Affinage

MAT2A

S-adenosylmethionine synthase isoform type-2 · UniProt P31153

Length
395 aa
Mass
43.7 kDa
Annotated
2026-06-10
87 papers in source corpus 39 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAT2A is the catalytic subunit of methionine adenosyltransferase II, generating S-adenosylmethionine (SAM) from ATP and methionine and thereby serving as a master node coupling methionine/one-carbon metabolism to epigenetic and metabolic programs (PMID:27068473, PMID:36975381). Its catalysis proceeds through an advanced SN2 transition state involving methionine sulfur attack on the 5'-C of ATP and well-advanced triphosphate departure, with a downstream triphosphate hydrolysis step in which a catalytic-site arginine directs a water nucleophile (PMID:28880543, PMID:34668717). Enzyme function is governed by the regulatory MAT2B subunit, which associates with MAT alpha to lower the Km for methionine and acts as either an inhibitor or activator depending on methionine/SAM levels by allosterically reshaping the active site; this allosteric pocket overlaps the binding site of small-molecule MAT2A inhibitors that trap SAM in the active site (PMID:10644686, PMID:28553945, PMID:33829783). Cellular SAM is homeostatically buffered through detained-intron splicing of MAT2A pre-mRNA decided cotranscriptionally, controlled by the CFIm complex (NUDT21/CFIm68/CFIm59) and by METTL16-mediated m6A modification of the transcript (PMID:29563249, PMID:33949310, PMID:35069973). Nuclear MAT2A supplies SAM locally for histone methylation—enhancing H3K4me2/3, H3K27me3 and H3K36me3 at specific promoters—to drive transcriptional programs in cancer, macrophage inflammation, immunoglobulin class-switch recombination, and developmental reprogramming (PMID:35422502, PMID:39107274, PMID:41402252). In MTAP-deleted cancers, accumulated MTA inhibits PRMT5 and MAT2A-produced SAM is required to sustain residual PRMT5 activity, defining the MAT2A/PRMT5 synthetic-lethal axis exploited by MAT2A inhibitors (PMID:27068473, PMID:33450196). MAT2A is further controlled transcriptionally by Sp factors, E2F, HIF-1α and NF-κB/p65, and post-transcriptionally/post-translationally by SIRT4-dependent ADP-ribosylation, NADP+-dependent MAT2B stabilization, and TRIM25-mediated mRNA destabilization (PMID:11124935, PMID:17317269, PMID:21460102, PMID:30926424, PMID:36371321, PMID:39353892, PMID:39216871). Rare missense variants that disrupt MAT IIα function predispose to thoracic aortic aneurysm (PMID:25557781).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Established that the MAT2B beta subunit is a genuine regulatory partner of MAT alpha rather than a structural bystander, by showing it lowers the Km for methionine and alters kinetics.

    Evidence Recombinant reconstitution of beta with E. coli and human MAT alpha subunits plus kinetic analysis

    PMID:10644686

    Open questions at the time
    • Structural basis of the allosteric modulation not resolved at this stage
    • Did not address cellular consequences of the interaction
  2. 2001 High

    Mapped the transcriptional control of MAT2A and MAT2B to specific Sp-family-bound promoter elements, defining how the gene pair is set in proliferating versus quiescent cells.

    Evidence Promoter deletion, EMSA/supershift, ChIP and reporter assays; MAT2B knockdown raising SAM

    PMID:11124935 PMID:11337507 PMID:11476892

    Open questions at the time
    • Did not link promoter occupancy to physiological signals
    • Cell-type-specific factor abundance only partially explained
  3. 2007 High

    Connected MAT2A transcription to cell-cycle and regeneration programs, showing E2F/Sp control and a switch between MAT2A and MAT1A driven by SAM levels with growth/apoptotic consequences.

    Evidence ChIP/EMSA during rat liver regeneration; siRNA knockdown in hepatoma with metabolite and apoptosis readouts

    PMID:17317269 PMID:17441811

    Open questions at the time
    • Mechanism of SAM-driven MAT1A/MAT2A switch not defined
    • In vivo relevance of growth phenotype not established
  4. 2011 High

    Showed MAT2A is a hypoxia-responsive gene whose induction reshapes the SAM pool and genomic DNA methylation, linking metabolism to epigenetics.

    Evidence Site-directed mutagenesis, EMSA, ChIP for HIF-1α binding; SAM and global methylation assays

    PMID:21460102

    Open questions at the time
    • Locus-specific methylation targets not identified
    • Roles of p300/HDAC1 co-recruitment mechanistically unresolved
  5. 2016 High

    Defined the central therapeutic rationale for MAT2A by establishing the MAT2A/PRMT5 synthetic-lethal dependency in MTAP-deleted cancers.

    Evidence shRNA screen, metabolomics, methyltransferase panel and PRMT5 activity assays in isogenic MTAP lines

    PMID:27068473

    Open questions at the time
    • Did not yet define downstream PRMT5-dependent effectors driving lethality
    • Pharmacological tractability not addressed
  6. 2017 High

    Resolved the catalytic and allosteric mechanism: MAT2A uses an advanced SN2 transition state, and an allosteric pocket overlapping the MAT2B site controls active-site conformation and turnover.

    Evidence Kinetic isotope effects with QM calculations; PF-9366 allosteric inhibitor characterization with kinetics and structure

    PMID:28553945 PMID:28880543

    Open questions at the time
    • Cellular conditions dictating MAT2B inhibitor-versus-activator switch not fully mapped
  7. 2018 High

    Established that SAM homeostasis is enforced cotranscriptionally through MAT2A detained-intron splicing, with retained-intron transcripts being dead-end RNAs for nuclear decay.

    Evidence Three independent precursor-product assays, nuclear fractionation, transcription inhibition and splicing reporters

    PMID:29563249

    Open questions at the time
    • Trans-acting factors reading SAM levels not identified in this study
  8. 2021 High

    Identified the trans-acting machinery for SAM-responsive MAT2A splicing/stability — the CFIm complex and METTL16 m6A — and additional mRNA-export and signaling layers (SYVN1-MTR4, TGF-β1/p65).

    Evidence CRISPR screens, splicing reporters, m6A assays, Co-IP/fractionation, NF-κB reporter and in vivo manipulation

    PMID:30926424 PMID:33859984 PMID:33949310 PMID:35069973

    Open questions at the time
    • How m6A, CFIm and export pathways integrate quantitatively is unresolved
    • Some regulatory layers shown in single contexts only
  9. 2021 High

    Advanced MAT2A inhibition toward the clinic and refined the structural model, showing inhibitors are substrate-noncompetitive allosteric blockers that prevent SAM release and produce PRMT5-dependent splicing/DNA-damage phenotypes in MTAP-null cells.

    Evidence Fragment screening with X-ray structures, enzyme kinetics, RNA-seq/proteomics and xenografts

    PMID:33450196 PMID:33829783

    Open questions at the time
    • Determinants of selective toxicity to MTAP-null over wild-type cells incompletely defined
  10. 2021 High

    Solved the transition state of the triphosphate hydrolysis step, completing the atomic-level catalytic picture for MAT2A.

    Evidence 1.07 Å crystal structures with MgF3-/AlF3 phosphoryl-transfer mimics validated by NMR

    PMID:34668717

    Open questions at the time
    • Linkage between this hydrolysis step and allosteric/regulatory control not addressed
  11. 2021 Medium

    Demonstrated that MAT2A-supplied SAM drives locus-specific histone methylation controlling diverse programs—HIV latency, ferroptosis resistance, and macrophage activation.

    Evidence CRISPR/overexpression with ChIP for DNA/histone marks at HIV LTR, ACSL3 and RIP1 promoters; functional assays

    PMID:33593829 PMID:34616406 PMID:35182729

    Open questions at the time
    • Mechanism targeting SAM/MAT2A to specific loci not defined
    • Single-lab observations per phenotype
  12. 2022 High

    Showed MAT2A engages chromatin partners directly (EZH2/MafK) and that distinct histone marks (H3K27me3, H3K36me3, H3K4me2) underlie its roles in adipogenesis, glioma vulnerability and prostate cancer.

    Evidence Co-IP, ChIP/ChIP-seq, ATAC-seq, MS histone PTM analysis, siRNA screen and in vivo models

    PMID:29133280 PMID:35422502 PMID:39107274

    Open questions at the time
    • Whether MAT2A is recruited to chromatin via stable complexes versus transient SAM delivery is unresolved
    • H3K27M-glioma feedback via decarboxylated SAM mechanistically incomplete
  13. 2022 Medium

    Defined post-translational and physiological control of MAT2A — SIRT4-dependent ADP-ribosylation at Glu111 via mTORC1-c-Myc, and an essential role in intestinal epithelial homeostasis.

    Evidence ADP-ribosylation site mapping with metabolomics/xenografts; IEC-specific conditional knockout with SAM rescue

    PMID:36371321 PMID:36975381

    Open questions at the time
    • Direct enzymatic effect of E111 ADP-ribosylation on catalysis not biochemically isolated
    • Intestinal mechanism downstream of SAM beyond caspase activation unclear
  14. 2024 Medium

    Revealed metabolic regulation of MAT2A protein abundance through NADP+-dependent MAT2B stabilization and TRIM25-mediated mRNA destabilization, with the latter controlling Wnt/β-catenin in vascular disease.

    Evidence Co-IP with NADP+ manipulation and protein/m6A/stability assays; RNA-binding assays with in vivo TAA rescue

    PMID:39216871 PMID:39353892

    Open questions at the time
    • Quantitative coupling of pentose phosphate/NADP+ flux to MAT2A levels not established
    • TRIM25-MAT2A axis shown in single disease context
  15. 2024 Medium

    Confirmed allosteric inhibitor binding mode by cryo-EM and identified SAM-independent and complex-dependent MAT2A functions (SUMOylation/polyamine, FMO4-promoted cysteine/glutathione).

    Evidence Cryo-EM of SCR-7952; SUMO E1 inhibitor and polyamine assays; FMO4 Co-IP and ferroptosis assays (some preprints)

    PMID:39309689

    Open questions at the time
    • MAT2A SUMOylation site not directly mapped (idx 32 Low/pharmacological)
    • FMO4-MAT2A-MAT2B mechanism not fully validated (idx 35 preprint)
  16. 2025 High

    Established nuclear, catalysis-dependent and catalysis-independent moonlighting roles of MAT2A — local SAM provision for class-switch recombination, H3K4me3-driven macrophage inflammation, and SAM-independent SRF stabilization in osteosarcoma.

    Evidence Active-site-dead/nuclear-targeted mutants, ChIP/ChIP-seq, conditional myeloid knockout, Co-IP with catalytic mutants and in vivo models

    PMID:41402252 PMID:41530371

    Open questions at the time
    • CSR role (idx 34) and SRF mechanism are single-lab/preprint findings
    • How MAT2A partitions between nuclear enzymatic and non-enzymatic scaffolding roles unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how MAT2A is targeted to specific genomic loci to deliver SAM for mark-specific histone methylation, and how its catalytic versus non-catalytic (scaffolding) functions are partitioned across compartments and cell states.
  • No defined recruitment mechanism for locus-specific SAM delivery
  • No structural model of nuclear MAT2A-chromatin/transcription-factor complexes
  • Relative contribution of SAM-dependent vs SAM-independent functions not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1430728 Metabolism 2
Partners
EZH2MAFKMAT2BMETTL16NUDT21PDCD6SRF
Complex memberships
MAT II (MAT2A-MAT2B heterocomplex)

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 The MAT2B (beta) regulatory subunit of MAT II was cloned and expressed; recombinant beta subunit associates with both E. coli and human MAT alpha subunits, changing kinetic properties and lowering the Km for L-methionine, confirming its long-suspected regulatory function. Recombinant protein expression in E. coli, co-association assay, kinetic analysis, antibody cross-reactivity studies The Journal of biological chemistry High 10644686
2000 The proximal MAT2A promoter contains three Sp1 sites; mutation of the Sp1-3 site (at -69) abolishes ~85% of in vivo promoter activity; supershift assays show Sp2 and Sp3 (not Sp1) are the transcription factors binding this essential site. Promoter deletion analysis, EMSA, supershift assay, site-directed mutagenesis, in vivo reporter assay The Journal of biological chemistry High 11124935
2001 MAT2B gene promoter is regulated by an Sp1 site at +9/+15 and a TATA element at -32; chromatin immunoprecipitation and supershift assays identify Sp3 (not Sp1) as the main factor binding the +9 site; down-regulation of MAT2B causes 6–10-fold increase in intracellular SAM. Promoter deletion analysis, EMSA, supershift assay, chromatin immunoprecipitation, luciferase reporter assay The Journal of biological chemistry High 11337507
2001 The proximal MAT2A promoter shows distinct patterns of protein–DNA complex formation in normal resting, PHA-stimulated, and leukemic T cells; low levels of Sp2 and Sp3 in normal T cells underlie reduced promoter activity compared to leukemic cells. EMSA, supershift assay, in vitro and in vivo promoter activity comparison Biochimica et biophysica acta Medium 11476892
2007 Transcription of MAT2A in regenerating rat liver and proliferating hepatocytes is driven by E2F1, E2F3 and E2F4 (during G1-S) and by Sp1 (during active transcription); p130 remains at the promoter during G0-G1 but dissociates at G1-S transition; histone-modifying enzyme binding to the promoter changes during liver regeneration. ChIP, EMSA, RNA-pol ChIP, chromatin analysis during liver regeneration The international journal of biochemistry & cell biology High 17317269
2007 siRNA-mediated silencing of MAT2A in hepatoma cells reduces MAT II enzyme activity, raises SAM levels and SAM:SAH ratio, inhibits cell growth, induces apoptosis, and causes a switch of MAT gene expression from MAT2A to MAT1A via upregulation of SAM. siRNA knockdown, MAT enzyme activity assay, SAM/SAH measurement, cell growth and apoptosis assays Hepatology research Medium 17441811
2011 HIF-1α binds an authentic consensus site in the MAT2A promoter under hypoxia (verified by site-directed mutagenesis, EMSA, and ChIP), inducing MAT2A transcription and requiring recruitment of p300 and HDAC1; upregulated MAT2A reduces steady-state SAM levels and causes genomic DNA demethylation in CpG islands. Site-directed mutagenesis, EMSA, ChIP, siRNA knockdown, SAM measurement, global DNA methylation assay Molecular cancer therapeutics High 21460102
2016 MAT2A produces SAM as substrate for PRMT5; in MTAP-deleted cells, accumulated MTA potently and selectively inhibits PRMT5 activity; MAT2A depletion reduces PRMT5 methylation activity and selectively suppresses growth of MTAP-deleted cells, establishing the MAT2A/PRMT5/RIOK1 synthetic lethal axis. shRNA screening, metabolomics, biochemical methyltransferase panel profiling, PRMT5 activity assay, cell viability assay in isogenic MTAP+/- lines Cell reports High 27068473
2017 A small-molecule inhibitor PF-9366 binds an allosteric site on MAT2A that overlaps the MAT2B binding site; allosteric binding of PF-9366 or MAT2B alters the MAT2A active site, increasing substrate affinity and decreasing enzyme turnover; MAT2B functions as an inhibitor of MAT2A when methionine/SAM levels are high, and as an activator when levels are low. Biochemical enzyme assay, X-ray crystallography (implied by structure-activity), inhibitor characterization with kinetic analysis Nature chemical biology High 28553945
2017 The transition state structure of human MAT2A was solved using kinetic isotope effects, commitment factors, and quantum mechanical calculations: the reaction proceeds via an advanced SN2 mechanism with bond formation from methionine sulfur to the 5'-C of ATP (2.03 Å, bond order 0.67) and well-advanced departure of triphosphate (2.32 Å, bond order 0.23). Interaction with the MAT2B regulatory subunit causes no change in intrinsic KIEs, indicating the same transition state structure. Kinetic isotope effect (KIE) measurement, commitment factor analysis, binding isotope effect, quantum mechanical calculations Journal of the American Chemical Society High 28880543
2018 Balance between MAT2A intron detention and mature mRNA is determined cotranscriptionally, not post-transcriptionally; polyadenylated MAT2A transcripts with detained introns are 'dead-end' RNAs destined for nuclear decay rather than precursors for mRNA; SAM deprivation increases cotranscriptional splicing of MAT2A detained introns. Three independent assays for precursor-product relationship, nuclear fractionation, transcription inhibition experiments, splicing reporter assays RNA (New York, N.Y.) High 29563249
2019 TGF-β1 induces phosphorylation of p65 (NF-κB activation), which promotes MAT2A mRNA transcription and protein expression, reducing intracellular SAM in hepatic stellate cells (HSCs); MAT2A knockdown in vivo alleviates fibrosis while overexpression facilitates it, placing MAT2A downstream of TGF-β1/p65 in liver fibrogenesis. NF-κB luciferase assay, LC-MS SAM measurement, AAV-mediated in vivo overexpression/knockdown, pharmacoproteomic profiling EBioMedicine High 30926424
2021 CFIm25 (NUDT21), a component of the cleavage factor Im (CFIm) complex, regulates MAT2A intron detention and intracellular SAM levels; CFIm25 promotes MAT2A splicing independent of poly(A) site selection, requiring RS domains of binding partners CFIm68 and CFIm59 as well as binding sites in the detained intron and 3' UTR. CRISPR knockout screen, splicing reporter assay, SAM level measurement, domain-deletion mutagenesis eLife High 33949310
2021 MAT2A inhibition with potent small-molecule inhibitors substantially reduces SAM levels, reduces PRMT5 activity, causes splicing perturbations (via RNA-seq), and induces DNA damage and mitotic defects in MTAP-deleted cells, providing rationale for combining MAT2A inhibition with antimitotic taxanes. In vitro MAT2A enzyme inhibition, RNA-seq, proteomics, SAM measurement, PRMT5 activity assay, DNA damage assay in HCT116 MTAP-/- cells, xenograft models Cancer cell High 33450196
2021 MAT2A catalyzes formation of SAM; fragment screening and iterative structure-guided design identified an allosteric binding site on MAT2A; allosteric MAT2A inhibitors are substrate-noncompetitive and inhibit release of the SAM product from the active site. Fragment screening, X-ray crystal structure-guided design, enzyme kinetics, cellular SAM measurement, xenograft models Journal of medicinal chemistry High 33829783
2021 The SYVN1-MTR4 axis regulates MAT2A mRNA nuclear export: under methionine restriction, the E3 ubiquitin ligase SYVN1 ubiquitinates MTR4, reducing MTR4 protein levels, which promotes export of MAT2A mRNA from the nucleus and increases MAT2A protein expression. Co-immunoprecipitation, nuclear-cytoplasmic fractionation, ubiquitination assay, transcriptome analysis Frontiers in cell and developmental biology Medium 33859984
2021 MAT2A modulates HIV-1 latency through SAM-mediated one-carbon flux; MAT2A knockout in CD4+ T cells enhances reactivation of latent HIV-1, while overexpression maintains latency; MAT2A knockout reduces DNA and histone methylation at the HIV-1 5'-LTR. CRISPR library knockout screen, MAT2A overexpression/knockout, ChIP for DNA/histone methylation at HIV LTR, cell model of HIV latency Frontiers in immunology Medium 34616406
2021 MAT2A transcript level regulation by METTL16: METTL16 methylates MAT2A pre-mRNA (m6A modification), shifting the balance of splicing, maturation, and degradation toward degradation under high SAM/oxidative stress conditions; under normal/low-SAM conditions, METTL16 promotes MAT2A splicing. siRNA knockdown of METTL16, lentiviral overexpression, m6A assay, cell apoptosis assay, IVDD animal model Oxidative medicine and cellular longevity Medium 35069973
2021 MAT2A acts as a driver of ferroptosis resistance in gastric cancer by mediating SAM production, which upregulates ACSL3 through increasing H3K4me3 trimethylation at the ACSL3 promoter. Genetic and pharmacological blockade of MAT2A, ChIP for H3K4me3 at ACSL3 promoter, ferroptosis assay, in vitro and in vivo experiments Free radical biology & medicine Medium 35182729
2021 MAT2A modulates tumor-associated macrophage activation by upregulating RIP1 expression through increasing H3K4me3 at the RIP1 promoter region, establishing a link between methionine metabolism and macrophage phenotype. Genetic MAT2A manipulation, ChIP for H3K4me3 at RIP1 promoter, macrophage polarization and activity assays Journal for immunotherapy of cancer Medium 33593829
2021 The transition-state for the MAT2A-catalyzed triphosphate hydrolysis step was determined: crystal structures with MgF3- and AlF3 trapped as phosphoryl-transfer mimics (confirmed by NMR) reveal a planar PO3- leaving group, with the phosphorus equidistant (~2 Å) between pyrophosphate oxygen and nucleophilic water; a catalytic-site arginine directs the water nucleophile. X-ray crystallography at 1.07 Å resolution, NMR (MgF3- and AlF3 binding), crystal structure with malonate + MgF3- Journal of the American Chemical Society High 34668717
2022 MAT2A interacts with the histone-lysine methyltransferase EZH2 and the transcription factor MafK; MAT2A-EZH2 complex is recruited to the Wnt10b promoter to increase H3K27 methylation and repress Wnt10b expression, inhibiting Wnt/β-catenin signaling and promoting adipogenesis; catalytic activity of MAT2A (SAM provision) and MAT2B are required. Co-immunoprecipitation, ChIP for H3K27me3 at Wnt10b promoter, overexpression/knockdown with functional adipogenesis readouts Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 29133280
2022 Loss of MAT2A in H3K27M mutant glioma depletes global H3K36me3 (a chromatin mark of transcriptional elongation), perturbing oncogenic and developmental transcriptional programs; this vulnerability is mediated by negative feedback from decarboxylated SAM (not MTAP deletion), and MAT2A protein levels are lower in DMG cells. siRNA screen, ChIP-seq for H3K36me3, MAT2A knockdown/inhibition, syngeneic mouse model, metabolite measurement Nature cancer High 35422502
2022 METTL16 promotes MAT2A expression by m6A methylation of the MAT2A mRNA 3'-UTR, increasing its stability; this METTL16-mediated MAT2A upregulation contributes to improved hippocampal global m6A levels, dendritic spine plasticity, and memory formation. m6A methylation assay, MAT2A mRNA stability assay, METTL16 overexpression/knockdown in vivo (Morris water maze model) Cell death discovery Medium 36307396
2022 mTORC1-c-Myc signaling rewires methionine metabolism in HCC: c-Myc promotes TRIM32-mediated degradation of SIRT4; loss of SIRT4 activates MAT2A by ADP-ribosylation on glutamic acid residue 111 of MAT2A, increasing SAM levels and driving HCC proliferation. Immunostaining, metabolomics, RNA-seq, sphere formation assays, xenograft/DEN-induced liver cancer models, ADP-ribosylation site identification Cell & bioscience Medium 36371321
2022 MAT2A promotes intestinal development and homeostasis by producing SAM; intestinal epithelial cell-specific knockout of Mat2a causes impaired intestinal development, reduced cell proliferation, IEC apoptosis (via caspase 3 and 8 activation), intestinal atrophy and inflammation; SAM supplementation rescues the defective intestinal epithelium. IEC-specific conditional knockout mouse, adult inducible knockout, SAM supplementation rescue, caspase activity measurement Development (Cambridge, England) High 36975381
2022 MAT2A enhances H3K4me2 at multiple genomic sites in ERG fusion-positive castration-resistant prostate cancer, promoting expression of pro-tumorigenic 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 MAT2A inhibition Nature communications High 39107274
2023 Combined MTAP inhibition (MTDIA) and MAT2A inhibition (AG-270) synergistically reduces SAM, raises intracellular MTA, inhibits PRMT5 activity, induces MDM4 alternative splicing and p53 activation, causing cell cycle arrest and apoptosis; this combination expands synthetic lethality to MTAP-wild-type colorectal cancer. Biochemical SAM/MTA measurement, PRMT5 activity assay, splicing analysis, cell viability, xenograft models, normal tissue histology The Journal of biological chemistry High 38000655
2024 MAT2B binds and stabilizes MAT2A protein in an NADP+-dependent manner; disruption of cellular NADP+ remodels MAT2A protein levels; the pentose phosphate pathway regulates MAT2A protein through NADP+-MAT2B interaction; MAT2B-MAT2A interaction also regulates mRNA m6A modification and stability. Co-immunoprecipitation, NADP+ manipulation, western blot for MAT2A protein levels, m6A assay, mRNA stability assay Cell death & disease Medium 39353892
2024 MAT2A depletion in porcine embryos at the 1-cell stage reduces H3K4me2, H3K9me2/3, and H3K27me3 levels at the four-cell stage, decreases EED and EZH2 expression, reduces ZGA transcriptional activity, and increases DNA damage and apoptosis; SAM supplementation rescues histone methylation and developmental arrest. dsRNA injection knockdown, immunofluorescence for histone marks, ZGA gene expression analysis, SAM rescue experiment Theriogenology Medium 39276507
2024 Cryo-EM structure of SCR-7952 (novel MAT2A inhibitor) bound to MAT2A confirms high binding affinity and an allosteric binding site; this inhibitor shows little influence on metabolic enzymes compared to AG-270 and does not increase plasma bilirubin. Cryo-EM structure determination, biochemical MAT2A inhibition assay, cellular and in vivo efficacy assays MedComm High 39309689
2024 TRIM25 destabilizes MAT2A mRNA, reducing MAT2A protein levels in vascular smooth muscle cells; reduced MAT2A activates Wnt/β-catenin signaling to promote thoracic aortic aneurysm injury; overexpression of MAT2A blocks Wnt/β-catenin pathway activation and alleviates aortic injury. RNA-binding protein assay (TRIM25-MAT2A mRNA interaction), MAT2A overexpression in TAA mouse model, Wnt/β-catenin reporter, CCK-8, Western blot Human molecular genetics Medium 39216871
2024 MAT2A SUMOylation (identified via SUMO E1 covalent allosteric inhibitors) modulates polyamine synthesis; inhibition of MAT2A SUMOylation unexpectedly stimulates polyamine synthesis via the MAT2A-AdoMetDC axis. Virtual screening, SUMO E1 CAI treatment, SUMOylation assay, polyamine synthesis measurement Bioorganic chemistry Low 40884915
2024 MAT2A knockdown in GBM cells induces oxidative stress, hinders cellular respiration (reduces spare respiratory capacity), changes the metabolic profile toward oxidative stress, and causes DNA damage; MAT2A regulates the redox buffer cystathionine, lipid and amino acid metabolism in GBM. Genetic knockdown, mitochondrial respiration assay (Seahorse), targeted metabolomics, cell viability assay bioRxivpreprint Low 39605416
2025 Nuclear MAT2A enzymatic activity is required for immunoglobulin class switch recombination (CSR) in B cells: expression of a catalytically inactive nuclear-targeted MAT2A (NLS-MAT2A D134A) suppresses CSR from IgM to IgA, reduces intracellular SAM, and downregulates AID (activation-induced cytidine deaminase) expression; ChIP shows MAT2A localizes to the IgA switch region. Catalytically inactive mutant (D134A) with nuclear localization signal, CSR assay, ChIP at switch region, SAM measurement, AID expression analysis bioRxivpreprint Medium
2025 FMO4 facilitates the interaction between MAT2A and MAT2B, promoting cysteine generation from methionine via the MAT2A/MAT2B complex, which boosts glutathione synthesis and protects lung adenocarcinoma cells against ferroptosis. Proteomic analysis, co-immunoprecipitation of FMO4-MAT2A-MAT2B, ferroptosis assay, in vivo FMO4 deletion in KRAS-driven mouse model bioRxivpreprint Low
2025 MAT2A downregulation in pericytes triggers cell senescence and drives inflammatory trained immunity of infiltrating macrophages through senescence-associated secretory phenotype (SASP) factors and cellular mitochondrial transfer; mechanistically, MAT2A downregulation reduces OTUB1 deubiquitinase recruitment to HMGCS1, lowering HMGCS1 expression and impairing coenzyme Q synthesis. Cspg4-CreERT2 conditional knockout, single-cell sequencing, senescence assays, mitochondrial transfer assay, OTUB1-HMGCS1 interaction analysis Nature communications Medium 41298385
2025 MAT2A promotes osteosarcoma progression through a SAM-independent mechanism: MAT2A interacts with transcription factor SRF, promotes SUMO-dependent stabilization of SRF in the nucleus, and enhances SRF-driven transcription of PARN; a catalytically inactive MAT2A mutant retains this function. Co-immunoprecipitation of MAT2A-SRF, catalytically inactive mutant, PARN transcription assay, glycolysis measurement, in vitro and in vivo tumor assays Communications biology Medium 41530371
2025 MAT2A-mediated methionine metabolism promotes monocyte/macrophage inflammation by enriching the transcription-permissive chromatin mark H3K4me3 at inflammatory and migratory gene promoters; norepinephrine activates mTOR-c-MYC axis to upregulate MAT2A expression; myeloid-specific MAT2A ablation or pharmacological inhibition reduces macrophage inflammation and attenuates atherosclerotic plaque vulnerability. Untargeted metabolomics, mass spectrometry, ChIP-seq for H3K4me3, myeloid-specific MAT2A knockout, pharmacological inhibition, atherosclerosis mouse models Nature communications High 41402252
2014 Rare missense variants in MAT2A (p.Glu344Ala and p.Arg356His) predispose to thoracic aortic aneurysms; structural analysis indicates these substitutions disrupt MAT IIα enzyme function; co-transfection of wild-type MAT2A mRNA rescues cardiovascular development defects in mat2aa zebrafish morpholino knockdown at significantly higher rates than mutant mRNA. Morpholino knockdown in zebrafish, mRNA rescue with WT vs. mutant MAT2A, structural analysis, Sanger sequencing American journal of human genetics Medium 25557781
2022 MAT2A facilitates PDCD6 methylation at K90; this interaction is mediated by AMPK activation under glucose deprivation and promotes PDCD6 protein stability; cells expressing PDCD6 K90R (methylation-null mutant) show increased apoptosis and suppressed growth. Co-immunoprecipitation, mass spectrometry, immunoblotting, PDCD6 K90R mutation, AMPK pathway inhibitor panel, flow cytometry apoptosis assay Cell death discovery Medium 35396512

Source papers

Stage 0 corpus · 87 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 364 27068473
2021 MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage. Cancer cell 189 33450196
2011 Hypoxia induces genomic DNA demethylation through the activation of HIF-1α and transcriptional upregulation of MAT2A in hepatoma cells. Molecular cancer therapeutics 130 21460102
2017 Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nature chemical biology 113 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 91 33829783
2014 MAT2A mutations predispose individuals to thoracic aortic aneurysms. American journal of human genetics 85 25557781
2022 Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors. Journal of medicinal chemistry 73 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 66 35182729
2022 Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome. Nature cancer 51 35422502
2019 TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM. EBioMedicine 50 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 44 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
2025 MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial. Nature communications 34 39762248
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
2022 mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell & bioscience 31 36371321
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
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
2022 Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads. Journal of medicinal chemistry 28 35293760
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
2023 Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. The Journal of biological chemistry 27 38000655
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 27 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
2022 Knockdown of METTL16 disrupts learning and memory by reducing the stability of MAT2A mRNA. Cell death discovery 22 36307396
2017 The Transition-State Structure for Human MAT2A from Isotope Effects. Journal of the American Chemical Society 22 28880543
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
2023 Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability. Journal of medicinal chemistry 21 36961373
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
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
2023 MAT2A inhibits the ferroptosis in osteosarcoma progression regulated by miR-26b-5p. Journal of bone oncology 18 37457846
2022 MAT2A facilitates PDCD6 methylation and promotes cell growth under glucose deprivation in cervical cancer. Cell death discovery 18 35396512
2021 Circ_0044516 Regulates miR-136/MAT2A Pathway to Facilitate Lung Cancer Development. Journal of immunology research 18 34258296
2024 MAT2A inhibition combats metabolic and transcriptional reprogramming in cancer. Drug discovery today 14 39306235
2023 S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency. Development (Cambridge, England) 14 36975381
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
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
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 8 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 8 39309689
2023 Discovery of novel methionine adenosyltransferase 2A (MAT2A) allosteric inhibitors by structure-based virtual screening. Bioorganic & medicinal chemistry letters 8 37591318
2025 Discovery of 2(1H)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers. Journal of medicinal chemistry 7 39760448
2025 Combined inhibition by PRMT5 and MAT2A demonstrates a strong synthetic lethality in MTAP homozygous-deficient glioma models. Cell death discovery 7 40450009
2025 Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models. Journal of medicinal chemistry 6 39835703
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 MAT2A is essential for zygotic genome activation by maintaining of histone methylation in porcine embryos. Theriogenology 6 39276507
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
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 6 34949650
2019 MAT2A/2B promote porcine intramuscular preadipocyte proliferation through ERK signaling pathway. Animal science journal = Nihon chikusan Gakkaiho 6 31293025
2024 Inhibition of MAT2A Impairs Skeletal Muscle Repair Function. Biomolecules 5 39334864
2001 Distinct patterns of protein binding to the MAT2A promoter in normal and leukemic T cells. Biochimica et biophysica acta 5 11476892
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 4 40308894
2024 RBM15-mediated the m6A modification of MAT2A promotes osteosarcoma cell proliferation, metastasis and suppresses ferroptosis. Molecular and cellular biochemistry 4 39527319
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 Norcantharidin inhibits the METTL16/MAT2A pathway to induce apoptosis and suppress tumor progression in ovarian cancer. Archives of biochemistry and biophysics 3 40517800
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
2026 Lack of Cancer Specificity of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 in Combination With Recombinant Methioninase In Vitro. Anticancer research 1 41617456
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
2025 A biomimetic senotherapy replenishing MAT2A promotes wound regeneration in preclinical models. Nature communications 1 41298385
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 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
2026 The Combination of Methionine Adenosyltransferase 2A (MAT2A) Inhibitor AG-270 and Recombinant Methioninase Is Not Cancer-selective in a Co-culture Model of Colon Cancer Cells and Normal Fibroblasts. Cancer diagnosis & prognosis 0 42078306
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 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

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