding pertains specifically to MAT2A/MAT IIα, not MAT1A.\",\n      \"method\": \"Co-IP, mutagenesis, in vivo ubiquitylation assays, Western blot\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 method but finding is about MAT2A (MAT IIα), not MAT1A — included only to clarify distinction\",\n      \"pmids\": [\"25925782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MAT1A expression and methionine adenosyltransferase I/III activity are reduced in preneoplastic liver lesions during hepatocarcinogenesis in rats, with corresponding decreases in S-adenosylmethionine production and IκB-α expression, linking MAT1A enzymatic activity to NF-κB pathway regulation in early liver carcinogenesis.\",\n      \"method\": \"Rat hepatocarcinogenesis model ('resistant hepatocyte' model), enzymatic activity assays, mRNA expression analysis, NF-κB binding activity measurement\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function model with defined biochemical phenotype linking MAT1A activity to NF-κB/IκB-α pathway\",\n      \"pmids\": [\"15498786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human liver MAT1A and GNMT protein levels are significantly correlated, suggesting coordinate regulation of methionine cycle enzymes. Two SNPs in the GNMT gene region are strongly associated with hepatic GNMT protein levels, but no MAT1A-specific functional SNPs were identified at the same significance level. Large individual variation in MAT1A protein expression was documented in human hepatic biopsy samples.\",\n      \"method\": \"Gene resequencing of 288 subjects, quantitative Western blot of 268 hepatic biopsies, reporter gene assays for SNP functional validation, correlation analyses\",\n      \"journal\": \"Drug metabolism and disposition\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlation of protein levels with some functional genomics, limited direct mechanistic insight into MAT1A function\",\n      \"pmids\": [\"22807109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-143 targets MAT1A mRNA in liver, and betaine supplementation down-regulates miR-143, which subsequently increases MAT1A expression and raises hepatic S-adenosylmethionine levels, linking the betaine/one-carbon metabolism pathway to MAT1A post-transcriptional regulation.\",\n      \"method\": \"miR-143 knockout mice, betaine supplementation, luciferase reporter assays, SAM level measurement, Western blot and qPCR\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with mechanistic follow-up (reporter assay confirming miR-143 targeting of MAT1A) and multiple orthogonal methods\",\n      \"pmids\": [\"35734958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The CTBP1/HDAC1/HDAC2 transcriptional repressor complex binds the MAT1A promoter and suppresses MAT1A transcription in hepatocellular carcinoma. MAT1A overexpression increases intracellular SAM levels, promoting ferroptosis directly and indirectly by enhancing CD8+ T-cell cytotoxicity and IFN-γ production, thereby suppressing HCC tumor growth.\",\n      \"method\": \"Co-IP to demonstrate CTBP1/HDAC1/HDAC2 complex formation, ChIP or promoter binding assays, MAT1A overexpression in cell lines and xenograft mouse models, SAM level measurement, ferroptosis assays, immune cell cytotoxicity assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP for complex, overexpression with defined phenotypic readouts (ferroptosis, SAM levels, immune response) in vitro and in vivo\",\n      \"pmids\": [\"37230466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAT1A overexpression in bladder cancer cells increases tolerance to gemcitabine and stalls cell proliferation, suggesting MAT1A upregulation enables cancer cells to persist in a quiescent state and evade chemotherapy.\",\n      \"method\": \"Transcriptomic profiling of PDX tumors pre/post chemotherapy, MAT1A overexpression in 5637 bladder cancer cells, gemcitabine tolerance assay, cell proliferation assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with phenotype but limited pathway mechanism established\",\n      \"pmids\": [\"31600961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Three novel MAT1A mutations cause MAT I/III deficiency with concurrent hyperhomocysteinemia, establishing that loss of MAT1A catalytic function leads not only to hypermethioninemia but also to elevated homocysteine, expanding the biochemical phenotype of MAT1A deficiency.\",\n      \"method\": \"Genetic sequencing of MAT1A, biochemical plasma metabolite analysis in patients\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — clinical genetic finding with biochemical phenotype, limited direct mechanistic characterization\",\n      \"pmids\": [\"16435220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAT1A encodes the catalytic subunit of liver-specific methionine adenosyltransferase I/III (MAT I/III), which synthesizes S-adenosylmethionine (SAM) from methionine and ATP; its expression is post-transcriptionally regulated by AUF1 (destabilizing) and miR-143 (suppressive), and transcriptionally repressed by a CTBP1/HDAC1/HDAC2 complex in HCC; dominant-negative R264H mutations produce a monomeric enzyme that heterodimerizes with wild-type subunits to abolish AdoMet synthesis while retaining tripolyphosphatase activity; and MAT1A-derived SAM production suppresses hepatocellular carcinoma by promoting ferroptosis and enhancing anti-tumor immune responses.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of papers relevant to MAT1A (human/mammalian methionine adenosyltransferase 1A):**\n\nKEEP papers (canonical MAT1A protein):\n- [12] HuR/AUF1 regulate MAT expression (PMID:20102719)\n- [46] R264H mutation - monomeric MAT with tripolyphosphatase activity (PMID:11278456)\n- Additional curated: [11] S-adenosylmethionine synthesis review (PMID:9175157), [16] miRNAs regulate MAT1A (PMID:23241961), [17] Multiple species of MAT synthetase (PMID:7213623), [19] Demyelination with MAT I/III deficiency (PMID:8770875), [20] Transcriptional/posttranscriptional regulation (PMID:22318685), [23] Full-length cDNA human liver MAT (PMID:8393662), [25] MAT I/III deficiency mutations (PMID:10677294), [26] Murine SAM synthetase cloning (PMID:8314764), [28] Crystal structures human MAT1A/MAT2A/MAT2B (PMID:23425511), [29] Formaldehyde regulates SAM biosynthesis via MAT1A (PMID:37917677), [30] Molecular mechanisms MAT deficiency (PMID:7560086)\n- [75] CTBP1/HDAC1/HDAC2 suppress MAT1A in HCC (PMID:37230466)\n- [80] MAT1A in bladder cancer chemoresistance (PMID:31600961)\n- [61] miR-143 targets MAT1a (PMID:35734958)\n- [70] Human liver MAT1A/GNMT genomics (PMID:22807109)\n\nEXCLUDE: All yeast MAT locus papers (symbol collision - yeast mating type), microbial mat papers, SAM papers in plants/C.elegans/rice/Arabidopsis, electrospun fiber mat papers, self-assembled monolayer (SAM) papers, leptospirosis MAT test papers, chromosomal mat notation papers, matrine (MAT) drug papers, mast cell activation test papers, and other unrelated papers.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"MAT1A (liver S-adenosylmethionine synthetase) is encoded by a single-copy gene expressed exclusively in the liver, producing a single mRNA species encoding a 395-amino-acid protein with a calculated molecular mass of ~43.6 kDa. The gene structure and tissue-specific expression were characterized by Southern, Northern, and primer extension analyses.\",\n      \"method\": \"cDNA cloning, Southern blotting, Northern blotting, primer extension\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full-length cDNA characterization with multiple orthogonal molecular methods; foundational paper\",\n      \"pmids\": [\"8393662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The murine MAT1A ortholog (adult liver S-adenosylmethionine synthetase) spans ~18 kb with nine exons, contains a TATA box at -28 to -23 bp, and the -365 to -2 bp region drives liver-specific expression. The enzyme shares 96% amino acid identity with the human enzyme and contains the conserved ATP-binding motif Gly-X-Gly-X-X-Gly.\",\n      \"method\": \"cDNA/genomic cloning, transient expression assays in hepatocytes, primer extension, RACE\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and functional characterization with multiple methods including promoter dissection\",\n      \"pmids\": [\"8314764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1981,\n      \"finding\": \"Rat liver contains two species of S-adenosylmethionine synthetase (MAT I/III): synthetase alpha (apparent MW ~210 kDa, 9S, tetramer) exhibits negative cooperativity with low S0.5 for methionine (~17 µM) and ATP (~0.5 mM), while synthetase beta (apparent MW ~160 kDa, 5.5S, dimer) shows positive cooperativity with higher S0.5 values. Both require Mg²⁺ and K⁺ and are inhibited by p-chloromercuribenzoate, indicating essential thiols.\",\n      \"method\": \"Partial purification (~200-1000-fold), gel filtration, sedimentation analysis, kinetic studies\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic characterization with kinetic analysis; foundational biochemical paper replicated across labs\",\n      \"pmids\": [\"7213623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Mammalian liver MAT (encoded by MAT1A) exists as two oligomeric forms: a homodimer (MAT III) and a homotetramer (MAT I) of the same catalytic subunit. Both isoenzymes are inhibited in human liver cirrhosis, explaining abnormal methionine metabolism in cirrhotic patients.\",\n      \"method\": \"Biochemical fractionation, molecular characterization, clinical liver biopsy analysis\",\n      \"journal\": \"Pharmacology & Therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical characterization of oligomeric forms replicated across multiple studies; review synthesizing foundational work\",\n      \"pmids\": [\"9175157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Mutations in the MAT1A gene cause partial inactivation of methionine adenosyltransferase activity, leading to isolated persistent hypermethioninemia. Site-directed mutagenesis of identified patient mutations and transient expression assays established that these mutations reduce but do not abolish MAT catalytic activity.\",\n      \"method\": \"Gene characterization, site-directed mutagenesis, transient expression assays\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis with functional assay; establishes structure-function relationship\",\n      \"pmids\": [\"7560086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Complete loss of MAT1A activity (homozygous truncating mutations) causes brain demyelination, while missense mutations that partially retain activity do not. Mutations in the MATA1 gene that alter the reading frame produce truncated, enzymatically inactive MATα1 subunits, and the resulting loss of S-adenosylmethionine impairs synthesis of myelin phospholipids (phosphatidylcholine and sphingomyelin).\",\n      \"method\": \"Patient MATA1 gene sequencing, mutation characterization, correlation of genotype with neurological phenotype\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genotype-phenotype correlation with molecular characterization across multiple patients; replicated in subsequent clinical studies\",\n      \"pmids\": [\"8770875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Six novel MAT1A mutations were identified; compound heterozygotes and homozygotes for truncating/severely inactivating mutations develop very high plasma methionine (1226-1870 µM) and manifest brain gray matter abnormalities or demyelination, while patients with inactivating missense mutations or the dominant R264H mutation show lower methionine (105-467 µM) and are clinically unaffected, establishing a genotype-phenotype correlation.\",\n      \"method\": \"MAT1A sequencing in hypermethioninemic patients, plasma methionine measurement, brain MRI\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple patients with molecular characterization; genotype-phenotype correlation replicated across studies\",\n      \"pmids\": [\"10677294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The R264H (R265H in rat) mutation produces a monomeric MAT with only 0.37% of AdoMet synthetic activity but retains tripolyphosphatase activity similar to wild-type. The R265H mutant subunit associates with wild-type subunit to form a heterodimer that cannot synthesize AdoMet; tripolyphosphatase activity is maintained in this hybrid but is not stimulated by methionine and ATP, indicating substrate binding is disrupted. This explains dominant inheritance of hypermethioninemia by dominant-negative subunit poisoning.\",\n      \"method\": \"Site-directed mutagenesis, in vivo expression, kinetic assays, activity measurements\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted mutant enzymes with in vitro activity assays and mutagenesis; explains dominant inheritance mechanism\",\n      \"pmids\": [\"11278456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AUF1 binds the 3'-UTR of MAT1A mRNA and destabilizes it, while HuR stabilizes MAT2A mRNA. During hepatic de-differentiation and in HCC, increased AUF1 and HuR expression drives the MAT1A→MAT2A switch. S-adenosylmethionine treatment shifts the balance toward methyl-HuR (an inhibitor of MAT2A mRNA stability), restoring MAT1A expression. Both RNA-binding proteins regulate the MAT switch during fetal liver development and HCC progression.\",\n      \"method\": \"RNA-binding protein pulldown, mRNA stability assays, immunofluorescence, RNP complex analysis, in vitro and in vivo studies\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal RNP analyses with multiple cell models and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"20102719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Three microRNAs — miR-664, miR-485-3p, and miR-495 — are upregulated in HCC and directly repress MAT1A expression. Knockdown of each miRNA individually or in combination induces MAT1A expression, reduces HCC cell growth, and increases apoptosis. Maintaining MAT1A expression significantly blocked the antitumorigenic effect of miRNA knockdown. Mechanistically, miRNA-mediated MAT1A repression reduces global CpG methylation and increases LIN28B expression.\",\n      \"method\": \"miRNA knockdown, stable overexpression, orthotopic liver cancer xenograft models, luciferase reporter assays\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple miRNAs validated with knockdown/OE, in vivo xenograft models, mechanistic rescue experiments\",\n      \"pmids\": [\"23241961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MAT1A promoter undergoes CpG hypermethylation and histone H4 deacetylation in fast-growing HCC, while MAT2A promoter shows hypomethylation and H4 acetylation, driving the MAT1A:MAT2A switch. AUF1 protein destabilizes MAT1A mRNA and HuR stabilizes MAT2A mRNA in HCC. Forced MAT1A overexpression in HCC cells raises SAM levels, decreases cell proliferation, increases apoptosis, downregulates Cyclin D1, E2F1, IKK, NF-κB, and antiapoptotic BCL2/XIAP, and upregulates proapoptotic BAX/BAK.\",\n      \"method\": \"Promoter methylation analysis (bisulfite sequencing), histone acetylation assays, RNP complex analysis, forced overexpression with proliferation and apoptosis readouts\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism plus functional overexpression with multiple downstream pathway readouts\",\n      \"pmids\": [\"22318685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of human MAT1A and MAT2A in binary complexes with their product SAM were determined, revealing a compact active site with a gating loop that accommodates different substrate/product conformations during catalysis. Comparison with E. coli and rat structures shows the structural basis for catalysis. MAT2B has an SDR core with an NADP/H cofactor specificity and the SDR catalytic triad (YxxxKS).\",\n      \"method\": \"X-ray crystallography, ligand-bound complex structures\",\n      \"journal\": \"The Biochemical Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with product-bound complexes, providing direct structural mechanism for catalysis\",\n      \"pmids\": [\"23425511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Formaldehyde (FA) inhibits MAT1A by reacting with a hyperreactive cysteine residue (Cys120) in the active site, reducing SAM production in a MAT-isoform-specific manner. A genetic mouse model of chronic FA overload showed decreased SAM and reduced methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a serve as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle.\",\n      \"method\": \"Chemoproteomics (cysteine reactivity profiling), in vitro MAT1A activity assays, genetic mouse model, histone methylation analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — chemical biology with site-specific cysteine identification, in vitro activity assay, and in vivo mouse model validation\",\n      \"pmids\": [\"37917677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A CTBP1/HDAC1/HDAC2 transcriptional repressor complex directly suppresses MAT1A transcription in HCC cells. Silencing HDAC1 or HDAC2, or overexpressing MAT1A, inhibited cancer cell malignancy. MAT1A overexpression increased intracellular SAM levels, which promoted ferroptosis of HCC cells and enhanced CD8+ T-cell cytotoxicity and IFN-γ production. In vivo, MAT1A overexpression suppressed CTBP1-induced xenograft tumor growth, and ferroptosis inhibitor ferrostatin-1 blocked these tumor-suppressive effects.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, MAT1A overexpression, xenograft mouse models, ferroptosis assays, CD8+ T-cell cytotoxicity assays\",\n      \"journal\": \"Laboratory Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying the repressor complex, functional rescue experiments, and in vivo xenograft validation with mechanistic pathway dissection\",\n      \"pmids\": [\"37230466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-143 targets MAT1a mRNA in liver, and betaine supplementation downregulates miR-143 expression, which in turn increases SAM levels by de-repressing MAT1a. This regulatory axis controls hepatic lipogenesis and gluconeogenesis, with miR-143 KO promoting lipolysis and glucose utilization through repression of GPNMB and targeting MAPK11.\",\n      \"method\": \"miR-143 knockout mouse model, betaine supplementation experiments, luciferase reporter assays for MAT1a 3'-UTR targeting, metabolic phenotyping\",\n      \"journal\": \"Journal of Agricultural and Food Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with metabolic readouts and reporter validation, but MAT1a role is partially indirect\",\n      \"pmids\": [\"35734958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAT1A overexpression in bladder cancer cells (5637 line) increased tolerance to gemcitabine and stalled cell proliferation, suggesting MAT1A upregulation allows cancer cells to persist in a quiescent state to evade chemotherapy. MAT1A was identified as significantly upregulated in patient-derived xenograft tumors following cisplatin/gemcitabine treatment.\",\n      \"method\": \"PDX transcriptomic profiling (RNA-seq), MAT1A overexpression in cell lines, proliferation and drug tolerance assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with cell proliferation phenotype, supported by PDX data, but limited mechanistic pathway placement\",\n      \"pmids\": [\"31600961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAT1A encodes the liver-specific catalytic subunit of methionine adenosyltransferase (MAT I/III), which exists as a homodimer (MAT III) or homotetramer (MAT I) and catalyzes S-adenosylmethionine (SAM) synthesis from methionine and ATP; its activity is inhibited by formaldehyde at Cys120, its expression is repressed by a CTBP1/HDAC1/HDAC2 complex and by miR-664/485-3p/495/143, and its mRNA is destabilized by AUF1 during HCC progression, with loss of MAT1A reducing hepatic SAM, impairing methylation reactions (including myelin phospholipid synthesis), and promoting HCC through NF-κB activation and reduced ferroptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAT1A encodes the catalytic α subunit of the liver-specific methionine adenosyltransferase isoforms I and III (MAT I/III), which catalyze the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. The enzyme assembles as homo-oligomers; the dominant-negative R264H mutation produces a monomer that heterodimerizes with wild-type subunits and abolishes AdoMet synthesis while retaining tripolyphosphatase activity, and germline loss-of-function mutations cause hypermethioninemia with concurrent hyperhomocysteinemia [PMID:11278456, PMID:16435220]. MAT1A expression is post-transcriptionally controlled by the mRNA-destabilizing protein AUF1 and by miR-143, and is transcriptionally repressed in hepatocellular carcinoma by a CTBP1/HDAC1/HDAC2 complex at its promoter [PMID:20102719, PMID:35734958, PMID:37230466]. MAT1A-derived SAM production suppresses hepatocellular carcinoma growth by promoting ferroptosis and enhancing CD8+ T-cell anti-tumor immunity, and loss of MAT1A activity in preneoplastic liver lesions is linked to deregulated NF-κB signaling [PMID:37230466, PMID:15498786].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Initial characterization established that MAT enzymatic activity is present in human brain with defined kinetic parameters, but whether this reflected MAT1A or MAT2A isoforms was unresolved.\",\n      \"evidence\": \"Enzymatic activity assays with kinetic characterization in human postmortem brain tissue\",\n      \"pmids\": [\"7894257\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Isoform identity (MAT1A vs MAT2A) in brain not determined\", \"Postmortem tissue with potential activity loss\", \"No functional consequence of brain MAT activity explored\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The discovery that a distinct MAT II β regulatory subunit associates with MAT α subunits (including MAT1A-encoded) and lowers the Km for methionine clarified how MAT enzymatic properties can be allosterically tuned by subunit composition.\",\n      \"evidence\": \"Recombinant protein co-association and kinetic characterization in E. coli expression system\",\n      \"pmids\": [\"10644686\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of MAT1A–β subunit interaction in liver uncertain, as β subunit primarily co-expressed with MAT2A\", \"Structural basis of Km modulation not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstitution of the R264H mutant revealed the molecular basis of dominant hypermethioninemia: the mutation yields a monomer that retains tripolyphosphatase activity but loses >99% of AdoMet synthetic activity and poison-pills wild-type subunits through heterodimerization.\",\n      \"evidence\": \"In vitro mutagenesis, dual enzymatic assays (AdoMet synthesis and tripolyphosphatase), and co-expression demonstrating dominant-negative heterodimer formation\",\n      \"pmids\": [\"11278456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the mutant heterodimer not obtained\", \"Whether other hypermethioninemia mutations share the same dominant-negative mechanism unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that MAT1A downregulation in preneoplastic liver lesions correlates with reduced SAM and IκB-α levels linked MAT1A enzymatic output to NF-κB pathway regulation during hepatocarcinogenesis.\",\n      \"evidence\": \"Rat resistant-hepatocyte carcinogenesis model with enzymatic activity, mRNA, and NF-κB binding assays\",\n      \"pmids\": [\"15498786\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal relationship between SAM depletion and NF-κB activation not formally tested by rescue\", \"Mechanism connecting SAM to IκB-α expression not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of novel MAT1A mutations causing both hypermethioninemia and hyperhomocysteinemia expanded the metabolic phenotype of MAT I/III deficiency beyond methionine accumulation.\",\n      \"evidence\": \"Genetic sequencing and plasma metabolite analysis in patients\",\n      \"pmids\": [\"16435220\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mutations not biochemically characterized in vitro\", \"Mechanism of homocysteine elevation (impaired remethylation vs transsulfuration flux) not established\", \"Single clinical report without independent replication\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that AUF1 binds the MAT1A 3′ UTR to destabilize its mRNA, with SAM shifting the AUF1/methyl-HuR balance, established a post-transcriptional feedback loop governing the MAT1A-to-MAT2A switch during liver de-differentiation and cancer.\",\n      \"evidence\": \"RNA-binding protein assays, mRNA stability measurements, SAM treatment in cell culture and liver tissue\",\n      \"pmids\": [\"20102719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct identification of AUF1 binding site within 3′ UTR not mapped at nucleotide resolution\", \"In vivo AUF1 knockdown/knockout effect on MAT1A not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of miR-143 as a direct suppressor of MAT1A mRNA added a second post-transcriptional regulatory axis and linked dietary betaine to MAT1A/SAM levels via miR-143 downregulation.\",\n      \"evidence\": \"miR-143 knockout mice, luciferase reporter assays confirming direct targeting, betaine supplementation with SAM quantification\",\n      \"pmids\": [\"35734958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-143 regulation is liver-specific or operates in other tissues not addressed\", \"Relative contribution of miR-143 vs AUF1 to MAT1A regulation not compared\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstration that CTBP1/HDAC1/HDAC2 transcriptionally represses MAT1A in HCC, and that restoring MAT1A-derived SAM drives ferroptosis and enhances CD8+ T-cell cytotoxicity, provided a unified mechanism linking MAT1A silencing to immune evasion and tumor progression.\",\n      \"evidence\": \"Co-IP for CTBP1/HDAC1/HDAC2 complex, ChIP/promoter assays, MAT1A overexpression in xenograft models, ferroptosis and immune cytotoxicity assays\",\n      \"pmids\": [\"37230466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CTBP1/HDAC-mediated repression is the primary silencing mechanism vs DNA methylation or miRNAs in human HCC not resolved\", \"Specific SAM-dependent methylation events that trigger ferroptosis not identified\", \"Immunocompetent tumor model validation limited\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise SAM-dependent methylation targets through which MAT1A suppresses tumor growth (ferroptosis substrates, chromatin marks, signaling intermediates) remain unidentified, and no structural model of the CTBP1/HDAC-mediated promoter repression complex at the MAT1A locus exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Downstream methylation substrates mediating ferroptosis induction unknown\", \"Structural basis of MAT I vs MAT III oligomerization and its regulation incompletely understood\", \"Relative in vivo contributions of transcriptional, post-transcriptional, and miRNA regulation to MAT1A silencing in HCC not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\n      \"MAT I (homotetramer)\",\n      \"MAT III (homodimer)\"\n    ],\n    \"partners\": [\n      \"AUF1\",\n      \"CTBP1\",\n      \"HDAC1\",\n      \"HDAC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MAT1A encodes the liver-specific catalytic subunit of methionine adenosyltransferase (MAT), which catalyzes S-adenosylmethionine (SAM) synthesis from methionine and ATP and assembles into kinetically distinct homodimeric (MAT III) and homotetrameric (MAT I) forms with differing methionine affinities [PMID:7213623, PMID:9175157]. Crystal structures reveal a compact active site with a gating loop that accommodates substrate and product conformations during catalysis, and the active-site Cys120 is a target for formaldehyde-mediated inhibition that reduces SAM production and downstream histone methylation in vivo [PMID:23425511, PMID:37917677]. MAT1A expression is silenced during hepatocarcinogenesis through CpG promoter hypermethylation, CTBP1/HDAC1/HDAC2 transcriptional repression, AUF1-mediated mRNA destabilization, and targeting by miR-664/miR-485-3p/miR-495/miR-143, and its restoration raises intracellular SAM, suppresses NF-κB signaling, and promotes ferroptosis in hepatocellular carcinoma cells [PMID:22318685, PMID:37230466, PMID:20102719, PMID:23241961]. Loss-of-function mutations in MAT1A cause autosomal recessive isolated persistent hypermethioninemia, with complete loss of activity leading to brain demyelination through impaired myelin phospholipid synthesis, while the dominant-negative R264H mutation poisons wild-type subunits within heterodimers [PMID:7560086, PMID:8770875, PMID:11278456].\",\n  \"teleology\": [\n    {\n      \"year\": 1981,\n      \"claim\": \"Establishing that liver SAM synthesis is catalyzed by two kinetically distinct oligomeric enzyme species answered the question of why hepatic methionine metabolism shows complex cooperativity: a high-affinity tetramer (MAT I) and a lower-affinity dimer (MAT III) partition methionine flux across physiological concentration ranges.\",\n      \"evidence\": \"Partial purification, gel filtration, sedimentation, and kinetic analysis of rat liver MAT species\",\n      \"pmids\": [\"7213623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit composition not yet linked to a specific gene\", \"Regulatory mechanisms controlling interconversion between dimer and tetramer unknown\", \"No structural information available\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Cloning the human and murine MAT1A genes established that a single liver-specific gene encodes the catalytic subunit of both MAT I and MAT III, resolving the molecular identity of the liver-type SAM synthetase and revealing its tissue-restricted promoter.\",\n      \"evidence\": \"cDNA cloning, Northern blotting, Southern blotting, primer extension, and promoter-reporter assays in hepatocytes\",\n      \"pmids\": [\"8393662\", \"8314764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor network driving liver-specific expression not defined\", \"No disease mutations yet identified\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of patient mutations established that MAT1A deficiency causes isolated persistent hypermethioninemia and revealed a dose-dependent genotype–phenotype correlation: complete loss of activity causes brain demyelination via impaired myelin phospholipid synthesis, while partial loss is clinically benign.\",\n      \"evidence\": \"Patient MAT1A sequencing, site-directed mutagenesis with transient expression, plasma methionine measurement, and brain MRI across multiple families\",\n      \"pmids\": [\"7560086\", \"8770875\", \"10677294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise threshold of residual activity that protects against neurological damage undefined\", \"Mechanism linking SAM depletion to demyelination only inferred from lipid composition\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Biochemical dissection of the R264H dominant mutation revealed a dominant-negative mechanism: the mutant subunit forms heterodimers with wild-type subunits that retain tripolyphosphatase activity but cannot synthesize SAM, explaining autosomal dominant hypermethioninemia.\",\n      \"evidence\": \"Site-directed mutagenesis, heterodimer reconstitution, kinetic assays for SAM synthesis and tripolyphosphatase activity\",\n      \"pmids\": [\"11278456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for disrupted substrate binding in heterodimer not resolved\", \"Whether other dominant mutations share the same mechanism unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Multi-layered silencing of MAT1A in hepatocellular carcinoma was established: promoter CpG hypermethylation and histone deacetylation suppress transcription, AUF1 destabilizes MAT1A mRNA, and miR-664/miR-485-3p/miR-495 directly repress translation, while forced MAT1A re-expression raises SAM, reduces proliferation, and downregulates NF-κB and Cyclin D1 signaling.\",\n      \"evidence\": \"Bisulfite sequencing, histone acetylation assays, RNP pulldown, miRNA knockdown/overexpression, luciferase reporters, orthotopic xenograft models\",\n      \"pmids\": [\"20102719\", \"22318685\", \"23241961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each silencing layer to the MAT1A→MAT2A switch not quantified\", \"Whether SAM-dependent tumor suppression operates identically across HCC subtypes untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Crystal structures of human MAT1A in complex with SAM revealed the active-site architecture and gating loop dynamics underlying catalysis, providing the first structural framework for understanding isoform-specific kinetics and mutational effects.\",\n      \"evidence\": \"X-ray crystallography of human MAT1A–SAM binary complex\",\n      \"pmids\": [\"23425511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No substrate (methionine + ATP) ternary complex captured\", \"Structural basis for tetramer vs. dimer assembly not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two new regulatory axes were identified: formaldehyde inhibits MAT1A by reacting with the hyperreactive Cys120 in the active site, coupling one-carbon metabolism to epigenetic output, while a CTBP1/HDAC1/HDAC2 repressor complex directly silences MAT1A transcription in HCC, with MAT1A re-expression promoting ferroptosis and enhancing anti-tumor CD8+ T-cell immunity.\",\n      \"evidence\": \"Chemoproteomics with cysteine profiling, genetic FA-overload mouse model, histone methylation analysis; Co-IP, ChIP, xenograft models, ferroptosis assays, CD8+ T-cell cytotoxicity assays\",\n      \"pmids\": [\"37917677\", \"37230466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cys120 modification is reversible in vivo and the identity of the repair pathway unknown\", \"How SAM mechanistically triggers ferroptosis (lipid peroxidation substrate or iron regulation) not delineated\", \"Interaction between formaldehyde sensing and HCC-associated MAT1A silencing unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for MAT I tetramer versus MAT III dimer equilibrium, the identity of factors that govern oligomeric interconversion in vivo, whether formaldehyde-Cys120 modification is enzymatically reversible, and the precise SAM-dependent mechanism by which MAT1A promotes ferroptosis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ternary substrate complex structure\", \"Dimer-tetramer interconversion mechanism unknown\", \"Ferroptosis pathway downstream of SAM not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 7, 11]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 8, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"complexes\": [\n      \"MAT I (homotetramer)\",\n      \"MAT III (homodimer)\"\n    ],\n    \"partners\": [\n      \"AUF1\",\n      \"CTBP1\",\n      \"HDAC1\",\n      \"HDAC2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}