{"gene":"MAT1A","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"The dominant R264H mutation in MAT1A (human MAT I/III) produces a monomeric enzyme with only 0.37% of normal AdoMet synthetic activity but retains tripolyphosphatase activity. The mutant R264H subunit associates with wild-type subunits to form a catalytically inactive heterodimer unable to synthesize AdoMet, providing the molecular mechanism for dominant inheritance of hypermethioninemia.","method":"In vitro enzymatic assay of recombinant mutant MAT (rat R265H equivalent), in vivo co-expression studies demonstrating heterodimer formation, activity measurements for AdoMet synthesis and tripolyphosphatase activity","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, in vivo subunit association experiments, multiple enzymatic assays in a single rigorous study","pmids":["11278456"],"is_preprint":false},{"year":2010,"finding":"MAT1A mRNA stability is regulated post-transcriptionally by the RNA-binding protein AUF1, which destabilizes MAT1A mRNA. During hepatic de-differentiation and liver carcinogenesis, increased AUF1 expression coincides with decreased MAT1A expression. S-adenosylmethionine treatment shifts the balance of AUF1 and methyl-HuR/HuR, modulating MAT1A mRNA stability.","method":"RNA-binding protein binding assays (in silico identification of AUF1 binding sites in MAT1A 3'UTR), functional studies in hepatic de-differentiation models, immunofluorescence, mRNA stability assays","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple experimental systems (cell culture, fetal liver, HCC), functional link between AUF1 and MAT1A mRNA stability demonstrated, single lab","pmids":["20102719"],"is_preprint":false},{"year":2011,"finding":"Downregulation of Mat1a in early rat hepatocarcinogenesis is associated with increased histone H3 lysine 27 trimethylation and decreased histone H3 lysine 18 acetylation at the Mat1a promoter/first exon. Additionally, miR-22 and miR-29b directly contribute to inhibition of Mat1a expression during 2-acetylaminofluorene-induced hepatocarcinogenesis.","method":"Chromatin immunoprecipitation (ChIP) for histone modifications at Mat1a promoter, microRNA expression profiling and functional studies in rat hepatocarcinogenesis model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP experiments with histone marks at Mat1a locus and miRNA functional association, single lab, single carcinogen model","pmids":["22213190"],"is_preprint":false},{"year":2023,"finding":"The CTBP1/HDAC1/HDAC2 transcriptional repressor complex suppresses MAT1A transcription in hepatocellular carcinoma. CTBP1 interacts with HDAC1 and HDAC2, and silencing of either HDAC1 or HDAC2 restores MAT1A expression. MAT1A overexpression increases S-adenosylmethionine levels, which promotes ferroptosis of HCC cells and enhances CD8+ T-cell cytotoxicity and interferon-γ production.","method":"Co-immunoprecipitation of CTBP1/HDAC1/HDAC2 complex, siRNA knockdown of HDAC1/HDAC2, MAT1A overexpression in cell lines, SAM level measurement, in vivo xenograft experiments with ferrostatin-1 treatment","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex identification, multiple functional assays (knockdown, overexpression, in vivo), single lab","pmids":["37230466"],"is_preprint":false},{"year":2022,"finding":"miR-143 targets MAT1a mRNA, and betaine supplementation down-regulates miR-143, which subsequently increases SAM levels in the liver by de-repressing MAT1a. This identifies a betaine-miR-143-MAT1a regulatory axis in hepatic one-carbon metabolism.","method":"miR-143 knockout mice, betaine supplementation experiments, luciferase reporter assay and expression analysis confirming MAT1a as miR-143 target, SAM level measurement","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miR-143 KO model combined with in vitro target validation and SAM measurements, single lab, multiple methods","pmids":["35734958"],"is_preprint":false},{"year":2024,"finding":"MAT1A promotes NSCLC progression by stabilizing CCND1 protein; MAT1A depletion accelerates CCND1 degradation via SKP2-mediated ubiquitination. CCND1 acts as a MAT1A partner to jointly regulate glycolytic metabolism in NSCLC cells.","method":"Stable MAT1A knockdown in NSCLC cell lines, proliferation/migration/apoptosis assays, co-immunoprecipitation of MAT1A and CCND1, ubiquitination assays showing SKP2-mediated CCND1 degradation upon MAT1A depletion, glycolysis measurements","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assays with KD phenotype, multiple functional readouts, single lab","pmids":["39438468"],"is_preprint":false},{"year":2019,"finding":"MAT1A overexpression in bladder cancer cells increases tolerance to gemcitabine and stalls cell proliferation, suggesting MAT1A upregulation enables cancer cells to persist in a quiescent state to evade chemotherapy.","method":"MAT1A overexpression in 5637 bladder cancer cell line, gemcitabine dose-response assays, cell proliferation measurements, RNA-sequencing of patient-derived xenograft tumors before and after cisplatin/gemcitabine treatment","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with proliferation and drug tolerance readouts, no pathway mechanism identified, single lab","pmids":["31600961"],"is_preprint":false}],"current_model":"MAT1A encodes the catalytic subunit of liver-specific methionine adenosyltransferase I/III, which synthesizes S-adenosylmethionine (SAM); the R264H dominant mutation produces a monomeric enzyme that poisons wild-type subunits via heterodimerization to abolish AdoMet synthesis; MAT1A expression is post-transcriptionally regulated by AUF1-mediated mRNA destabilization and by miR-22, miR-29b, and miR-143; its transcription is epigenetically repressed in HCC by a CTBP1/HDAC1/HDAC2 complex; and in cancer contexts MAT1A can stabilize CCND1 against SKP2-mediated ubiquitination to promote glycolysis and cell cycle progression."},"narrative":{"mechanistic_narrative":"MAT1A encodes the catalytic subunit of methionine adenosyltransferase I/III, the enzyme that synthesizes S-adenosylmethionine (SAM) and thereby governs hepatic one-carbon metabolism [PMID:11278456]. The dominant R264H mutation produces a monomeric subunit retaining tripolyphosphatase activity but only ~0.37% of normal AdoMet synthetic activity; because the mutant subunit associates with wild-type subunits into catalytically inactive heterodimers, it acts dominantly to abolish AdoMet synthesis, explaining dominant hypermethioninemia [PMID:11278456]. MAT1A expression is controlled at multiple post-transcriptional and epigenetic levels: the RNA-binding protein AUF1 destabilizes MAT1A mRNA during hepatic de-differentiation and carcinogenesis, with SAM itself shifting the AUF1/methyl-HuR balance [PMID:20102719]; miR-22, miR-29b, and miR-143 repress MAT1A, the latter forming a betaine–miR-143–MAT1A axis that tunes hepatic SAM levels [PMID:22213190, PMID:35734958]; and a CTBP1/HDAC1/HDAC2 repressor complex silences MAT1A transcription in hepatocellular carcinoma, where restoring MAT1A and raising SAM promotes ferroptosis and enhances CD8+ T-cell cytotoxicity [PMID:37230466]. In cancer contexts MAT1A also exerts a non-canonical role, stabilizing CCND1 against SKP2-mediated ubiquitination to drive glycolysis and proliferation in NSCLC [PMID:39438468].","teleology":[{"year":2001,"claim":"Established the molecular basis of dominantly inherited hypermethioninemia by showing how a single MAT1A mutation abolishes SAM synthesis even in the presence of wild-type subunits.","evidence":"In vitro enzymatic assays of recombinant R264H/R265H mutant MAT plus in vivo co-expression demonstrating inactive heterodimer formation","pmids":["11278456"],"confidence":"High","gaps":["Does not resolve the structural basis of why the monomeric mutant retains tripolyphosphatase but loses AdoMet synthesis","No in vivo demonstration of the heterodimer poisoning effect in patient liver"]},{"year":2010,"claim":"Identified post-transcriptional control of MAT1A by linking AUF1-mediated mRNA destabilization to the loss of MAT1A during liver de-differentiation and carcinogenesis.","evidence":"AUF1 binding site identification, mRNA stability assays, and immunofluorescence in hepatic de-differentiation and HCC models","pmids":["20102719"],"confidence":"Medium","gaps":["Direct AUF1–MAT1A 3'UTR binding partly in silico","Mechanism by which SAM shifts the AUF1/methyl-HuR balance not fully defined","Single-lab data"]},{"year":2011,"claim":"Showed that MAT1A silencing in early hepatocarcinogenesis is driven by combined epigenetic chromatin changes and microRNA repression.","evidence":"ChIP for H3K27me3/H3K18ac at the Mat1a promoter and miR-22/miR-29b functional studies in a rat 2-AAF hepatocarcinogenesis model","pmids":["22213190"],"confidence":"Medium","gaps":["Single carcinogen model in rat","Direct miRNA–MAT1A target binding not validated by reporter assay in this study","Relative contributions of chromatin vs miRNA repression unquantified"]},{"year":2022,"claim":"Defined a dietary-to-metabolic regulatory axis showing miR-143 directly represses MAT1A and that betaine raises hepatic SAM by de-repressing it.","evidence":"miR-143 knockout mice, betaine supplementation, luciferase reporter target validation, and SAM measurements","pmids":["35734958"],"confidence":"Medium","gaps":["Physiological context limited to dietary betaine","Single-lab data","Downstream consequences of altered SAM not characterized"]},{"year":2023,"claim":"Connected transcriptional repression of MAT1A to tumor immunometabolism, showing a CTBP1/HDAC1/HDAC2 complex silences MAT1A and that restoring it promotes ferroptosis and antitumor immunity.","evidence":"Co-IP of CTBP1/HDAC1/HDAC2, siRNA knockdown, MAT1A overexpression, SAM measurement, and xenografts with ferrostatin-1","pmids":["37230466"],"confidence":"Medium","gaps":["Mechanism linking SAM elevation to ferroptosis not detailed","Single-lab data","Direct CTBP1 occupancy at the MAT1A promoter not shown"]},{"year":2024,"claim":"Revealed a non-canonical, extra-hepatic role for MAT1A as a protein stabilizer driving cancer metabolism beyond its SAM-synthesizing function.","evidence":"Stable MAT1A knockdown in NSCLC cells, MAT1A–CCND1 co-IP, SKP2-mediated CCND1 ubiquitination assays, and glycolysis measurements","pmids":["39438468"],"confidence":"Medium","gaps":["Whether the CCND1-stabilizing role depends on MAT1A catalytic activity unknown","Direct MAT1A–CCND1 binding interface not mapped","Single-lab data"]},{"year":2019,"claim":"Observed that MAT1A overexpression confers chemotolerance via growth arrest, hinting at a role in cancer cell persistence.","evidence":"MAT1A overexpression in 5637 bladder cancer cells with gemcitabine dose-response and patient-derived xenograft RNA-seq","pmids":["31600961"],"confidence":"Low","gaps":["No pathway mechanism identified linking MAT1A to quiescence or drug tolerance","Single overexpression experiment","No in vivo validation of the quiescence model"]},{"year":null,"claim":"It remains unresolved whether MAT1A's non-canonical protein-stabilizing and chemotolerance roles depend on its SAM-synthesizing activity, and how its multilayered repression integrates across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Catalytic dependence of CCND1 stabilization untested","No unified model connecting AUF1, miRNA, and CTBP1/HDAC repression","Structural model of the catalytic enzyme absent from this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[5]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["AUF1","CCND1","SKP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q00266","full_name":"S-adenosylmethionine synthase isoform type-1","aliases":["Methionine adenosyltransferase 1","MAT 1","Methionine adenosyltransferase I/III","MAT-I/III"],"length_aa":395,"mass_kda":43.6,"function":"Catalyzes the formation of S-adenosylmethionine from methionine and ATP. The reaction comprises two steps that are both catalyzed by the same enzyme: formation of S-adenosylmethionine (AdoMet) and triphosphate, and subsequent hydrolysis of the triphosphate","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q00266/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAT1A","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAT1A","total_profiled":1310},"omim":[{"mim_id":"610550","title":"METHIONINE ADENOSYLTRANSFERASE I, ALPHA; MAT1A","url":"https://www.omim.org/entry/610550"},{"mim_id":"607608","title":"SPHINGOMYELIN PHOSPHODIESTERASE 1, ACID LYSOSOMAL; SMPD1","url":"https://www.omim.org/entry/607608"},{"mim_id":"601468","title":"METHIONINE ADENOSYLTRANSFERASE II, ALPHA; MAT2A","url":"https://www.omim.org/entry/601468"},{"mim_id":"250850","title":"METHIONINE ADENOSYLTRANSFERASE I/III DEFICIENCY","url":"https://www.omim.org/entry/250850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":1259.5}],"url":"https://www.proteinatlas.org/search/MAT1A"},"hgnc":{"alias_symbol":["MAT","SAMS","MATA1","SAMS1","MAT-I/III"],"prev_symbol":[]},"alphafold":{"accession":"Q00266","domains":[{"cath_id":"3.30.300.10","chopping":"16-25_151-254","consensus_level":"medium","plddt":98.2749,"start":16,"end":254},{"cath_id":"3.30.300.10","chopping":"29-125","consensus_level":"medium","plddt":98.5703,"start":29,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00266","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q00266-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q00266-F1-predicted_aligned_error_v6.png","plddt_mean":96.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAT1A","jax_strain_url":"https://www.jax.org/strain/search?query=MAT1A"},"sequence":{"accession":"Q00266","fasta_url":"https://rest.uniprot.org/uniprotkb/Q00266.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q00266/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q00266"}},"corpus_meta":[{"pmid":"22555442","id":"PMC_22555442","title":"Mating-type 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A monomeric methionine adenosyltransferase with tripolyphosphatase activity.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278456","citation_count":25,"is_preprint":false},{"pmid":"10394905","id":"PMC_10394905","title":"A novel role for the mating type (MAT) locus in the maintenance of cell wall integrity in Saccharomyces cerevisiae.","date":"1999","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/10394905","citation_count":25,"is_preprint":false},{"pmid":"37021373","id":"PMC_37021373","title":"Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.","date":"2023","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/37021373","citation_count":24,"is_preprint":false},{"pmid":"32915919","id":"PMC_32915919","title":"Combined PCR and MAT improves the early diagnosis of the biphasic illness leptospirosis.","date":"2020","source":"PloS 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Controls.","date":"2020","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33255427","citation_count":22,"is_preprint":false},{"pmid":"28535347","id":"PMC_28535347","title":"Preparation and Characterization of Protein-Loaded Electrospun Fiber Mat and Its Release Kinetics.","date":"2017","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28535347","citation_count":22,"is_preprint":false},{"pmid":"23347101","id":"PMC_23347101","title":"Phylogenetic group-associated differences in regulation of the common colonization factor Mat fimbria in Escherichia coli.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23347101","citation_count":22,"is_preprint":false},{"pmid":"14517690","id":"PMC_14517690","title":"Isolation and characterisation of the mating-type (MAT) locus from Rhynchosporium secalis.","date":"2003","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14517690","citation_count":22,"is_preprint":false},{"pmid":"38456490","id":"PMC_38456490","title":"Peptide-based self-assembled monolayers (SAMs): what peptides can do for SAMs and vice versa.","date":"2024","source":"Chemical Society reviews","url":"https://pubmed.ncbi.nlm.nih.gov/38456490","citation_count":21,"is_preprint":false},{"pmid":"20335551","id":"PMC_20335551","title":"MAT1A variants are associated with hypertension, stroke, and markers of DNA damage and are modulated by plasma vitamin B-6 and folate.","date":"2010","source":"The American journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/20335551","citation_count":21,"is_preprint":false},{"pmid":"15498786","id":"PMC_15498786","title":"Chemopreventive N-(4-hydroxyphenyl)retinamide (fenretinide) targets deregulated NF-{kappa}B and Mat1A genes in the early stages of rat liver carcinogenesis.","date":"2004","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/15498786","citation_count":21,"is_preprint":false},{"pmid":"20856882","id":"PMC_20856882","title":"Chemical and physical environmental conditions underneath mat- and canopy-forming macroalgae, and their effects on understorey corals.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20856882","citation_count":21,"is_preprint":false},{"pmid":"35734958","id":"PMC_35734958","title":"miR-143-Mediated Responses to Betaine Supplement Repress Lipogenesis and Hepatic Gluconeogenesis by Targeting MAT1a and MAPK11.","date":"2022","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35734958","citation_count":20,"is_preprint":false},{"pmid":"22496730","id":"PMC_22496730","title":"Regulation of mat responses by a differentiation MAPK pathway in Saccharomyces cerevisiae.","date":"2012","source":"PloS 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/1922071","citation_count":18,"is_preprint":false},{"pmid":"29463658","id":"PMC_29463658","title":"Functional and Expression Analyses of the Pneumocystis MAT Genes Suggest Obligate Sexuality through Primary Homothallism within Host Lungs.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/29463658","citation_count":18,"is_preprint":false},{"pmid":"18338909","id":"PMC_18338909","title":"Molecular organization in SAMs used for neuronal cell growth.","date":"2008","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/18338909","citation_count":18,"is_preprint":false},{"pmid":"22807109","id":"PMC_22807109","title":"Human liver methionine cycle: MAT1A and GNMT gene resequencing, functional genomics, and hepatic genotype-phenotype correlation.","date":"2012","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/22807109","citation_count":17,"is_preprint":false},{"pmid":"27816361","id":"PMC_27816361","title":"Genetic Variants in CD44 and MAT1A Confer Susceptibility to Acute Skin Reaction in Breast Cancer Patients Undergoing Radiation Therapy.","date":"2016","source":"International journal of radiation oncology, biology, physics","url":"https://pubmed.ncbi.nlm.nih.gov/27816361","citation_count":17,"is_preprint":false},{"pmid":"14708103","id":"PMC_14708103","title":"Lissencephaly with der(17)t(17;20)(p13.3;p12.2)mat.","date":"2004","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/14708103","citation_count":17,"is_preprint":false},{"pmid":"30544497","id":"PMC_30544497","title":"Going with the Flo: The Role of Flo11-Dependent and Independent Interactions in Yeast Mat Formation.","date":"2018","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30544497","citation_count":17,"is_preprint":false},{"pmid":"31227767","id":"PMC_31227767","title":"Seasonal development of a coastal microbial mat.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31227767","citation_count":16,"is_preprint":false},{"pmid":"35725208","id":"PMC_35725208","title":"Protein and polysaccharide-based asymmetric mat with tuned bilayer configuration for enhanced wound healing efficiency.","date":"2022","source":"Carbohydrate polymers","url":"https://pubmed.ncbi.nlm.nih.gov/35725208","citation_count":16,"is_preprint":false},{"pmid":"36823173","id":"PMC_36823173","title":"Antibacterial and antioxidant double-layered nanofibrous mat promotes wound healing in diabetic rats.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36823173","citation_count":15,"is_preprint":false},{"pmid":"24445979","id":"PMC_24445979","title":"Thirteen Patients with MAT1A Mutations Detected Through Newborn Screening: 13 Years' Experience.","date":"2014","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/24445979","citation_count":15,"is_preprint":false},{"pmid":"33339287","id":"PMC_33339287","title":"Investigating the Smuts: Common Cues, Signaling Pathways, and the Role of MAT in Dimorphic Switching and Pathogenesis.","date":"2020","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33339287","citation_count":15,"is_preprint":false},{"pmid":"21185701","id":"PMC_21185701","title":"MAT1A variants modulate the effect of dietary fatty acids on plasma homocysteine concentrations.","date":"2010","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/21185701","citation_count":14,"is_preprint":false},{"pmid":"29763286","id":"PMC_29763286","title":"Engineering of Neuron Growth and Enhancing Cell-Chip Communication via Mixed SAMs.","date":"2018","source":"ACS applied materials & interfaces","url":"https://pubmed.ncbi.nlm.nih.gov/29763286","citation_count":14,"is_preprint":false},{"pmid":"37659492","id":"PMC_37659492","title":"Electrospun nanofiber composite mat based on ulvan for wound dressing applications.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/37659492","citation_count":14,"is_preprint":false},{"pmid":"21908597","id":"PMC_21908597","title":"Vacuolar protein sorting genes regulate mat formation in Saccharomyces cerevisiae by Flo11p-dependent and -independent mechanisms.","date":"2011","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/21908597","citation_count":14,"is_preprint":false},{"pmid":"31600961","id":"PMC_31600961","title":"Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31600961","citation_count":13,"is_preprint":false},{"pmid":"35067057","id":"PMC_35067057","title":"Magnolol Hybrid Nanofibrous Mat with Antibacterial, Anti-Inflammatory, and Microvascularized Properties for Wound Treatment.","date":"2022","source":"Biomacromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35067057","citation_count":13,"is_preprint":false},{"pmid":"15598821","id":"PMC_15598821","title":"Repression of the yeast HO gene by the MATalpha2 and MATa1 homeodomain proteins.","date":"2004","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/15598821","citation_count":13,"is_preprint":false},{"pmid":"32766980","id":"PMC_32766980","title":"Mast Cell Activation Test (MAT).","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32766980","citation_count":12,"is_preprint":false},{"pmid":"26724599","id":"PMC_26724599","title":"MAT--gene structure and mating behavior of Hymenoscyphus fraxineus and Hymenoscyphus albidus.","date":"2015","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/26724599","citation_count":12,"is_preprint":false},{"pmid":"30056710","id":"PMC_30056710","title":"Low-Fouling Characteristics of Ultrathin Zwitterionic Cysteine SAMs.","date":"2018","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/30056710","citation_count":12,"is_preprint":false},{"pmid":"31582217","id":"PMC_31582217","title":"SAHH and SAMS form a methyl donor complex with CCoAOMT7 for methylation of phenolic compounds.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31582217","citation_count":12,"is_preprint":false},{"pmid":"10955992","id":"PMC_10955992","title":"Cooperative ordering in homeodomain-DNA recognition: solution structure and dynamics of the MATa1 homeodomain.","date":"2000","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10955992","citation_count":11,"is_preprint":false},{"pmid":"29116347","id":"PMC_29116347","title":"Methanogenic and Sulfate-Reducing Activities in a Hypersaline Microbial Mat and Associated Microbial Diversity.","date":"2017","source":"Microbial ecology","url":"https://pubmed.ncbi.nlm.nih.gov/29116347","citation_count":11,"is_preprint":false},{"pmid":"27799927","id":"PMC_27799927","title":"Microbial Mat Compositional and Functional Sensitivity to Environmental Disturbance.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27799927","citation_count":11,"is_preprint":false},{"pmid":"12674481","id":"PMC_12674481","title":"Characterization of sams genes of Amoeba proteus and the endosymbiotic X-bacteria.","date":"2003","source":"The Journal of eukaryotic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12674481","citation_count":11,"is_preprint":false},{"pmid":"28770003","id":"PMC_28770003","title":"Formation of upd(7)mat by trisomic rescue: SNP array typing provides new insights in chromosomal nondisjunction.","date":"2017","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28770003","citation_count":11,"is_preprint":false},{"pmid":"37250028","id":"PMC_37250028","title":"Genomic and phenotypic characterization of a red-pigmented strain of Massilia frigida isolated from an Antarctic microbial mat.","date":"2023","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/37250028","citation_count":11,"is_preprint":false},{"pmid":"39438468","id":"PMC_39438468","title":"MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39438468","citation_count":10,"is_preprint":false},{"pmid":"37524857","id":"PMC_37524857","title":"MAT as a promising therapeutic strategy against triple-negative breast cancer via inhibiting PI3K/AKT pathway.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37524857","citation_count":10,"is_preprint":false},{"pmid":"35524573","id":"PMC_35524573","title":"Deep phenotyping: symptom annotation made simple with SAMS.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/35524573","citation_count":10,"is_preprint":false},{"pmid":"3054807","id":"PMC_3054807","title":"Splicing and spliceosome formation of the yeast MATa1 transcript require a minimum distance from the 5' splice site to the internal branch acceptor site.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3054807","citation_count":10,"is_preprint":false},{"pmid":"17590024","id":"PMC_17590024","title":"Electron transfer of plurimodified DNA SAMs.","date":"2007","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/17590024","citation_count":10,"is_preprint":false},{"pmid":"23905840","id":"PMC_23905840","title":"Effects of hydrophobicity and mat thickness on release from hydrogel-electrospun fiber mat composites.","date":"2013","source":"Journal of biomaterials science. Polymer edition","url":"https://pubmed.ncbi.nlm.nih.gov/23905840","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49073,"output_tokens":2331,"usd":0.091092,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9050,"output_tokens":2770,"usd":0.05725,"stage2_stop_reason":"end_turn"},"total_usd":0.148342,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts for papers about MAT1A (methionine adenosyltransferase 1A, the liver-specific isoform encoding MAT I/III):\n\nRelevant papers: 11 (HuR/AUF1 regulation), 33 (epigenetic/miRNA regulation), 39 (MAT1A R264H mutation/hypermethioninemia), 47 (R264H biochemical mechanism), 60 (Mat1A in liver carcinogenesis), 62 (miR-143/MAT1a), 65 (CTBP1/HDAC complex), 82 (MAT1A in drug resistance), 95 (MAT1A/CCND1/glycolysis), 15 (MAT II beta subunit - this is MAT2B, not MAT1A - exclude), 24 (MAT IIα acetylation - this is MAT2A, not MAT1A - exclude), 25 (MAT2A/folate - exclude), 69 (MAT1A resequencing/genotype-phenotype).\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The dominant R264H mutation in MAT1A (human MAT I/III) produces a monomeric enzyme with only 0.37% of normal AdoMet synthetic activity but retains tripolyphosphatase activity. The mutant R264H subunit associates with wild-type subunits to form a catalytically inactive heterodimer unable to synthesize AdoMet, providing the molecular mechanism for dominant inheritance of hypermethioninemia.\",\n      \"method\": \"In vitro enzymatic assay of recombinant mutant MAT (rat R265H equivalent), in vivo co-expression studies demonstrating heterodimer formation, activity measurements for AdoMet synthesis and tripolyphosphatase activity\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, in vivo subunit association experiments, multiple enzymatic assays in a single rigorous study\",\n      \"pmids\": [\"11278456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAT1A mRNA stability is regulated post-transcriptionally by the RNA-binding protein AUF1, which destabilizes MAT1A mRNA. During hepatic de-differentiation and liver carcinogenesis, increased AUF1 expression coincides with decreased MAT1A expression. S-adenosylmethionine treatment shifts the balance of AUF1 and methyl-HuR/HuR, modulating MAT1A mRNA stability.\",\n      \"method\": \"RNA-binding protein binding assays (in silico identification of AUF1 binding sites in MAT1A 3'UTR), functional studies in hepatic de-differentiation models, immunofluorescence, mRNA stability assays\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple experimental systems (cell culture, fetal liver, HCC), functional link between AUF1 and MAT1A mRNA stability demonstrated, single lab\",\n      \"pmids\": [\"20102719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Downregulation of Mat1a in early rat hepatocarcinogenesis is associated with increased histone H3 lysine 27 trimethylation and decreased histone H3 lysine 18 acetylation at the Mat1a promoter/first exon. Additionally, miR-22 and miR-29b directly contribute to inhibition of Mat1a expression during 2-acetylaminofluorene-induced hepatocarcinogenesis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for histone modifications at Mat1a promoter, microRNA expression profiling and functional studies in rat hepatocarcinogenesis model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP experiments with histone marks at Mat1a locus and miRNA functional association, single lab, single carcinogen model\",\n      \"pmids\": [\"22213190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The CTBP1/HDAC1/HDAC2 transcriptional repressor complex suppresses MAT1A transcription in hepatocellular carcinoma. CTBP1 interacts with HDAC1 and HDAC2, and silencing of either HDAC1 or HDAC2 restores MAT1A expression. MAT1A overexpression increases S-adenosylmethionine levels, which promotes ferroptosis of HCC cells and enhances CD8+ T-cell cytotoxicity and interferon-γ production.\",\n      \"method\": \"Co-immunoprecipitation of CTBP1/HDAC1/HDAC2 complex, siRNA knockdown of HDAC1/HDAC2, MAT1A overexpression in cell lines, SAM level measurement, in vivo xenograft experiments with ferrostatin-1 treatment\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex identification, multiple functional assays (knockdown, overexpression, in vivo), single lab\",\n      \"pmids\": [\"37230466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-143 targets MAT1a mRNA, and betaine supplementation down-regulates miR-143, which subsequently increases SAM levels in the liver by de-repressing MAT1a. This identifies a betaine-miR-143-MAT1a regulatory axis in hepatic one-carbon metabolism.\",\n      \"method\": \"miR-143 knockout mice, betaine supplementation experiments, luciferase reporter assay and expression analysis confirming MAT1a as miR-143 target, SAM level measurement\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miR-143 KO model combined with in vitro target validation and SAM measurements, single lab, multiple methods\",\n      \"pmids\": [\"35734958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAT1A promotes NSCLC progression by stabilizing CCND1 protein; MAT1A depletion accelerates CCND1 degradation via SKP2-mediated ubiquitination. CCND1 acts as a MAT1A partner to jointly regulate glycolytic metabolism in NSCLC cells.\",\n      \"method\": \"Stable MAT1A knockdown in NSCLC cell lines, proliferation/migration/apoptosis assays, co-immunoprecipitation of MAT1A and CCND1, ubiquitination assays showing SKP2-mediated CCND1 degradation upon MAT1A depletion, glycolysis measurements\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assays with KD phenotype, multiple functional readouts, single lab\",\n      \"pmids\": [\"39438468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAT1A overexpression in bladder cancer cells increases tolerance to gemcitabine and stalls cell proliferation, suggesting MAT1A upregulation enables cancer cells to persist in a quiescent state to evade chemotherapy.\",\n      \"method\": \"MAT1A overexpression in 5637 bladder cancer cell line, gemcitabine dose-response assays, cell proliferation measurements, RNA-sequencing of patient-derived xenograft tumors before and after cisplatin/gemcitabine treatment\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with proliferation and drug tolerance readouts, no pathway mechanism identified, single lab\",\n      \"pmids\": [\"31600961\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAT1A encodes the catalytic subunit of liver-specific methionine adenosyltransferase I/III, which synthesizes S-adenosylmethionine (SAM); the R264H dominant mutation produces a monomeric enzyme that poisons wild-type subunits via heterodimerization to abolish AdoMet synthesis; MAT1A expression is post-transcriptionally regulated by AUF1-mediated mRNA destabilization and by miR-22, miR-29b, and miR-143; its transcription is epigenetically repressed in HCC by a CTBP1/HDAC1/HDAC2 complex; and in cancer contexts MAT1A can stabilize CCND1 against SKP2-mediated ubiquitination to promote glycolysis and cell cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAT1A encodes the catalytic subunit of methionine adenosyltransferase I/III, the enzyme that synthesizes S-adenosylmethionine (SAM) and thereby governs hepatic one-carbon metabolism [#0]. The dominant R264H mutation produces a monomeric subunit retaining tripolyphosphatase activity but only ~0.37% of normal AdoMet synthetic activity; because the mutant subunit associates with wild-type subunits into catalytically inactive heterodimers, it acts dominantly to abolish AdoMet synthesis, explaining dominant hypermethioninemia [#0]. MAT1A expression is controlled at multiple post-transcriptional and epigenetic levels: the RNA-binding protein AUF1 destabilizes MAT1A mRNA during hepatic de-differentiation and carcinogenesis, with SAM itself shifting the AUF1/methyl-HuR balance [#1]; miR-22, miR-29b, and miR-143 repress MAT1A, the latter forming a betaine–miR-143–MAT1A axis that tunes hepatic SAM levels [#2, #4]; and a CTBP1/HDAC1/HDAC2 repressor complex silences MAT1A transcription in hepatocellular carcinoma, where restoring MAT1A and raising SAM promotes ferroptosis and enhances CD8+ T-cell cytotoxicity [#3]. In cancer contexts MAT1A also exerts a non-canonical role, stabilizing CCND1 against SKP2-mediated ubiquitination to drive glycolysis and proliferation in NSCLC [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the molecular basis of dominantly inherited hypermethioninemia by showing how a single MAT1A mutation abolishes SAM synthesis even in the presence of wild-type subunits.\",\n      \"evidence\": \"In vitro enzymatic assays of recombinant R264H/R265H mutant MAT plus in vivo co-expression demonstrating inactive heterodimer formation\",\n      \"pmids\": [\"11278456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Does not resolve the structural basis of why the monomeric mutant retains tripolyphosphatase but loses AdoMet synthesis\",\n        \"No in vivo demonstration of the heterodimer poisoning effect in patient liver\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified post-transcriptional control of MAT1A by linking AUF1-mediated mRNA destabilization to the loss of MAT1A during liver de-differentiation and carcinogenesis.\",\n      \"evidence\": \"AUF1 binding site identification, mRNA stability assays, and immunofluorescence in hepatic de-differentiation and HCC models\",\n      \"pmids\": [\"20102719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct AUF1–MAT1A 3'UTR binding partly in silico\",\n        \"Mechanism by which SAM shifts the AUF1/methyl-HuR balance not fully defined\",\n        \"Single-lab data\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that MAT1A silencing in early hepatocarcinogenesis is driven by combined epigenetic chromatin changes and microRNA repression.\",\n      \"evidence\": \"ChIP for H3K27me3/H3K18ac at the Mat1a promoter and miR-22/miR-29b functional studies in a rat 2-AAF hepatocarcinogenesis model\",\n      \"pmids\": [\"22213190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single carcinogen model in rat\",\n        \"Direct miRNA–MAT1A target binding not validated by reporter assay in this study\",\n        \"Relative contributions of chromatin vs miRNA repression unquantified\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a dietary-to-metabolic regulatory axis showing miR-143 directly represses MAT1A and that betaine raises hepatic SAM by de-repressing it.\",\n      \"evidence\": \"miR-143 knockout mice, betaine supplementation, luciferase reporter target validation, and SAM measurements\",\n      \"pmids\": [\"35734958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological context limited to dietary betaine\",\n        \"Single-lab data\",\n        \"Downstream consequences of altered SAM not characterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected transcriptional repression of MAT1A to tumor immunometabolism, showing a CTBP1/HDAC1/HDAC2 complex silences MAT1A and that restoring it promotes ferroptosis and antitumor immunity.\",\n      \"evidence\": \"Co-IP of CTBP1/HDAC1/HDAC2, siRNA knockdown, MAT1A overexpression, SAM measurement, and xenografts with ferrostatin-1\",\n      \"pmids\": [\"37230466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking SAM elevation to ferroptosis not detailed\",\n        \"Single-lab data\",\n        \"Direct CTBP1 occupancy at the MAT1A promoter not shown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical, extra-hepatic role for MAT1A as a protein stabilizer driving cancer metabolism beyond its SAM-synthesizing function.\",\n      \"evidence\": \"Stable MAT1A knockdown in NSCLC cells, MAT1A–CCND1 co-IP, SKP2-mediated CCND1 ubiquitination assays, and glycolysis measurements\",\n      \"pmids\": [\"39438468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the CCND1-stabilizing role depends on MAT1A catalytic activity unknown\",\n        \"Direct MAT1A–CCND1 binding interface not mapped\",\n        \"Single-lab data\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Observed that MAT1A overexpression confers chemotolerance via growth arrest, hinting at a role in cancer cell persistence.\",\n      \"evidence\": \"MAT1A overexpression in 5637 bladder cancer cells with gemcitabine dose-response and patient-derived xenograft RNA-seq\",\n      \"pmids\": [\"31600961\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No pathway mechanism identified linking MAT1A to quiescence or drug tolerance\",\n        \"Single overexpression experiment\",\n        \"No in vivo validation of the quiescence model\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether MAT1A's non-canonical protein-stabilizing and chemotolerance roles depend on its SAM-synthesizing activity, and how its multilayered repression integrates across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Catalytic dependence of CCND1 stabilization untested\",\n        \"No unified model connecting AUF1, miRNA, and CTBP1/HDAC repression\",\n        \"Structural model of the catalytic enzyme absent from this corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AUF1\", \"CCND1\", \"SKP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":4,"faith_pct":75.0}}