Affinage

MAT2A

S-adenosylmethionine synthase isoform type-2 · UniProt P31153

Length
395 aa
Mass
43.7 kDa
Annotated
2026-04-28
86 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2000 High

    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

    PMID:10644686

    Open questions at the time
    • Structural basis of MAT2A–MAT2B interaction not yet resolved
    • In vivo stoichiometry unknown
    • Tissue-specific regulation by MAT2B not addressed
  2. 2000 High

    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

    PMID:11124935

    Open questions at the time
    • No chromatin context or enhancer elements mapped
    • Regulation in non-hepatic tissues unexplored
  3. 2007 High

    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

    PMID:17317269

    Open questions at the time
    • Direct E2F site mutagenesis not performed
    • Whether E2F regulation operates in non-hepatic tissues unknown
  4. 2007 Medium

    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

    PMID:17441811

    Open questions at the time
    • Mechanism of SAM-mediated MAT1A re-expression not defined
    • Single cell line study
  5. 2011 High

    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

    PMID:21460102

    Open questions at the time
    • Whether other hypoxia-responsive methyltransferases are co-regulated not tested
    • In vivo validation lacking
  6. 2016 High

    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

    PMID:27068473

    Open questions at the time
    • Whether other methyltransferases contribute to synthetic lethality not fully explored
    • Patient tumor heterogeneity in MTA levels not assessed
  7. 2017 High

    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

    PMID:28553945

    Open questions at the time
    • Full co-crystal structure of MAT2A–MAT2B with inhibitor not obtained in this study
    • In vivo allosteric regulation dynamics unknown
  8. 2017 High

    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

    PMID:28880543

    Open questions at the time
    • Transition state for the second half-reaction (triphosphate hydrolysis) addressed later
    • Transition-state analogues for SAM formation not yet synthesized
  9. 2018 High

    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

    PMID:29563249

    Open questions at the time
    • Identity of the nuclear decay machinery acting on DI transcripts not defined
    • How SAM levels signal to the splicing machinery not resolved
  10. 2021 High

    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

    PMID:33949310

    Open questions at the time
    • How SAM depletion signals to CFIm complex not determined
    • Whether CFIm regulation is tissue-specific unknown
  11. 2021 High

    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

    PMID:34668717

    Open questions at the time
    • Full catalytic cycle dynamics (substrate binding order, product release) not captured crystallographically
    • No structures of MAT2A with allosteric inhibitors bound simultaneously with TSA
  12. 2021 High

    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

    PMID:33450196 PMID:33829783

    Open questions at the time
    • Clinical efficacy in patients not yet demonstrated
    • Resistance mechanisms to MAT2A inhibitors not characterized
  13. 2022 Medium

    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

    PMID:29133280

    Open questions at the time
    • Whether MAT2A is recruited genome-wide or to select loci not determined
    • Mechanism of MAT2A nuclear targeting unknown
    • Single-model (porcine) system
  14. 2022 High

    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

    PMID:35422502

    Open questions at the time
    • Whether H3K36me3 loss is direct or secondary to altered SAM distribution not resolved
    • Contribution of other SAM-consuming enzymes in glioma not tested
  15. 2022 Medium

    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

    PMID:35069973 PMID:36307396

    Open questions at the time
    • Conflicting stabilization vs. degradation outcomes across studies not reconciled
    • Precise m6A reader proteins mediating the downstream effect not identified
  16. 2022 Medium

    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

    PMID:36371321

    Open questions at the time
    • Structural basis of how E111 ADP-ribosylation inhibits catalysis unknown
    • Single lab, not independently replicated
  17. 2023 High

    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

    PMID:36975381

    Open questions at the time
    • Whether lethality reflects SAM depletion alone or also loss of non-catalytic MAT2A functions not tested
    • Specific methyltransferases mediating the intestinal phenotype not identified
  18. 2024 Medium

    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

    PMID:39353892

    Open questions at the time
    • Structural basis of NADP⁺-dependent MAT2A–MAT2B interaction not resolved
    • Single lab, awaits independent confirmation
  19. 2024 High

    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

    PMID:39107274

    Open questions at the time
    • Whether MAT2A–ERG cooperation involves direct physical interaction not determined
    • Clinical translatability of combination strategies untested
  20. 2024 High

    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

    PMID:39309689

    Open questions at the time
    • Full dynamic conformational ensemble of MAT2A upon allosteric inhibitor binding not captured
    • FANCA splicing as biomarker not clinically validated
  21. 2025 Medium

    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

    PMID:41530371

    Open questions at the time
    • Generality of SAM-independent functions beyond SRF not explored
    • Single lab, awaits independent confirmation
    • Structural basis of MAT2A–SRF interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No structural model of chromatin-recruited MAT2A
  • No clinical trial outcome data for MAT2A inhibitors
  • Non-catalytic protein interaction network incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-5357801 Programmed Cell Death 3
Partners
EZH2MAFKMAT2BMETTL16PDCD6PRMT5SIRT4SRF
Complex memberships
MAT II (MAT2A–MAT2B heteromer)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 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. Recombinant protein expression, co-association assay, kinetic characterization The Journal of biological chemistry High 10644686
2000 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. Promoter deletion analysis, EMSA, supershift assay, in vivo reporter assay The Journal of biological chemistry High 11124935
2001 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. Promoter deletion analysis, EMSA, supershift assay, ChIP The Journal of biological chemistry High 11337507
2001 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. EMSA, supershift assay, in vivo reporter assay comparison between normal and leukemic T cells Biochimica et biophysica acta Medium 11476892
2007 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. RNA interference, enzymatic activity assay, metabolite measurement, cell growth and apoptosis assays Hepatology research Medium 17441811
2007 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. RNApol-ChIP, EMSA, ChIP for transcription factors and histone modifiers The international journal of biochemistry & cell biology High 17317269
2011 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. Site-directed mutagenesis of HIF-1α binding site, EMSA, ChIP, SAM measurement, methylation assay Molecular cancer therapeutics High 21460102
2016 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. shRNA screening, metabolomics, biochemical methyltransferase profiling, cell viability assays Cell reports High 27068473
2017 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. Biochemical enzyme kinetics, allosteric inhibitor characterization, structural overlap analysis Nature chemical biology High 28553945
2017 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. Kinetic isotope effects, commitment factors, binding isotope effects, quantum mechanical calculations Journal of the American Chemical Society High 28880543
2018 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. Three independent assays for precursor-product relationship, transcriptional run-on, nuclear fractionation RNA High 29563249
2019 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. Luciferase reporter assay, LC-MS SAM measurement, AAV-mediated in vivo overexpression/knockdown, pharmacoproteomics EBioMedicine High 30926424
2021 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. RNA sequencing, proteomics, SAM measurement, DNA damage assays, cell viability in MTAP-/- cells Cancer cell High 33450196
2021 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. CRISPR knockout screen, splicing assays, domain deletion analysis eLife High 33949310
2021 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. Fragment screening, structure-guided design, enzymatic assays, xenograft models Journal of medicinal chemistry High 33829783
2021 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. ChIP for H3K4me3, pharmacological and genetic MAT2A inhibition, macrophage polarization assays Journal for immunotherapy of cancer Medium 33593829
2021 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. CRISPR library screen, KO/OE experiments, chromatin methylation analysis at HIV-1 LTR Frontiers in immunology Medium 34616406
2021 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. Co-immunoprecipitation, cytoplasm/nucleus fractionation, ubiquitination assay Frontiers in cell and developmental biology Medium 33859984
2021 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. X-ray crystallography at 1.07 Å resolution, NMR, crystal structures with transition-state analogues Journal of the American Chemical Society High 34668717
2022 MAT2A mediates ferroptosis resistance in gastric cancer by producing SAM, which upregulates ACSL3 by increasing H3K4me3 trimethylation at the ACSL3 promoter. ChIP for H3K4me3, genetic and pharmacological MAT2A inhibition, ferroptosis assays in vitro and in vivo Free radical biology & medicine Medium 35182729
2022 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. siRNA screen, ChIP-seq/histone modification analysis, mouse models with methionine-restricted diet Nature cancer High 35422502
2022 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. m6A modification assay, lentiviral METTL16 overexpression/siRNA, mRNA stability assay, in vivo IVDD model Oxidative medicine and cellular longevity Medium 35069973
2022 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. Co-IP, ChIP for H3K27me3, overexpression/knockdown, adipogenesis assays Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 29133280
2022 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. Immunostaining, metabolomics, RNA-seq, mouse models, identification of ADP-ribosylation site Cell & bioscience Medium 36371321
2022 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. m6A methylation assay, METTL16 KD/OE in hippocampus, mRNA stability assay, Morris water maze Cell death discovery Medium 36307396
2022 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. Co-immunoprecipitation, mass spectrometry, immunoblotting, PDCD6 K90R mutation analysis Cell death discovery Medium 35396512
2023 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. Conditional KO mouse model, SAM supplementation rescue, caspase expression and activity measurement Development High 36975381
2023 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. Drug combination synergy assays, SAM/MTA metabolite measurement, PRMT5 activity assay, MDM4 splicing analysis, xenograft models The Journal of biological chemistry High 38000655
2024 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. Co-IP, protein stability assay, m6A modification analysis, NADP+ perturbation experiments Cell death & disease Medium 39353892
2024 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. RNA-seq, ATAC-seq, ChIP-seq, histone PTM analysis by mass spectrometry, genetic and pharmacological inhibition Nature communications High 39107274
2024 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. Cryo-EM structural determination, biochemical inhibition assay, RNA splicing analysis, xenograft models MedComm High 39309689
2024 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. Cspg4-CreERT2/Mat2aflox/flox mouse model, single-cell sequencing, mechanistic protein interaction and mitochondrial function assays Nature communications Medium 41298385
2024 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. ChIP for H3K4me3, myeloid-specific MAT2A KO mouse model, pharmacological inhibition, metabolomics Nature communications High 41402252
2024 MAT2A SUMOylation is regulated by SUMO E1; inhibition of MAT2A SUMOylation unexpectedly stimulates polyamine synthesis via the MAT2A-AdoMetDC axis. SUMOylation assay, metabolite measurement, synergy assays with polyamine synthesis inhibitor Bioorganic chemistry Medium 40884915
2024 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. RNA stability assay, Co-IP, Western blot, in vivo TAA model Human molecular genetics Medium 39216871
2024 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. dsRNA injection KD, immunofluorescence for histone marks, SAM rescue experiment, embryo development assay Theriogenology Medium 39276507
2024 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. MeRIP assay, dual-luciferase reporter assay, xenograft model, ferroptosis measurements Molecular and cellular biochemistry Medium 39527319
2025 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. Nuclear-localized WT vs. catalytically inactive MAT2A expression, CSR assay, ChIP at IgA switch region, AID expression analysis bioRxivpreprint Medium bio_10.1101_2025.10.24.684368
2025 FMO4 facilitates the interaction between MAT2A and MAT2B, promoting cysteine generation from methionine, boosting glutathione synthesis and protecting lung adenocarcinoma cells from ferroptosis. Proteomic analysis, Co-IP for MAT2A-MAT2B complex, in vivo KO model, ferroptosis assays bioRxivpreprint Medium bio_10.1101_2025.03.31.646284
2025 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. Co-IP, SUMO stabilization assay, catalytically inactive mutant, RNA-seq, glycolysis measurement, in vivo xenograft Communications biology Medium 41530371

Source papers

Stage 0 corpus · 86 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell reports 352 27068473
2021 MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer cell 179 33450196
2011 Hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. Molecular cancer therapeutics 128 21460102
2017 Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nature chemical biology 112 28553945
2021 Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion. Journal of medicinal chemistry 85 33829783
2014 MAT2A mutations predispose individuals to thoracic aortic aneurysms. American journal of human genetics 84 25557781
2022 Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. Journal of medicinal chemistry 71 35796517
2000 Cloning, expression, and functional characterization of the beta regulatory subunit of human methionine adenosyltransferase (MAT II). The Journal of biological chemistry 69 10644686
2022 Activation of MAT2A-ACSL3 pathway protects cells from ferroptosis in gastric cancer. Free radical biology & medicine 64 35182729
2022 Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome. Nature cancer 50 35422502
2019 TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM. EBioMedicine 49 30926424
2001 Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase, MAT II. The Journal of biological chemistry 49 11337507
2021 Activation of MAT2A-RIP1 signaling axis reprograms monocytes in gastric cancer. Journal for immunotherapy of cancer 42 33593829
2021 SAM homeostasis is regulated by CFIm-mediated splicing of MAT2A. eLife 42 33949310
2022 Oxidative Stress Aggravates Apoptosis of Nucleus Pulposus Cells through m6A Modification of MAT2A Pre-mRNA by METTL16. Oxidative medicine and cellular longevity 35 35069973
2012 Overexpression of methionine adenosyltransferase II alpha (MAT2A) in gastric cancer and induction of cell cycle arrest and apoptosis in SGC-7901 cells by shRNA-mediated silencing of MAT2A gene. Acta histochemica 34 22542325
2020 Circular RNA hsa_circ_0007364 increases cervical cancer progression through activating methionine adenosyltransferase II alpha (MAT2A) expression by restraining microRNA-101-5p. Bioengineered 33 33138667
2007 Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cells. Hepatology research : the official journal of the Japan Society of Hepatology 31 17441811
2022 mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell & bioscience 30 36371321
2018 Balance between MAT2A intron detention and splicing is determined cotranscriptionally. RNA (New York, N.Y.) 30 29563249
2020 MAT2A as Key Regulator and Therapeutic Target in MLLr Leukemogenesis. Cancers 29 32456310
2009 The Sequence Analysis and Management System -- SAMS-2.0: data management and sequence analysis adapted to changing requirements from traditional sanger sequencing to ultrafast sequencing technologies. Journal of biotechnology 28 19297685
2022 Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads. Journal of medicinal chemistry 27 35293760
2021 MiR-26b-5p-modified hUB-MSCs derived exosomes attenuate early brain injury during subarachnoid hemorrhage via MAT2A-mediated the p38 MAPK/STAT3 signaling pathway. Brain research bulletin 27 34284075
2020 CBS and MAT2A improve methionine-mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation. Cell proliferation 26 33179842
2000 Regulation of the human MAT2A gene encoding the catalytic alpha 2 subunit of methionine adenosyltransferase, MAT II: gene organization, promoter characterization, and identification of a site in the proximal promoter that is essential for its activity. The Journal of biological chemistry 26 11124935
2025 MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial. Nature communications 25 39762248
2023 Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. The Journal of biological chemistry 23 38000655
2007 Transcription of the MAT2A gene, coding for methionine adenosyltransferase, is up-regulated by E2F and Sp1 at a chromatin level during proliferation of liver cells. The international journal of biochemistry & cell biology 22 17317269
2017 The Transition-State Structure for Human MAT2A from Isotope Effects. Journal of the American Chemical Society 21 28880543
2017 MAT2A promotes porcine adipogenesis by mediating H3K27me3 at Wnt10b locus and repressing Wnt/β-catenin signaling. Biochimica et biophysica acta. Molecular and cell biology of lipids 21 29133280
2023 Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability. Journal of medicinal chemistry 20 36961373
2021 MALAT1 Inhibits Proliferation of HPV16-Positive Cervical Cancer by Sponging miR-485-5p to Promote Expression of MAT2A. DNA and cell biology 20 34610246
2022 Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA. Cell death discovery 19 36307396
2021 Circ_0044516 Regulates miR-136/MAT2A Pathway to Facilitate Lung Cancer Development. Journal of immunology research 18 34258296
2022 MAT2A facilitates PDCD6 methylation and promotes cell growth under glucose deprivation in cervical cancer. Cell death discovery 17 35396512
2023 MAT2A inhibits the ferroptosis in osteosarcoma progression regulated by miR-26b-5p. Journal of bone oncology 16 37457846
2021 SYVN1-MTR4-MAT2A Signaling Axis Regulates Methionine Metabolism in Glioma Cells. Frontiers in cell and developmental biology 14 33859984
2019 Quercetin Promotes Cell Cycle Arrest and Apoptosis and Attenuates the Proliferation of Human Chronic Myeloid Leukemia Cell Line-K562 Through Interaction with HSPs (70 and 90), MAT2A and FOXM1. Anti-cancer agents in medicinal chemistry 14 31362681
2023 S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency. Development (Cambridge, England) 13 36975381
2024 MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer. Drug discovery today 12 39306235
2022 A patent review of MAT2a inhibitors (2018-2021). Expert opinion on therapeutic patents 12 36043503
2024 Epigenome-wide impact of MAT2A sustains the androgen-indifferent state and confers synthetic vulnerability in ERG fusion-positive prostate cancer. Nature communications 9 39107274
2022 Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 35064691
2022 Inhibition of MAT2A-Related Methionine Metabolism Enhances The Efficacy of Cisplatin on Cisplatin-Resistant Cells in Lung Cancer. Cell journal 9 35674024
2020 Hsa_circ_0000337 promotes proliferation, migration and invasion in glioma by competitively binding miRNA-942-5p and thus upregulates MAT2A. European review for medical and pharmacological sciences 9 33336744
2023 Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening. Bioorganic & medicinal chemistry letters 8 37591318
2024 Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy. Journal of medicinal chemistry 7 38818879
2024 SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors. MedComm 7 39309689
2025 Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers. Journal of medicinal chemistry 6 39760448
2024 8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia. Leukemia 6 38643304
2024 MAT2B regulates the protein level of MAT2A to preserve RNA N6-methyladenosine. Cell death & disease 6 39353892
2022 Single Nucleotide Polymorphisms of ALDH18A1 and MAT2A Genes and Their Genetic Associations with Milk Production Traits of Chinese Holstein Cows. Genes 6 36011348
2021 MAT2A-Mediated S-Adenosylmethionine Level in CD4+ T Cells Regulates HIV-1 Latent Infection. Frontiers in immunology 6 34616406
2019 MAT2A/2B promote porcine intramuscular preadipocyte proliferation through ERK signaling pathway. Animal science journal = Nihon chikusan Gakkaiho 6 31293025
2025 Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models. Journal of medicinal chemistry 5 39835703
2024 MAT2A is essential for zygotic genome activation by maintaining of histone methylation in porcine embryos. Theriogenology 5 39276507
2021 The Andrographolide Analogue 3A.1 Synergizes with Taxane Derivatives in Aggressive Metastatic Prostate Cancers by Upregulation of Heat Shock Proteins and Downregulation of MAT2A-Mediated Cell Migration and Invasion. The Journal of pharmacology and experimental therapeutics 5 34949650
2001 Distinct patterns of protein binding to the MAT2A promoter in normal and leukemic T cells. Biochimica et biophysica acta 5 11476892
2024 Inhibition of MAT2A Impairs Skeletal Muscle Repair Function. Biomolecules 4 39334864
2022 Expression of vimentin, TPI and MAT2A in human dermal microvascular endothelial cells during angiogenesis in vitro. PloS one 4 35482724
2021 PPARγ induces the paroxysm of endometriosis by regulating the transcription of MAT2A gene. American journal of translational research 4 33841663
2021 Mechanism of Triphosphate Hydrolysis by Human MAT2A at 1.07 Å Resolution. Journal of the American Chemical Society 4 34668717
2026 Quercetin Inhibits Ectopic Lesion Formation in Mice by Modulating the MAT2A/PRMT5 Pathway through PPARγ Activation. Combinatorial chemistry & high throughput screening 3 39995138
2025 Effects of m6A methylation of MAT2A mRNA regulated by METTL16 on learning and memory, hippocampal synaptic plasticity and Aβ1-42 in 5 × FAD mice. Frontiers in aging neuroscience 3 40308894
2025 Combined inhibition by PRMT5 and MAT2A demonstrates a strong synthetic lethality in MTAP homozygous-deficient glioma models. Cell death discovery 3 40450009
2025 Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer. Archives of biochemistry and biophysics 3 40517800
2024 RBM15-mediated the m6A modification of MAT2A promotes osteosarcoma cell proliferation, metastasis and suppresses ferroptosis. Molecular and cellular biochemistry 3 39527319
2024 MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival. bioRxiv : the preprint server for biology 3 39605416
2022 Circ-ERC2 Is Involved in Melatonin Synthesis by Regulating the miR-125a-5p/MAT2A Axis. International journal of molecular sciences 3 36555116
2023 MAT2A inhibition suppresses inflammation in Porphyromonas gingivalis-infected human gingival fibroblasts. Journal of oral microbiology 2 38130504
2025 Discovery of Potential Scaffolds for Methionine Adenosyltransferase 2A (MAT2A) Inhibitors: Virtual Screening, Synthesis, and Biological Evaluation. Molecules (Basel, Switzerland) 1 40430308
2025 Furo[2,3-f]quinazolin-7(6H)-one Derivatives as Potent, Selective, and Orally Bioavailable MAT2A Inhibitors for MTAP-Deficient Cancer Therapy. Journal of medicinal chemistry 1 41247922
2024 Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition. Archives of toxicology 1 38755480
2026 MAT2A enhances PARN transcription via SRF to accelerate glycolysis and drive malignant progression in osteosarcoma. Communications biology 0 41530371
2026 Lack of Cancer Specificity of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 in Combination With Recombinant Methioninase In Vitro. Anticancer research 0 41617456
2026 EGR1/miR-4306/MAT2A axis aggravates pyroptosis and extracellular matrix degradation of nucleus pulposus cells in intervertebral disc degeneration. Cell biology and toxicology 0 41653251
2026 Design and Discovery of Pyridazinone-Based MAT2A Inhibitors Targeting MTAP-Deficient Cancers. Journal of medicinal chemistry 0 42024642
2025 Transcription factor GTF2I regulates osteoclast differentiation through mediating miR-134-5p and MAT2A expressions. Journal of cell communication and signaling 0 40191097
2025 SUMO E1 covalent allosteric inhibitors upregulate polyamine synthesis via the MAT2A-AdoMetDC axis. Bioorganic chemistry 0 40884915
2025 Methionine-MAT2A-SAM axis controls lipid levels by regulating ACSL4. Oncology letters 0 41078715
2025 Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification. Journal of orthopaedic translation 0 41146859
2025 A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models. Nature communications 0 41298385
2025 MAT2A promotes atherosclerotic plaque vulnerability by mediating epigenetic reprogramming of macrophages. Nature communications 0 41402252
2025 Silencing of MAT2A inhibits gastric cancer cell proliferation, migration, and invasion through activation of the p53 pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 0 41419675
2024 TRIM25 activates Wnt/β-catenin signalling by destabilising MAT2A mRNA to drive thoracic aortic aneurysm development. Human molecular genetics 0 39216871