{"gene":"MAT2A","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2000,"finding":"The beta (MAT2B) regulatory subunit of human MAT II was cloned and shown to associate with both E. coli and human MAT alpha subunits, changing their kinetic properties and lowering the Km for L-methionine, confirming its regulatory function.","method":"Recombinant protein expression, co-association assay, kinetic characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted protein interaction with functional kinetic readout in a single rigorous study","pmids":["10644686"],"is_preprint":false},{"year":2000,"finding":"The MAT2A proximal promoter contains an Sp1 site at position -69 (Sp1-3) essential for in vitro and in vivo promoter activity, with Sp2 and Sp3 (not Sp1) being the primary transcription factors binding this site as shown by supershift assay and ChIP.","method":"Promoter deletion analysis, EMSA, supershift assay, in vivo reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in a single study","pmids":["11124935"],"is_preprint":false},{"year":2001,"finding":"The MAT2B gene promoter has a minimal promoter between +52 and +93, with an Sp1 site at +9/+15 and a TATA at -32 conferring full activity; Sp3 (not Sp1) is the primary factor binding the Sp1 site as determined by ChIP and supershift assays.","method":"Promoter deletion analysis, EMSA, supershift assay, ChIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in a single study","pmids":["11337507"],"is_preprint":false},{"year":2001,"finding":"Leukemic T cells show distinct protein-DNA interaction patterns at the MAT2A proximal promoter compared to normal T cells, with higher expression of Sp2/Sp3 in leukemic cells correlating with increased in vitro promoter activity.","method":"EMSA, supershift assay, in vivo reporter assay comparison between normal and leukemic T cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods but single lab, comparative study","pmids":["11476892"],"is_preprint":false},{"year":2007,"finding":"siRNA-mediated silencing of MAT2A in hepatoma cells reduced MAT II activity, increased SAM levels and the SAM:SAH ratio, inhibited cell growth, induced apoptosis, and caused a switch of MAT gene expression from MAT2A to MAT1A mediated by elevated SAM.","method":"RNA interference, enzymatic activity assay, metabolite measurement, cell growth and apoptosis assays","journal":"Hepatology research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined metabolic and cellular phenotype, single lab","pmids":["17441811"],"is_preprint":false},{"year":2007,"finding":"MAT2A transcription is induced at two discrete time points during liver regeneration (G0-G1 and G1-S transitions), regulated by E2F1/E2F3/E2F4 factors and Sp1 binding to the promoter with accompanying changes in histone-modifying enzyme occupancy.","method":"RNApol-ChIP, EMSA, ChIP for transcription factors and histone modifiers","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 2 — ChIP and EMSA with functional context, multiple orthogonal methods","pmids":["17317269"],"is_preprint":false},{"year":2011,"finding":"Hypoxia-induced MAT2A expression is HIF-1α-dependent and requires recruitment of p300 and HDAC1 to an authentic HIF-1α binding site in the MAT2A promoter, leading to reduced SAM levels and global DNA demethylation in hepatoma cells.","method":"Site-directed mutagenesis of HIF-1α binding site, EMSA, ChIP, SAM measurement, methylation assay","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis, EMSA and ChIP with functional metabolic readout","pmids":["21460102"],"is_preprint":false},{"year":2016,"finding":"MAT2A produces SAM as substrate for PRMT5, and MTAP loss causes accumulation of MTA which selectively inhibits PRMT5; MAT2A depletion selectively reduces PRMT5 methylation activity and growth in MTAP-deleted cells, establishing a MAT2A/PRMT5/RIOK1 synthetic lethal axis.","method":"shRNA screening, metabolomics, biochemical methyltransferase profiling, cell viability assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, widely replicated across the field","pmids":["27068473"],"is_preprint":false},{"year":2017,"finding":"PF-9366 binds an allosteric site on MAT2A overlapping with the MAT2B binding site; allosteric binding of PF-9366 or MAT2B increases substrate affinity but decreases enzyme turnover, with MAT2B functioning as inhibitor when methionine/SAM levels are high and activator when levels are low.","method":"Biochemical enzyme kinetics, allosteric inhibitor characterization, structural overlap analysis","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic reconstitution with mechanistic detail, single rigorous study","pmids":["28553945"],"is_preprint":false},{"year":2017,"finding":"Human MAT2A catalyzes SAM formation through an advanced SN2 transition state with the bond-forming methionine sulfur to ATP 5'-C at 2.03 Å and bond-breaking triphosphate at 2.32 Å; interaction with MAT2B regulatory subunit does not alter the intrinsic transition state.","method":"Kinetic isotope effects, commitment factors, binding isotope effects, quantum mechanical calculations","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 — rigorous transition-state analysis with multiple isotope effect measurements and QM validation","pmids":["28880543"],"is_preprint":false},{"year":2018,"finding":"The MAT2A detained intron (DI) transcript is not a precursor to mRNA but a 'dead-end' RNA fated for nuclear decay; under SAM-deprived conditions, cotranscriptional splicing of MAT2A detained introns increases, providing a cotranscriptional regulatory mechanism for SAM homeostasis.","method":"Three independent assays for precursor-product relationship, transcriptional run-on, nuclear fractionation","journal":"RNA","confidence":"High","confidence_rationale":"Tier 2 — three independent orthogonal assays in a single rigorous study","pmids":["29563249"],"is_preprint":false},{"year":2019,"finding":"TGF-β1 activates NF-κB (p65 phosphorylation), which promotes MAT2A transcription, reducing intracellular SAM concentration in hepatic stellate cells and driving liver fibrogenesis; NF-κB transcriptional activity on the MAT2A promoter was confirmed by luciferase assay.","method":"Luciferase reporter assay, LC-MS SAM measurement, AAV-mediated in vivo overexpression/knockdown, pharmacoproteomics","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo genetic manipulation and direct metabolite measurement","pmids":["30926424"],"is_preprint":false},{"year":2021,"finding":"MAT2A inhibition with potent inhibitors substantially reduces SAM levels, reduces PRMT5 activity, causes splicing perturbations (RNA-seq), induces DNA damage and mitotic defects in MTAP-deleted cells, rationalizing combination with antimitotic taxanes.","method":"RNA sequencing, proteomics, SAM measurement, DNA damage assays, cell viability in MTAP-/- cells","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal omics and biochemical methods in a single rigorous study","pmids":["33450196"],"is_preprint":false},{"year":2021,"finding":"CFIm25 (NUDT21), identified via unbiased CRISPR knockout screen, promotes MAT2A detained intron splicing independent of poly(A) site selection; this requires RS domains of its binding partners CFIm68 and CFIm59 and binding sites in the detained intron and 3' UTR.","method":"CRISPR knockout screen, splicing assays, domain deletion analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — unbiased screen validated with mechanistic follow-up using domain mutants","pmids":["33949310"],"is_preprint":false},{"year":2021,"finding":"AG-270 is an allosteric MAT2A inhibitor that binds substrate non-competitively and inhibits release of SAM product from the active site; fragment screening and structure-guided design improved potency >10,000-fold, and AG-270 selectively blocks proliferation of MTAP-null cells in vivo.","method":"Fragment screening, structure-guided design, enzymatic assays, xenograft models","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — structural and biochemical characterization of allosteric mechanism with in vivo validation","pmids":["33829783"],"is_preprint":false},{"year":2021,"finding":"MAT2A modulates the activation and phenotype of tumor-associated macrophages in gastric cancer by mediating upregulation of RIP1 through increased H3K4me3 at the RIP1 promoter via SAM-dependent histone methylation.","method":"ChIP for H3K4me3, pharmacological and genetic MAT2A inhibition, macrophage polarization assays","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP with functional phenotype, single lab","pmids":["33593829"],"is_preprint":false},{"year":2021,"finding":"MAT2A knockout in CD4+ T cells enhanced reactivation of latent HIV-1, while overexpression suppressed reactivation; mechanistically, MAT2A modulates HIV-1 latency through SAM-mediated one-carbon flux controlling DNA and histone methylation at the HIV-1 5'-LTR.","method":"CRISPR library screen, KO/OE experiments, chromatin methylation analysis at HIV-1 LTR","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen validated with mechanistic follow-up, single lab","pmids":["34616406"],"is_preprint":false},{"year":2021,"finding":"MAT2A mRNA nuclear export is regulated by MTR4; under methionine restriction, SYVN1 (E3 ubiquitin ligase) ubiquitinates MTR4, reducing its protein level, thereby promoting MAT2A mRNA export and increasing MAT2A protein expression.","method":"Co-immunoprecipitation, cytoplasm/nucleus fractionation, ubiquitination assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and fractionation with functional consequence, single lab","pmids":["33859984"],"is_preprint":false},{"year":2021,"finding":"The triphosphate hydrolysis step of MAT2A proceeds through a loose, near-symmetric dissociative transition state: crystal structures with MgF3- (PO3- mimic) and AlF30 show the phosphorus equidistant (~2 Å) between pyrophosphate oxygen and nucleophilic water; a catalytic arginine directs the nucleophilic water.","method":"X-ray crystallography at 1.07 Å resolution, NMR, crystal structures with transition-state analogues","journal":"Journal of the American Chemical Society","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structures with multiple transition-state analogues and NMR validation","pmids":["34668717"],"is_preprint":false},{"year":2022,"finding":"MAT2A mediates ferroptosis resistance in gastric cancer by producing SAM, which upregulates ACSL3 by increasing H3K4me3 trimethylation at the ACSL3 promoter.","method":"ChIP for H3K4me3, genetic and pharmacological MAT2A inhibition, ferroptosis assays in vitro and in vivo","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP with functional ferroptosis readout, single lab","pmids":["35182729"],"is_preprint":false},{"year":2022,"finding":"In H3K27M mutant DMG glioma, MAT2A depletion induces global loss of H3K36me3 (transcriptional elongation mark), perturbing oncogenic and developmental transcriptional programs; MAT2A protein levels are controlled by negative feedback from decarboxylated SAM.","method":"siRNA screen, ChIP-seq/histone modification analysis, mouse models with methionine-restricted diet","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 — epigenome-wide profiling with mechanistic follow-up and in vivo validation","pmids":["35422502"],"is_preprint":false},{"year":2022,"finding":"METTL16 m6A modification of MAT2A pre-mRNA shifts the balance from splicing/maturation toward degradation under oxidative stress; this mechanism reduces MAT2A protein expression and aggravates nucleus pulposus cell apoptosis.","method":"m6A modification assay, lentiviral METTL16 overexpression/siRNA, mRNA stability assay, in vivo IVDD model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic manipulation with mechanistic mRNA analysis, single lab","pmids":["35069973"],"is_preprint":false},{"year":2022,"finding":"MAT2A interacts with EZH2 and is recruited to the Wnt10b promoter to repress its expression by promoting H3K27 methylation; MAT2A also interacts with MafK at MARE elements at Wnt10b, and catalytic activity and MAT2B interaction are required for Wnt10b repression and adipogenesis promotion.","method":"Co-IP, ChIP for H3K27me3, overexpression/knockdown, adipogenesis assays","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and ChIP with functional readout, single lab (porcine model relevant to mammalian biology)","pmids":["29133280"],"is_preprint":false},{"year":2022,"finding":"mTORC1-c-Myc axis regulates MAT2A activity through TRIM32-mediated SIRT4 degradation; SIRT4 ADP-ribosylates MAT2A at glutamic acid residue 111, and loss of SIRT4 activates MAT2A to increase SAM levels and promote HCC proliferation.","method":"Immunostaining, metabolomics, RNA-seq, mouse models, identification of ADP-ribosylation site","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — identification of PTM site with mechanistic context, single lab","pmids":["36371321"],"is_preprint":false},{"year":2022,"finding":"METTL16 promotes MAT2A expression by m6A methylation of the MAT2A mRNA 3'UTR, increasing its stability; this mechanism contributes to improved hippocampal synaptic plasticity and memory formation.","method":"m6A methylation assay, METTL16 KD/OE in hippocampus, mRNA stability assay, Morris water maze","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — m6A modification with functional readout, single lab","pmids":["36307396"],"is_preprint":false},{"year":2022,"finding":"MAT2A interacts with PDCD6; this interaction is mediated by AMPK activation and facilitates PDCD6 K90 methylation, promoting PDCD6 protein stability and cervical cancer cell growth under glucose deprivation.","method":"Co-immunoprecipitation, mass spectrometry, immunoblotting, PDCD6 K90R mutation analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP/MS with site-specific mutation validation, single lab","pmids":["35396512"],"is_preprint":false},{"year":2023,"finding":"Intestinal epithelial cell-specific knockout of Mat2a in mice causes impaired intestinal development, reduced cell proliferation, IEC apoptosis, and neonatal lethality; SAM supplementation suppresses caspases 3 and 8 expression and activation, protecting IECs from apoptosis.","method":"Conditional KO mouse model, SAM supplementation rescue, caspase expression and activity measurement","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined phenotype and rescue experiment, in vivo","pmids":["36975381"],"is_preprint":false},{"year":2023,"finding":"Simultaneous MTAP inhibition (MTDIA) and MAT2A inhibition (AG-270) synergistically increases the intracellular MTA:SAM ratio, inhibiting PRMT5 activity and causing MDM4 alternative splicing, p53 activation, and apoptotic cell death in MTAP+/+ colorectal cancer cells.","method":"Drug combination synergy assays, SAM/MTA metabolite measurement, PRMT5 activity assay, MDM4 splicing analysis, xenograft models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical and cellular readouts with in vivo validation","pmids":["38000655"],"is_preprint":false},{"year":2024,"finding":"MAT2B binds MAT2A in an NADP+-dependent manner to stabilize MAT2A protein; disruption of cellular NADP+ (e.g., by keto diet or pentose phosphate pathway modulation) reduces MAT2A protein levels and consequently m6A mRNA modification and stability.","method":"Co-IP, protein stability assay, m6A modification analysis, NADP+ perturbation experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional consequences, single lab","pmids":["39353892"],"is_preprint":false},{"year":2024,"finding":"MAT2A is upregulated in CRPC and cooperates with ERG to enhance H3K4me2 at multiple genomic sites, promoting expression of non-canonical AR target genes; MAT2A inhibition reverses transcriptional and epigenetic remodeling and improves response to AR and EZH2 inhibitors.","method":"RNA-seq, ATAC-seq, ChIP-seq, histone PTM analysis by mass spectrometry, genetic and pharmacological inhibition","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multi-omic epigenome-wide profiling with functional validation","pmids":["39107274"],"is_preprint":false},{"year":2024,"finding":"SCR-7952 binds an allosteric site on MAT2A as confirmed by cryo-EM; MAT2A inhibition combined with PRMT5 inhibitors causes aggravated PRMT5 inhibition and FANCA splicing perturbations.","method":"Cryo-EM structural determination, biochemical inhibition assay, RNA splicing analysis, xenograft models","journal":"MedComm","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural confirmation of binding mode with functional validation","pmids":["39309689"],"is_preprint":false},{"year":2024,"finding":"MAT2A downregulation in pericytes reduces OTUB1 recruitment to HMGCS1, decreasing HMGCS1 expression and coenzyme Q synthesis, impairing mitochondrial function and inducing cell senescence that drives inflammatory macrophage trained immunity in diabetic wounds.","method":"Cspg4-CreERT2/Mat2aflox/flox mouse model, single-cell sequencing, mechanistic protein interaction and mitochondrial function assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO model with mechanistic follow-up, single lab, novel pathway","pmids":["41298385"],"is_preprint":false},{"year":2024,"finding":"Norepinephrine activates the mTOR-c-MYC axis to upregulate MAT2A expression in macrophages; MAT2A-mediated SAM production enriches H3K4me3 at inflammatory and migratory gene promoters, promoting atherosclerotic plaque vulnerability.","method":"ChIP for H3K4me3, myeloid-specific MAT2A KO mouse model, pharmacological inhibition, metabolomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with epigenome profiling and mechanistic signaling pathway in vivo","pmids":["41402252"],"is_preprint":false},{"year":2024,"finding":"MAT2A SUMOylation is regulated by SUMO E1; inhibition of MAT2A SUMOylation unexpectedly stimulates polyamine synthesis via the MAT2A-AdoMetDC axis.","method":"SUMOylation assay, metabolite measurement, synergy assays with polyamine synthesis inhibitor","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — PTM identification with functional metabolic readout, single lab","pmids":["40884915"],"is_preprint":false},{"year":2024,"finding":"TRIM25 destabilizes MAT2A mRNA, leading to activation of Wnt/β-catenin signaling; in VSMCs, MAT2A upregulation increased cellular activity and repressed β-catenin protein expression, and TRIM25 knockdown promoted VSMC activity by binding to MAT2A.","method":"RNA stability assay, Co-IP, Western blot, in vivo TAA model","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — mRNA stability and binding assays with functional cell and in vivo readout, single lab","pmids":["39216871"],"is_preprint":false},{"year":2024,"finding":"MAT2A knockdown in porcine embryos reduced H3K4me2, H3K9me2/3, and H3K27me3 levels at the four-cell stage, reduced EED and EZH2 expression, impaired ZGA gene transcription, and caused developmental arrest; SAM supplementation rescued these defects.","method":"dsRNA injection KD, immunofluorescence for histone marks, SAM rescue experiment, embryo development assay","journal":"Theriogenology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple histone mark readouts and rescue, porcine ortholog","pmids":["39276507"],"is_preprint":false},{"year":2024,"finding":"RBM15 promotes MAT2A expression by N6-methyladenosine (m6A) modification of MAT2A mRNA; MAT2A knockdown in osteosarcoma reduces proliferation, migration, invasion, and enhances ferroptosis both in vitro and in vivo.","method":"MeRIP assay, dual-luciferase reporter assay, xenograft model, ferroptosis measurements","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — m6A site validation with functional assays, single lab","pmids":["39527319"],"is_preprint":false},{"year":2025,"finding":"Nuclear MAT2A enzymatic activity is required for immunoglobulin class switch recombination (CSR); expression of a catalytically inactive MAT2A (D134A) targeted to the nucleus suppressed CSR from IgM to IgA, reduced intracellular SAM, and downregulated AID expression while enhancing germline transcripts.","method":"Nuclear-localized WT vs. catalytically inactive MAT2A expression, CSR assay, ChIP at IgA switch region, AID expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis and ChIP with functional CSR readout, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.10.24.684368"],"is_preprint":true},{"year":2025,"finding":"FMO4 facilitates the interaction between MAT2A and MAT2B, promoting cysteine generation from methionine, boosting glutathione synthesis and protecting lung adenocarcinoma cells from ferroptosis.","method":"Proteomic analysis, Co-IP for MAT2A-MAT2B complex, in vivo KO model, ferroptosis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP interaction with in vivo genetic KO and ferroptosis functional assay, preprint","pmids":["bio_10.1101_2025.03.31.646284"],"is_preprint":true},{"year":2025,"finding":"MAT2A interacts with transcription factor SRF, promotes its SUMO-dependent nuclear stabilization, and enhances SRF-driven PARN transcription to increase glycolysis via the PARN-PI3K-AKT pathway; a catalytically inactive MAT2A retains this SRF-stabilizing function, indicating a SAM-independent mechanism.","method":"Co-IP, SUMO stabilization assay, catalytically inactive mutant, RNA-seq, glycolysis measurement, in vivo xenograft","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with catalytic mutant distinguishing SAM-independent function, single lab","pmids":["41530371"],"is_preprint":false}],"current_model":"MAT2A is the ubiquitous methionine adenosyltransferase that catalyzes SAM synthesis from methionine and ATP via an advanced SN2 (for SAM formation) and dissociative (for triphosphate hydrolysis) transition state; it is allosterically regulated by its non-catalytic MAT2B subunit (which overlaps with small-molecule allosteric inhibitor binding sites) and by SIRT4-mediated ADP-ribosylation and SUMOylation; it functions both cytoplasmically to control the SAM pool (controlling PRMT5 substrate availability, histone methylation, ferroptosis resistance via ACSL3/ACSL4, and mRNA m6A levels) and in the nucleus where its catalytic activity locally supplies SAM for histone methylation marks including H3K4me2/3, H3K36me3, and H3K27me3, and is required for immunoglobulin class switch recombination; MAT2A expression is regulated transcriptionally by HIF-1α, NF-κB/p65, E2F/Sp3, and PPARγ, and post-transcriptionally through METTL16-mediated m6A modification of its pre-mRNA that controls detained intron splicing versus nuclear decay, with CFIm complex promoting productive splicing; in MTAP-deleted cancers, loss of MTA catabolism elevates MTA which selectively inhibits PRMT5, creating synthetic lethality upon MAT2A inhibition that reduces SAM/PRMT5 activity, disrupts splicing, and induces DNA damage."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of MAT2B as a regulatory subunit that physically associates with MAT2A and alters its kinetic properties resolved how the enzyme's methionine sensitivity is tuned in vivo.","evidence":"Recombinant co-expression and kinetic characterization of MAT2A–MAT2B complexes","pmids":["10644686"],"confidence":"High","gaps":["Structural basis of MAT2A–MAT2B interaction not yet resolved","In vivo stoichiometry unknown","Tissue-specific regulation by MAT2B not addressed"]},{"year":2000,"claim":"Mapping the MAT2A promoter revealed that Sp3 (not Sp1) is the primary transcription factor driving basal expression, establishing the transcriptional framework for MAT2A regulation.","evidence":"Promoter deletions, EMSA, supershift, and ChIP in human cells","pmids":["11124935"],"confidence":"High","gaps":["No chromatin context or enhancer elements mapped","Regulation in non-hepatic tissues unexplored"]},{"year":2007,"claim":"Cell cycle–regulated MAT2A transcription via E2F family members linked SAM production to proliferative signaling, explaining why MAT2A is induced during liver regeneration.","evidence":"RNApol-ChIP, EMSA, and ChIP for E2F1/E2F3/E2F4 at the MAT2A promoter during liver regeneration","pmids":["17317269"],"confidence":"High","gaps":["Direct E2F site mutagenesis not performed","Whether E2F regulation operates in non-hepatic tissues unknown"]},{"year":2007,"claim":"MAT2A knockdown in hepatoma cells demonstrated that MAT2A activity directly controls the intracellular SAM pool and that SAM levels feed back to regulate MAT gene isoform switching (MAT2A→MAT1A).","evidence":"siRNA knockdown with SAM/SAH measurement, growth and apoptosis assays in hepatoma cells","pmids":["17441811"],"confidence":"Medium","gaps":["Mechanism of SAM-mediated MAT1A re-expression not defined","Single cell line study"]},{"year":2011,"claim":"Demonstration that HIF-1α directly binds the MAT2A promoter under hypoxia connected oxygen sensing to methyl metabolism, showing how hypoxia reduces SAM and causes global DNA demethylation.","evidence":"HIF-1α binding site mutagenesis, ChIP for HIF-1α/p300/HDAC1, SAM and methylation assays in hepatoma cells","pmids":["21460102"],"confidence":"High","gaps":["Whether other hypoxia-responsive methyltransferases are co-regulated not tested","In vivo validation lacking"]},{"year":2016,"claim":"The discovery that MTAP deletion elevates MTA to selectively inhibit PRMT5, creating synthetic lethality with MAT2A depletion, established the therapeutic rationale for targeting MAT2A in MTAP-null cancers.","evidence":"shRNA screen, metabolomics, PRMT5 methyltransferase profiling, cell viability assays in MTAP-deleted vs. WT cells","pmids":["27068473"],"confidence":"High","gaps":["Whether other methyltransferases contribute to synthetic lethality not fully explored","Patient tumor heterogeneity in MTA levels not assessed"]},{"year":2017,"claim":"Characterization of PF-9366 binding to an allosteric site overlapping with MAT2B revealed that MAT2B functions as a context-dependent activator or inhibitor depending on methionine/SAM levels, unifying prior kinetic observations.","evidence":"Biochemical enzyme kinetics with allosteric inhibitor and MAT2B, structural overlap analysis","pmids":["28553945"],"confidence":"High","gaps":["Full co-crystal structure of MAT2A–MAT2B with inhibitor not obtained in this study","In vivo allosteric regulation dynamics unknown"]},{"year":2017,"claim":"Transition-state analysis established that MAT2A catalyzes SAM formation via an advanced SN2 mechanism (S–C distance 2.03 Å), providing a chemical framework for inhibitor design.","evidence":"Kinetic isotope effects, commitment factors, binding isotope effects, QM calculations","pmids":["28880543"],"confidence":"High","gaps":["Transition state for the second half-reaction (triphosphate hydrolysis) addressed later","Transition-state analogues for SAM formation not yet synthesized"]},{"year":2018,"claim":"The finding that MAT2A detained intron transcripts are dead-end products destined for nuclear decay — not mRNA precursors — established cotranscriptional splicing as the regulatory switch for SAM homeostasis.","evidence":"Three independent precursor-product relationship assays, transcriptional run-on, nuclear fractionation","pmids":["29563249"],"confidence":"High","gaps":["Identity of the nuclear decay machinery acting on DI transcripts not defined","How SAM levels signal to the splicing machinery not resolved"]},{"year":2021,"claim":"A CRISPR screen identified the CFIm complex (NUDT21/CFIm25, CFIm68, CFIm59) as a direct promoter of MAT2A detained intron splicing, requiring RS domains and binding sites in the intron and 3′ UTR, revealing the splicing factor machinery controlling SAM-responsive MAT2A regulation.","evidence":"Genome-wide CRISPR KO screen with domain deletion analysis of CFIm subunits","pmids":["33949310"],"confidence":"High","gaps":["How SAM depletion signals to CFIm complex not determined","Whether CFIm regulation is tissue-specific unknown"]},{"year":2021,"claim":"Structural resolution of the triphosphate hydrolysis transition state (MgF3⁻ and AlF3⁰ mimics at 1.07 Å) completed the mechanistic picture of both MAT2A half-reactions, showing a loose dissociative mechanism with catalytic arginine-directed water nucleophile.","evidence":"X-ray crystallography with transition-state analogues, NMR validation","pmids":["34668717"],"confidence":"High","gaps":["Full catalytic cycle dynamics (substrate binding order, product release) not captured crystallographically","No structures of MAT2A with allosteric inhibitors bound simultaneously with TSA"]},{"year":2021,"claim":"Potent MAT2A allosteric inhibitors (AG-270) were shown to trap SAM in the active site, reduce intracellular SAM, impair PRMT5-dependent splicing, and induce DNA damage selectively in MTAP-null tumors in vivo, validating MAT2A as a drug target.","evidence":"Fragment-to-lead optimization, enzymatic assays, RNA-seq, DNA damage assays, xenograft efficacy models","pmids":["33829783","33450196"],"confidence":"High","gaps":["Clinical efficacy in patients not yet demonstrated","Resistance mechanisms to MAT2A inhibitors not characterized"]},{"year":2022,"claim":"Nuclear MAT2A interacts with EZH2 and MafK at specific promoters to locally supply SAM for H3K27me3 deposition, establishing a chromatin-targeted, non-bulk metabolic role for MAT2A.","evidence":"Co-IP, ChIP for H3K27me3 at Wnt10b promoter, catalytic mutant and MAT2B-dependence analysis in porcine adipocytes","pmids":["29133280"],"confidence":"Medium","gaps":["Whether MAT2A is recruited genome-wide or to select loci not determined","Mechanism of MAT2A nuclear targeting unknown","Single-model (porcine) system"]},{"year":2022,"claim":"MAT2A depletion in H3K27M-mutant glioma globally reduced H3K36me3, linking MAT2A-dependent SAM production to transcriptional elongation marks and revealing vulnerability of developmental tumors to methionine metabolism perturbation.","evidence":"siRNA screen, ChIP-seq for histone marks, mouse methionine-restricted diet models","pmids":["35422502"],"confidence":"High","gaps":["Whether H3K36me3 loss is direct or secondary to altered SAM distribution not resolved","Contribution of other SAM-consuming enzymes in glioma not tested"]},{"year":2022,"claim":"METTL16-mediated m6A modification of MAT2A mRNA was shown to regulate its stability and splicing, with opposing outcomes (stabilization vs. degradation) depending on cellular context, establishing a feedback loop between SAM-dependent m6A writing and MAT2A expression.","evidence":"m6A modification assays, METTL16 overexpression/knockdown, mRNA stability assays in multiple cell systems","pmids":["35069973","36307396"],"confidence":"Medium","gaps":["Conflicting stabilization vs. degradation outcomes across studies not reconciled","Precise m6A reader proteins mediating the downstream effect not identified"]},{"year":2022,"claim":"SIRT4 was found to ADP-ribosylate MAT2A at E111, and mTORC1–c-Myc-driven TRIM32-mediated SIRT4 degradation activates MAT2A, integrating nutrient sensing with SAM production in hepatocellular carcinoma.","evidence":"ADP-ribosylation site identification, metabolomics, RNA-seq, mouse models","pmids":["36371321"],"confidence":"Medium","gaps":["Structural basis of how E111 ADP-ribosylation inhibits catalysis unknown","Single lab, not independently replicated"]},{"year":2023,"claim":"Intestinal epithelial-specific Mat2a knockout caused neonatal lethality with proliferation failure and apoptosis, rescued by SAM supplementation, demonstrating that MAT2A-dependent SAM is essential for intestinal epithelial homeostasis.","evidence":"Conditional KO mouse (Villin-Cre), SAM rescue, caspase activity measurement","pmids":["36975381"],"confidence":"High","gaps":["Whether lethality reflects SAM depletion alone or also loss of non-catalytic MAT2A functions not tested","Specific methyltransferases mediating the intestinal phenotype not identified"]},{"year":2024,"claim":"MAT2B was shown to stabilize MAT2A protein in an NADP⁺-dependent manner, connecting cellular redox/cofactor state to SAM production capacity and downstream m6A mRNA modification.","evidence":"Co-IP, protein stability assays, NADP⁺ perturbation, m6A analysis","pmids":["39353892"],"confidence":"Medium","gaps":["Structural basis of NADP⁺-dependent MAT2A–MAT2B interaction not resolved","Single lab, awaits independent confirmation"]},{"year":2024,"claim":"Multi-omic profiling in CRPC showed that MAT2A cooperates with ERG to remodel H3K4me2 at non-canonical AR target genes, and that MAT2A inhibition reverses this epigenetic program and sensitizes tumors to AR/EZH2 inhibitors.","evidence":"RNA-seq, ATAC-seq, ChIP-seq, histone PTM mass spectrometry, pharmacological and genetic MAT2A inhibition","pmids":["39107274"],"confidence":"High","gaps":["Whether MAT2A–ERG cooperation involves direct physical interaction not determined","Clinical translatability of combination strategies untested"]},{"year":2024,"claim":"Cryo-EM structure of MAT2A with allosteric inhibitor SCR-7952 confirmed the allosteric binding mode, and combination with PRMT5 inhibitors aggravated splicing perturbations including FANCA mis-splicing.","evidence":"Cryo-EM, biochemical inhibition, RNA splicing analysis, xenograft models","pmids":["39309689"],"confidence":"High","gaps":["Full dynamic conformational ensemble of MAT2A upon allosteric inhibitor binding not captured","FANCA splicing as biomarker not clinically validated"]},{"year":2025,"claim":"A SAM-independent scaffolding function of MAT2A was uncovered: catalytically inactive MAT2A retains the ability to stabilize SRF via SUMOylation and drive SRF-dependent transcription of glycolytic genes, demonstrating a non-enzymatic role.","evidence":"Co-IP, SUMO stabilization assay, catalytically inactive mutant, RNA-seq, glycolysis measurement, xenograft","pmids":["41530371"],"confidence":"Medium","gaps":["Generality of SAM-independent functions beyond SRF not explored","Single lab, awaits independent confirmation","Structural basis of MAT2A–SRF interaction unknown"]},{"year":null,"claim":"Key unresolved questions include: (1) how MAT2A is targeted to specific chromatin loci to locally supply SAM; (2) the structural basis of NADP⁺-dependent MAT2A–MAT2B stabilization; (3) clinical efficacy and resistance mechanisms for MAT2A allosteric inhibitors; and (4) the full scope of SAM-independent scaffolding functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of chromatin-recruited MAT2A","No clinical trial outcome data for MAT2A inhibitors","Non-catalytic protein interaction network incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,8,9,14,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[22,39]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,7,8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,29,35,37]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,8,9,14,18,27]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[20,22,29,35]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,6,11]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10,13,21,24]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,19,26]}],"complexes":["MAT II (MAT2A–MAT2B heteromer)"],"partners":["MAT2B","EZH2","PRMT5","SRF","METTL16","SIRT4","PDCD6","MAFK"],"other_free_text":[]},"mechanistic_narrative":"MAT2A is the ubiquitously expressed catalytic subunit of methionine adenosyltransferase II that synthesizes S-adenosylmethionine (SAM) from methionine and ATP, serving as the principal supplier of methyl groups for DNA, histone, RNA, and protein methylation reactions across mammalian tissues [PMID:28880543, PMID:34668717]. Its catalytic activity is allosterically regulated by the MAT2B regulatory subunit, which binds an overlapping site with small-molecule inhibitors to modulate substrate affinity and turnover in a methionine/SAM concentration-dependent manner, and MAT2B stabilizes MAT2A protein in an NADP⁺-dependent fashion [PMID:28553945, PMID:39353892]. MAT2A expression is controlled transcriptionally by E2F/Sp3, HIF-1α, NF-κB, and mTOR–c-MYC signaling, and post-transcriptionally through METTL16-mediated m6A modification of its pre-mRNA that governs detained intron splicing versus nuclear decay, with the CFIm complex promoting productive splicing under SAM-depleted conditions [PMID:11124935, PMID:21460102, PMID:29563249, PMID:33949310, PMID:35069973]. Beyond its cytoplasmic metabolic role, nuclear MAT2A locally supplies SAM for chromatin-modifying enzymes including EZH2 and H3K4 methyltransferases, thereby controlling histone marks (H3K4me2/3, H3K27me3, H3K36me3) that regulate gene expression programs in contexts ranging from embryonic development and immune cell function to the MTAP-deleted cancer synthetic lethal axis where MAT2A inhibition depletes PRMT5 substrates and induces splicing defects and DNA damage [PMID:29133280, PMID:35422502, PMID:27068473, PMID:33450196]."},"prefetch_data":{"uniprot":{"accession":"P31153","full_name":"S-adenosylmethionine synthase isoform type-2","aliases":["Methionine adenosyltransferase 2","MAT 2","Methionine adenosyltransferase II","MAT-II"],"length_aa":395,"mass_kda":43.7,"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/P31153/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MAT2A","classification":"Common Essential","n_dependent_lines":1150,"n_total_lines":1208,"dependency_fraction":0.9519867549668874},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2},{"gene":"VCP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAT2A","total_profiled":1310},"omim":[{"mim_id":"616350","title":"PROMOTER OF MAT2A ANTISENSE RADIATION-INDUCED CIRCULATING LONG NONCODING RNA; PARTICL","url":"https://www.omim.org/entry/616350"},{"mim_id":"611531","title":"EMG1 N1-SPECIFIC PSEUDOURIDINE METHYLTRANSFERASE; EMG1","url":"https://www.omim.org/entry/611531"},{"mim_id":"610550","title":"METHIONINE ADENOSYLTRANSFERASE I, ALPHA; MAT1A","url":"https://www.omim.org/entry/610550"},{"mim_id":"607086","title":"AORTIC ANEURYSM, FAMILIAL THORACIC 1; AAT1","url":"https://www.omim.org/entry/607086"},{"mim_id":"605527","title":"METHIONINE ADENOSYLTRANSFERASE II, BETA; MAT2B","url":"https://www.omim.org/entry/605527"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"pancreas","ntpm":825.0}],"url":"https://www.proteinatlas.org/search/MAT2A"},"hgnc":{"alias_symbol":["SAMS2","MATA2","MATII","MAT-II"],"prev_symbol":[]},"alphafold":{"accession":"P31153","domains":[{"cath_id":"3.30.300.10","chopping":"16-25_152-253","consensus_level":"medium","plddt":97.7844,"start":16,"end":253}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P31153","model_url":"https://alphafold.ebi.ac.uk/files/AF-P31153-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P31153-F1-predicted_aligned_error_v6.png","plddt_mean":96.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAT2A","jax_strain_url":"https://www.jax.org/strain/search?query=MAT2A"},"sequence":{"accession":"P31153","fasta_url":"https://rest.uniprot.org/uniprotkb/P31153.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P31153/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P31153"}},"corpus_meta":[{"pmid":"27068473","id":"PMC_27068473","title":"MTAP 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human MAT alpha subunits, changing their kinetic properties and lowering the Km for L-methionine, confirming its regulatory function.\",\n      \"method\": \"Recombinant protein expression, co-association assay, kinetic characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted protein interaction with functional kinetic readout in a single rigorous study\",\n      \"pmids\": [\"10644686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The MAT2A proximal promoter contains an Sp1 site at position -69 (Sp1-3) essential for in vitro and in vivo promoter activity, with Sp2 and Sp3 (not Sp1) being the primary transcription factors binding this site as shown by supershift assay and ChIP.\",\n      \"method\": \"Promoter deletion analysis, EMSA, supershift assay, in vivo reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11124935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The MAT2B gene promoter has a minimal promoter between +52 and +93, with an Sp1 site at +9/+15 and a TATA at -32 conferring full activity; Sp3 (not Sp1) is the primary factor binding the Sp1 site as determined by ChIP and supershift assays.\",\n      \"method\": \"Promoter deletion analysis, EMSA, supershift assay, ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11337507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Leukemic T cells show distinct protein-DNA interaction patterns at the MAT2A proximal promoter compared to normal T cells, with higher expression of Sp2/Sp3 in leukemic cells correlating with increased in vitro promoter activity.\",\n      \"method\": \"EMSA, supershift assay, in vivo reporter assay comparison between normal and leukemic T cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods but single lab, comparative study\",\n      \"pmids\": [\"11476892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"siRNA-mediated silencing of MAT2A in hepatoma cells reduced MAT II activity, increased SAM levels and the SAM:SAH ratio, inhibited cell growth, induced apoptosis, and caused a switch of MAT gene expression from MAT2A to MAT1A mediated by elevated SAM.\",\n      \"method\": \"RNA interference, enzymatic activity assay, metabolite measurement, cell growth and apoptosis assays\",\n      \"journal\": \"Hepatology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined metabolic and cellular phenotype, single lab\",\n      \"pmids\": [\"17441811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MAT2A transcription is induced at two discrete time points during liver regeneration (G0-G1 and G1-S transitions), regulated by E2F1/E2F3/E2F4 factors and Sp1 binding to the promoter with accompanying changes in histone-modifying enzyme occupancy.\",\n      \"method\": \"RNApol-ChIP, EMSA, ChIP for transcription factors and histone modifiers\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and EMSA with functional context, multiple orthogonal methods\",\n      \"pmids\": [\"17317269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypoxia-induced MAT2A expression is HIF-1α-dependent and requires recruitment of p300 and HDAC1 to an authentic HIF-1α binding site in the MAT2A promoter, leading to reduced SAM levels and global DNA demethylation in hepatoma cells.\",\n      \"method\": \"Site-directed mutagenesis of HIF-1α binding site, EMSA, ChIP, SAM measurement, methylation assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis, EMSA and ChIP with functional metabolic readout\",\n      \"pmids\": [\"21460102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAT2A produces SAM as substrate for PRMT5, and MTAP loss causes accumulation of MTA which selectively inhibits PRMT5; MAT2A depletion selectively reduces PRMT5 methylation activity and growth in MTAP-deleted cells, establishing a MAT2A/PRMT5/RIOK1 synthetic lethal axis.\",\n      \"method\": \"shRNA screening, metabolomics, biochemical methyltransferase profiling, cell viability assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, widely replicated across the field\",\n      \"pmids\": [\"27068473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PF-9366 binds an allosteric site on MAT2A overlapping with the MAT2B binding site; allosteric binding of PF-9366 or MAT2B increases substrate affinity but decreases enzyme turnover, with MAT2B functioning as inhibitor when methionine/SAM levels are high and activator when levels are low.\",\n      \"method\": \"Biochemical enzyme kinetics, allosteric inhibitor characterization, structural overlap analysis\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic reconstitution with mechanistic detail, single rigorous study\",\n      \"pmids\": [\"28553945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human MAT2A catalyzes SAM formation through an advanced SN2 transition state with the bond-forming methionine sulfur to ATP 5'-C at 2.03 Å and bond-breaking triphosphate at 2.32 Å; interaction with MAT2B regulatory subunit does not alter the intrinsic transition state.\",\n      \"method\": \"Kinetic isotope effects, commitment factors, binding isotope effects, quantum mechanical calculations\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous transition-state analysis with multiple isotope effect measurements and QM validation\",\n      \"pmids\": [\"28880543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The MAT2A detained intron (DI) transcript is not a precursor to mRNA but a 'dead-end' RNA fated for nuclear decay; under SAM-deprived conditions, cotranscriptional splicing of MAT2A detained introns increases, providing a cotranscriptional regulatory mechanism for SAM homeostasis.\",\n      \"method\": \"Three independent assays for precursor-product relationship, transcriptional run-on, nuclear fractionation\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three independent orthogonal assays in a single rigorous study\",\n      \"pmids\": [\"29563249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TGF-β1 activates NF-κB (p65 phosphorylation), which promotes MAT2A transcription, reducing intracellular SAM concentration in hepatic stellate cells and driving liver fibrogenesis; NF-κB transcriptional activity on the MAT2A promoter was confirmed by luciferase assay.\",\n      \"method\": \"Luciferase reporter assay, LC-MS SAM measurement, AAV-mediated in vivo overexpression/knockdown, pharmacoproteomics\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo genetic manipulation and direct metabolite measurement\",\n      \"pmids\": [\"30926424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAT2A inhibition with potent inhibitors substantially reduces SAM levels, reduces PRMT5 activity, causes splicing perturbations (RNA-seq), induces DNA damage and mitotic defects in MTAP-deleted cells, rationalizing combination with antimitotic taxanes.\",\n      \"method\": \"RNA sequencing, proteomics, SAM measurement, DNA damage assays, cell viability in MTAP-/- cells\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal omics and biochemical methods in a single rigorous study\",\n      \"pmids\": [\"33450196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CFIm25 (NUDT21), identified via unbiased CRISPR knockout screen, promotes MAT2A detained intron splicing independent of poly(A) site selection; this requires RS domains of its binding partners CFIm68 and CFIm59 and binding sites in the detained intron and 3' UTR.\",\n      \"method\": \"CRISPR knockout screen, splicing assays, domain deletion analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — unbiased screen validated with mechanistic follow-up using domain mutants\",\n      \"pmids\": [\"33949310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AG-270 is an allosteric MAT2A inhibitor that binds substrate non-competitively and inhibits release of SAM product from the active site; fragment screening and structure-guided design improved potency >10,000-fold, and AG-270 selectively blocks proliferation of MTAP-null cells in vivo.\",\n      \"method\": \"Fragment screening, structure-guided design, enzymatic assays, xenograft models\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — structural and biochemical characterization of allosteric mechanism with in vivo validation\",\n      \"pmids\": [\"33829783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAT2A modulates the activation and phenotype of tumor-associated macrophages in gastric cancer by mediating upregulation of RIP1 through increased H3K4me3 at the RIP1 promoter via SAM-dependent histone methylation.\",\n      \"method\": \"ChIP for H3K4me3, pharmacological and genetic MAT2A inhibition, macrophage polarization assays\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP with functional phenotype, single lab\",\n      \"pmids\": [\"33593829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAT2A knockout in CD4+ T cells enhanced reactivation of latent HIV-1, while overexpression suppressed reactivation; mechanistically, MAT2A modulates HIV-1 latency through SAM-mediated one-carbon flux controlling DNA and histone methylation at the HIV-1 5'-LTR.\",\n      \"method\": \"CRISPR library screen, KO/OE experiments, chromatin methylation analysis at HIV-1 LTR\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen validated with mechanistic follow-up, single lab\",\n      \"pmids\": [\"34616406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MAT2A mRNA nuclear export is regulated by MTR4; under methionine restriction, SYVN1 (E3 ubiquitin ligase) ubiquitinates MTR4, reducing its protein level, thereby promoting MAT2A mRNA export and increasing MAT2A protein expression.\",\n      \"method\": \"Co-immunoprecipitation, cytoplasm/nucleus fractionation, ubiquitination assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and fractionation with functional consequence, single lab\",\n      \"pmids\": [\"33859984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The triphosphate hydrolysis step of MAT2A proceeds through a loose, near-symmetric dissociative transition state: crystal structures with MgF3- (PO3- mimic) and AlF30 show the phosphorus equidistant (~2 Å) between pyrophosphate oxygen and nucleophilic water; a catalytic arginine directs the nucleophilic water.\",\n      \"method\": \"X-ray crystallography at 1.07 Å resolution, NMR, crystal structures with transition-state analogues\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structures with multiple transition-state analogues and NMR validation\",\n      \"pmids\": [\"34668717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAT2A mediates ferroptosis resistance in gastric cancer by producing SAM, which upregulates ACSL3 by increasing H3K4me3 trimethylation at the ACSL3 promoter.\",\n      \"method\": \"ChIP for H3K4me3, genetic and pharmacological MAT2A inhibition, ferroptosis assays in vitro and in vivo\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP with functional ferroptosis readout, single lab\",\n      \"pmids\": [\"35182729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In H3K27M mutant DMG glioma, MAT2A depletion induces global loss of H3K36me3 (transcriptional elongation mark), perturbing oncogenic and developmental transcriptional programs; MAT2A protein levels are controlled by negative feedback from decarboxylated SAM.\",\n      \"method\": \"siRNA screen, ChIP-seq/histone modification analysis, mouse models with methionine-restricted diet\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epigenome-wide profiling with mechanistic follow-up and in vivo validation\",\n      \"pmids\": [\"35422502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL16 m6A modification of MAT2A pre-mRNA shifts the balance from splicing/maturation toward degradation under oxidative stress; this mechanism reduces MAT2A protein expression and aggravates nucleus pulposus cell apoptosis.\",\n      \"method\": \"m6A modification assay, lentiviral METTL16 overexpression/siRNA, mRNA stability assay, in vivo IVDD model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic manipulation with mechanistic mRNA analysis, single lab\",\n      \"pmids\": [\"35069973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAT2A interacts with EZH2 and is recruited to the Wnt10b promoter to repress its expression by promoting H3K27 methylation; MAT2A also interacts with MafK at MARE elements at Wnt10b, and catalytic activity and MAT2B interaction are required for Wnt10b repression and adipogenesis promotion.\",\n      \"method\": \"Co-IP, ChIP for H3K27me3, overexpression/knockdown, adipogenesis assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and ChIP with functional readout, single lab (porcine model relevant to mammalian biology)\",\n      \"pmids\": [\"29133280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"mTORC1-c-Myc axis regulates MAT2A activity through TRIM32-mediated SIRT4 degradation; SIRT4 ADP-ribosylates MAT2A at glutamic acid residue 111, and loss of SIRT4 activates MAT2A to increase SAM levels and promote HCC proliferation.\",\n      \"method\": \"Immunostaining, metabolomics, RNA-seq, mouse models, identification of ADP-ribosylation site\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — identification of PTM site with mechanistic context, single lab\",\n      \"pmids\": [\"36371321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL16 promotes MAT2A expression by m6A methylation of the MAT2A mRNA 3'UTR, increasing its stability; this mechanism contributes to improved hippocampal synaptic plasticity and memory formation.\",\n      \"method\": \"m6A methylation assay, METTL16 KD/OE in hippocampus, mRNA stability assay, Morris water maze\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — m6A modification with functional readout, single lab\",\n      \"pmids\": [\"36307396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAT2A interacts with PDCD6; this interaction is mediated by AMPK activation and facilitates PDCD6 K90 methylation, promoting PDCD6 protein stability and cervical cancer cell growth under glucose deprivation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunoblotting, PDCD6 K90R mutation analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/MS with site-specific mutation validation, single lab\",\n      \"pmids\": [\"35396512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Intestinal epithelial cell-specific knockout of Mat2a in mice causes impaired intestinal development, reduced cell proliferation, IEC apoptosis, and neonatal lethality; SAM supplementation suppresses caspases 3 and 8 expression and activation, protecting IECs from apoptosis.\",\n      \"method\": \"Conditional KO mouse model, SAM supplementation rescue, caspase expression and activity measurement\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined phenotype and rescue experiment, in vivo\",\n      \"pmids\": [\"36975381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Simultaneous MTAP inhibition (MTDIA) and MAT2A inhibition (AG-270) synergistically increases the intracellular MTA:SAM ratio, inhibiting PRMT5 activity and causing MDM4 alternative splicing, p53 activation, and apoptotic cell death in MTAP+/+ colorectal cancer cells.\",\n      \"method\": \"Drug combination synergy assays, SAM/MTA metabolite measurement, PRMT5 activity assay, MDM4 splicing analysis, xenograft models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical and cellular readouts with in vivo validation\",\n      \"pmids\": [\"38000655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2B binds MAT2A in an NADP+-dependent manner to stabilize MAT2A protein; disruption of cellular NADP+ (e.g., by keto diet or pentose phosphate pathway modulation) reduces MAT2A protein levels and consequently m6A mRNA modification and stability.\",\n      \"method\": \"Co-IP, protein stability assay, m6A modification analysis, NADP+ perturbation experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional consequences, single lab\",\n      \"pmids\": [\"39353892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2A is upregulated in CRPC and cooperates with ERG to enhance H3K4me2 at multiple genomic sites, promoting expression of non-canonical AR target genes; MAT2A inhibition reverses transcriptional and epigenetic remodeling and improves response to AR and EZH2 inhibitors.\",\n      \"method\": \"RNA-seq, ATAC-seq, ChIP-seq, histone PTM analysis by mass spectrometry, genetic and pharmacological inhibition\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omic epigenome-wide profiling with functional validation\",\n      \"pmids\": [\"39107274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SCR-7952 binds an allosteric site on MAT2A as confirmed by cryo-EM; MAT2A inhibition combined with PRMT5 inhibitors causes aggravated PRMT5 inhibition and FANCA splicing perturbations.\",\n      \"method\": \"Cryo-EM structural determination, biochemical inhibition assay, RNA splicing analysis, xenograft models\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural confirmation of binding mode with functional validation\",\n      \"pmids\": [\"39309689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2A downregulation in pericytes reduces OTUB1 recruitment to HMGCS1, decreasing HMGCS1 expression and coenzyme Q synthesis, impairing mitochondrial function and inducing cell senescence that drives inflammatory macrophage trained immunity in diabetic wounds.\",\n      \"method\": \"Cspg4-CreERT2/Mat2aflox/flox mouse model, single-cell sequencing, mechanistic protein interaction and mitochondrial function assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO model with mechanistic follow-up, single lab, novel pathway\",\n      \"pmids\": [\"41298385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Norepinephrine activates the mTOR-c-MYC axis to upregulate MAT2A expression in macrophages; MAT2A-mediated SAM production enriches H3K4me3 at inflammatory and migratory gene promoters, promoting atherosclerotic plaque vulnerability.\",\n      \"method\": \"ChIP for H3K4me3, myeloid-specific MAT2A KO mouse model, pharmacological inhibition, metabolomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with epigenome profiling and mechanistic signaling pathway in vivo\",\n      \"pmids\": [\"41402252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2A SUMOylation is regulated by SUMO E1; inhibition of MAT2A SUMOylation unexpectedly stimulates polyamine synthesis via the MAT2A-AdoMetDC axis.\",\n      \"method\": \"SUMOylation assay, metabolite measurement, synergy assays with polyamine synthesis inhibitor\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — PTM identification with functional metabolic readout, single lab\",\n      \"pmids\": [\"40884915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM25 destabilizes MAT2A mRNA, leading to activation of Wnt/β-catenin signaling; in VSMCs, MAT2A upregulation increased cellular activity and repressed β-catenin protein expression, and TRIM25 knockdown promoted VSMC activity by binding to MAT2A.\",\n      \"method\": \"RNA stability assay, Co-IP, Western blot, in vivo TAA model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mRNA stability and binding assays with functional cell and in vivo readout, single lab\",\n      \"pmids\": [\"39216871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT2A knockdown in porcine embryos reduced H3K4me2, H3K9me2/3, and H3K27me3 levels at the four-cell stage, reduced EED and EZH2 expression, impaired ZGA gene transcription, and caused developmental arrest; SAM supplementation rescued these defects.\",\n      \"method\": \"dsRNA injection KD, immunofluorescence for histone marks, SAM rescue experiment, embryo development assay\",\n      \"journal\": \"Theriogenology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple histone mark readouts and rescue, porcine ortholog\",\n      \"pmids\": [\"39276507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15 promotes MAT2A expression by N6-methyladenosine (m6A) modification of MAT2A mRNA; MAT2A knockdown in osteosarcoma reduces proliferation, migration, invasion, and enhances ferroptosis both in vitro and in vivo.\",\n      \"method\": \"MeRIP assay, dual-luciferase reporter assay, xenograft model, ferroptosis measurements\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — m6A site validation with functional assays, single lab\",\n      \"pmids\": [\"39527319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear MAT2A enzymatic activity is required for immunoglobulin class switch recombination (CSR); expression of a catalytically inactive MAT2A (D134A) targeted to the nucleus suppressed CSR from IgM to IgA, reduced intracellular SAM, and downregulated AID expression while enhancing germline transcripts.\",\n      \"method\": \"Nuclear-localized WT vs. catalytically inactive MAT2A expression, CSR assay, ChIP at IgA switch region, AID expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis and ChIP with functional CSR readout, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.10.24.684368\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FMO4 facilitates the interaction between MAT2A and MAT2B, promoting cysteine generation from methionine, boosting glutathione synthesis and protecting lung adenocarcinoma cells from ferroptosis.\",\n      \"method\": \"Proteomic analysis, Co-IP for MAT2A-MAT2B complex, in vivo KO model, ferroptosis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP interaction with in vivo genetic KO and ferroptosis functional assay, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.03.31.646284\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAT2A interacts with transcription factor SRF, promotes its SUMO-dependent nuclear stabilization, and enhances SRF-driven PARN transcription to increase glycolysis via the PARN-PI3K-AKT pathway; a catalytically inactive MAT2A retains this SRF-stabilizing function, indicating a SAM-independent mechanism.\",\n      \"method\": \"Co-IP, SUMO stabilization assay, catalytically inactive mutant, RNA-seq, glycolysis measurement, in vivo xenograft\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with catalytic mutant distinguishing SAM-independent function, single lab\",\n      \"pmids\": [\"41530371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAT2A is the ubiquitous methionine adenosyltransferase that catalyzes SAM synthesis from methionine and ATP via an advanced SN2 (for SAM formation) and dissociative (for triphosphate hydrolysis) transition state; it is allosterically regulated by its non-catalytic MAT2B subunit (which overlaps with small-molecule allosteric inhibitor binding sites) and by SIRT4-mediated ADP-ribosylation and SUMOylation; it functions both cytoplasmically to control the SAM pool (controlling PRMT5 substrate availability, histone methylation, ferroptosis resistance via ACSL3/ACSL4, and mRNA m6A levels) and in the nucleus where its catalytic activity locally supplies SAM for histone methylation marks including H3K4me2/3, H3K36me3, and H3K27me3, and is required for immunoglobulin class switch recombination; MAT2A expression is regulated transcriptionally by HIF-1α, NF-κB/p65, E2F/Sp3, and PPARγ, and post-transcriptionally through METTL16-mediated m6A modification of its pre-mRNA that controls detained intron splicing versus nuclear decay, with CFIm complex promoting productive splicing; in MTAP-deleted cancers, loss of MTA catabolism elevates MTA which selectively inhibits PRMT5, creating synthetic lethality upon MAT2A inhibition that reduces SAM/PRMT5 activity, disrupts splicing, and induces DNA damage.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAT2A is the ubiquitously expressed catalytic subunit of methionine adenosyltransferase II that synthesizes S-adenosylmethionine (SAM) from methionine and ATP, serving as the principal supplier of methyl groups for DNA, histone, RNA, and protein methylation reactions across mammalian tissues [PMID:28880543, PMID:34668717]. Its catalytic activity is allosterically regulated by the MAT2B regulatory subunit, which binds an overlapping site with small-molecule inhibitors to modulate substrate affinity and turnover in a methionine/SAM concentration-dependent manner, and MAT2B stabilizes MAT2A protein in an NADP⁺-dependent fashion [PMID:28553945, PMID:39353892]. MAT2A expression is controlled transcriptionally by E2F/Sp3, HIF-1α, NF-κB, and mTOR–c-MYC signaling, and post-transcriptionally through METTL16-mediated m6A modification of its pre-mRNA that governs detained intron splicing versus nuclear decay, with the CFIm complex promoting productive splicing under SAM-depleted conditions [PMID:11124935, PMID:21460102, PMID:29563249, PMID:33949310, PMID:35069973]. Beyond its cytoplasmic metabolic role, nuclear MAT2A locally supplies SAM for chromatin-modifying enzymes including EZH2 and H3K4 methyltransferases, thereby controlling histone marks (H3K4me2/3, H3K27me3, H3K36me3) that regulate gene expression programs in contexts ranging from embryonic development and immune cell function to the MTAP-deleted cancer synthetic lethal axis where MAT2A inhibition depletes PRMT5 substrates and induces splicing defects and DNA damage [PMID:29133280, PMID:35422502, PMID:27068473, PMID:33450196].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of MAT2B as a regulatory subunit that physically associates with MAT2A and alters its kinetic properties resolved how the enzyme's methionine sensitivity is tuned in vivo.\",\n      \"evidence\": \"Recombinant co-expression and kinetic characterization of MAT2A–MAT2B complexes\",\n      \"pmids\": [\"10644686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MAT2A–MAT2B interaction not yet resolved\", \"In vivo stoichiometry unknown\", \"Tissue-specific regulation by MAT2B not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping the MAT2A promoter revealed that Sp3 (not Sp1) is the primary transcription factor driving basal expression, establishing the transcriptional framework for MAT2A regulation.\",\n      \"evidence\": \"Promoter deletions, EMSA, supershift, and ChIP in human cells\",\n      \"pmids\": [\"11124935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No chromatin context or enhancer elements mapped\", \"Regulation in non-hepatic tissues unexplored\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Cell cycle–regulated MAT2A transcription via E2F family members linked SAM production to proliferative signaling, explaining why MAT2A is induced during liver regeneration.\",\n      \"evidence\": \"RNApol-ChIP, EMSA, and ChIP for E2F1/E2F3/E2F4 at the MAT2A promoter during liver regeneration\",\n      \"pmids\": [\"17317269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct E2F site mutagenesis not performed\", \"Whether E2F regulation operates in non-hepatic tissues unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"MAT2A knockdown in hepatoma cells demonstrated that MAT2A activity directly controls the intracellular SAM pool and that SAM levels feed back to regulate MAT gene isoform switching (MAT2A→MAT1A).\",\n      \"evidence\": \"siRNA knockdown with SAM/SAH measurement, growth and apoptosis assays in hepatoma cells\",\n      \"pmids\": [\"17441811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SAM-mediated MAT1A re-expression not defined\", \"Single cell line study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstration that HIF-1α directly binds the MAT2A promoter under hypoxia connected oxygen sensing to methyl metabolism, showing how hypoxia reduces SAM and causes global DNA demethylation.\",\n      \"evidence\": \"HIF-1α binding site mutagenesis, ChIP for HIF-1α/p300/HDAC1, SAM and methylation assays in hepatoma cells\",\n      \"pmids\": [\"21460102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other hypoxia-responsive methyltransferases are co-regulated not tested\", \"In vivo validation lacking\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that MTAP deletion elevates MTA to selectively inhibit PRMT5, creating synthetic lethality with MAT2A depletion, established the therapeutic rationale for targeting MAT2A in MTAP-null cancers.\",\n      \"evidence\": \"shRNA screen, metabolomics, PRMT5 methyltransferase profiling, cell viability assays in MTAP-deleted vs. WT cells\",\n      \"pmids\": [\"27068473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other methyltransferases contribute to synthetic lethality not fully explored\", \"Patient tumor heterogeneity in MTA levels not assessed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterization of PF-9366 binding to an allosteric site overlapping with MAT2B revealed that MAT2B functions as a context-dependent activator or inhibitor depending on methionine/SAM levels, unifying prior kinetic observations.\",\n      \"evidence\": \"Biochemical enzyme kinetics with allosteric inhibitor and MAT2B, structural overlap analysis\",\n      \"pmids\": [\"28553945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full co-crystal structure of MAT2A–MAT2B with inhibitor not obtained in this study\", \"In vivo allosteric regulation dynamics unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Transition-state analysis established that MAT2A catalyzes SAM formation via an advanced SN2 mechanism (S–C distance 2.03 Å), providing a chemical framework for inhibitor design.\",\n      \"evidence\": \"Kinetic isotope effects, commitment factors, binding isotope effects, QM calculations\",\n      \"pmids\": [\"28880543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transition state for the second half-reaction (triphosphate hydrolysis) addressed later\", \"Transition-state analogues for SAM formation not yet synthesized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The finding that MAT2A detained intron transcripts are dead-end products destined for nuclear decay — not mRNA precursors — established cotranscriptional splicing as the regulatory switch for SAM homeostasis.\",\n      \"evidence\": \"Three independent precursor-product relationship assays, transcriptional run-on, nuclear fractionation\",\n      \"pmids\": [\"29563249\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the nuclear decay machinery acting on DI transcripts not defined\", \"How SAM levels signal to the splicing machinery not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A CRISPR screen identified the CFIm complex (NUDT21/CFIm25, CFIm68, CFIm59) as a direct promoter of MAT2A detained intron splicing, requiring RS domains and binding sites in the intron and 3′ UTR, revealing the splicing factor machinery controlling SAM-responsive MAT2A regulation.\",\n      \"evidence\": \"Genome-wide CRISPR KO screen with domain deletion analysis of CFIm subunits\",\n      \"pmids\": [\"33949310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SAM depletion signals to CFIm complex not determined\", \"Whether CFIm regulation is tissue-specific unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Structural resolution of the triphosphate hydrolysis transition state (MgF3⁻ and AlF3⁰ mimics at 1.07 Å) completed the mechanistic picture of both MAT2A half-reactions, showing a loose dissociative mechanism with catalytic arginine-directed water nucleophile.\",\n      \"evidence\": \"X-ray crystallography with transition-state analogues, NMR validation\",\n      \"pmids\": [\"34668717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full catalytic cycle dynamics (substrate binding order, product release) not captured crystallographically\", \"No structures of MAT2A with allosteric inhibitors bound simultaneously with TSA\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Potent MAT2A allosteric inhibitors (AG-270) were shown to trap SAM in the active site, reduce intracellular SAM, impair PRMT5-dependent splicing, and induce DNA damage selectively in MTAP-null tumors in vivo, validating MAT2A as a drug target.\",\n      \"evidence\": \"Fragment-to-lead optimization, enzymatic assays, RNA-seq, DNA damage assays, xenograft efficacy models\",\n      \"pmids\": [\"33829783\", \"33450196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical efficacy in patients not yet demonstrated\", \"Resistance mechanisms to MAT2A inhibitors not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Nuclear MAT2A interacts with EZH2 and MafK at specific promoters to locally supply SAM for H3K27me3 deposition, establishing a chromatin-targeted, non-bulk metabolic role for MAT2A.\",\n      \"evidence\": \"Co-IP, ChIP for H3K27me3 at Wnt10b promoter, catalytic mutant and MAT2B-dependence analysis in porcine adipocytes\",\n      \"pmids\": [\"29133280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAT2A is recruited genome-wide or to select loci not determined\", \"Mechanism of MAT2A nuclear targeting unknown\", \"Single-model (porcine) system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MAT2A depletion in H3K27M-mutant glioma globally reduced H3K36me3, linking MAT2A-dependent SAM production to transcriptional elongation marks and revealing vulnerability of developmental tumors to methionine metabolism perturbation.\",\n      \"evidence\": \"siRNA screen, ChIP-seq for histone marks, mouse methionine-restricted diet models\",\n      \"pmids\": [\"35422502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3K36me3 loss is direct or secondary to altered SAM distribution not resolved\", \"Contribution of other SAM-consuming enzymes in glioma not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"METTL16-mediated m6A modification of MAT2A mRNA was shown to regulate its stability and splicing, with opposing outcomes (stabilization vs. degradation) depending on cellular context, establishing a feedback loop between SAM-dependent m6A writing and MAT2A expression.\",\n      \"evidence\": \"m6A modification assays, METTL16 overexpression/knockdown, mRNA stability assays in multiple cell systems\",\n      \"pmids\": [\"35069973\", \"36307396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflicting stabilization vs. degradation outcomes across studies not reconciled\", \"Precise m6A reader proteins mediating the downstream effect not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"SIRT4 was found to ADP-ribosylate MAT2A at E111, and mTORC1–c-Myc-driven TRIM32-mediated SIRT4 degradation activates MAT2A, integrating nutrient sensing with SAM production in hepatocellular carcinoma.\",\n      \"evidence\": \"ADP-ribosylation site identification, metabolomics, RNA-seq, mouse models\",\n      \"pmids\": [\"36371321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of how E111 ADP-ribosylation inhibits catalysis unknown\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Intestinal epithelial-specific Mat2a knockout caused neonatal lethality with proliferation failure and apoptosis, rescued by SAM supplementation, demonstrating that MAT2A-dependent SAM is essential for intestinal epithelial homeostasis.\",\n      \"evidence\": \"Conditional KO mouse (Villin-Cre), SAM rescue, caspase activity measurement\",\n      \"pmids\": [\"36975381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lethality reflects SAM depletion alone or also loss of non-catalytic MAT2A functions not tested\", \"Specific methyltransferases mediating the intestinal phenotype not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MAT2B was shown to stabilize MAT2A protein in an NADP⁺-dependent manner, connecting cellular redox/cofactor state to SAM production capacity and downstream m6A mRNA modification.\",\n      \"evidence\": \"Co-IP, protein stability assays, NADP⁺ perturbation, m6A analysis\",\n      \"pmids\": [\"39353892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of NADP⁺-dependent MAT2A–MAT2B interaction not resolved\", \"Single lab, awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multi-omic profiling in CRPC showed that MAT2A cooperates with ERG to remodel H3K4me2 at non-canonical AR target genes, and that MAT2A inhibition reverses this epigenetic program and sensitizes tumors to AR/EZH2 inhibitors.\",\n      \"evidence\": \"RNA-seq, ATAC-seq, ChIP-seq, histone PTM mass spectrometry, pharmacological and genetic MAT2A inhibition\",\n      \"pmids\": [\"39107274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MAT2A–ERG cooperation involves direct physical interaction not determined\", \"Clinical translatability of combination strategies untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM structure of MAT2A with allosteric inhibitor SCR-7952 confirmed the allosteric binding mode, and combination with PRMT5 inhibitors aggravated splicing perturbations including FANCA mis-splicing.\",\n      \"evidence\": \"Cryo-EM, biochemical inhibition, RNA splicing analysis, xenograft models\",\n      \"pmids\": [\"39309689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full dynamic conformational ensemble of MAT2A upon allosteric inhibitor binding not captured\", \"FANCA splicing as biomarker not clinically validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A SAM-independent scaffolding function of MAT2A was uncovered: catalytically inactive MAT2A retains the ability to stabilize SRF via SUMOylation and drive SRF-dependent transcription of glycolytic genes, demonstrating a non-enzymatic role.\",\n      \"evidence\": \"Co-IP, SUMO stabilization assay, catalytically inactive mutant, RNA-seq, glycolysis measurement, xenograft\",\n      \"pmids\": [\"41530371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of SAM-independent functions beyond SRF not explored\", \"Single lab, awaits independent confirmation\", \"Structural basis of MAT2A–SRF interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) how MAT2A is targeted to specific chromatin loci to locally supply SAM; (2) the structural basis of NADP⁺-dependent MAT2A–MAT2B stabilization; (3) clinical efficacy and resistance mechanisms for MAT2A allosteric inhibitors; and (4) the full scope of SAM-independent scaffolding functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of chromatin-recruited MAT2A\", \"No clinical trial outcome data for MAT2A inhibitors\", \"Non-catalytic protein interaction network incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 8, 9, 14, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [22, 39]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 29, 35, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 8, 9, 14, 18, 27]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [20, 22, 29, 35]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 13, 21, 24]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 19, 26]}\n    ],\n    \"complexes\": [\n      \"MAT II (MAT2A–MAT2B heteromer)\"\n    ],\n    \"partners\": [\n      \"MAT2B\",\n      \"EZH2\",\n      \"PRMT5\",\n      \"SRF\",\n      \"METTL16\",\n      \"SIRT4\",\n      \"PDCD6\",\n      \"MafK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}