{"gene":"TMT1B","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2021,"finding":"METTL7B (TMT1B) encodes an alkyl thiol methyltransferase that catalyzes transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules including captopril, 7α-thiospironolactone, and L-penicillamine. Gene knockdown in HepG2 cells and overexpression in HeLa cells directly alter captopril methylation. Recombinantly expressed enzyme methylates substrates in a time- and concentration-dependent manner. S-adenosyl-L-homocysteine (AdoHcy) competitively inhibits activity. Mutation of the conserved active-site aspartate D98A abolishes methylation activity.","method":"Gene knockdown (shRNA) in HepG2 cells, overexpression in HeLa cells, recombinant protein expression and purification, in vitro methylation assays, active-site mutagenesis (D98A), competitive inhibition assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant enzyme, active-site mutagenesis, and cell-based knockdown/overexpression; multiple orthogonal methods in a single rigorous study","pmids":["33649426"],"is_preprint":false},{"year":2023,"finding":"Both METTL7B (TMT1B) and its paralog METTL7A (TMT1A) are responsible for microsomal alkyl thiol methyltransferase (TMT) activity in human liver. Quantitative proteomics of human liver microsomes shows TMT activity correlates with METTL7A and METTL7B protein levels. Purified recombinant METTL7A methylates exogenous thiol substrates including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. The classic TMT inhibitor DCMB inhibits METTL7A (IC50 = 1.17 μM) but does not inhibit METTL7B, indicating both enzymes contribute to total TMT activity.","method":"Quantitative proteomics of human liver microsomes, recombinant protein purification, in vitro enzyme activity assays, gene modulation in HepG2 and HeLa cells, inhibitor IC50 determination","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, quantitative proteomics, cell-based gene modulation; multiple orthogonal methods in a single rigorous study","pmids":["37137720"],"is_preprint":false},{"year":2024,"finding":"METTL7B (TMT1B) and METTL7A confer resistance to thiol-based histone deacetylase inhibitors (romidepsin and other thiol-HDACis) by methylating and inactivating the zinc-binding thiol moiety of these drugs. Expression of either enzyme in MCF-7 cells selected for romidepsin resistance confers selective resistance to thiol-based HDACis but not to non-thiol HDACis (belinostat, panobinostat, vorinostat). Both enzymes were shown capable of methylating thiol-containing HDACis in vitro.","method":"Drug-selection resistance model, RNA-sequencing, overexpression, in vitro methylation of HDACi substrates, pharmacological profiling across HDACi drug panel","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro enzyme activity on drug substrates plus cell-based resistance phenotype; single lab but two orthogonal approaches","pmids":["38151817"],"is_preprint":false},{"year":2017,"finding":"METTL7B is a downstream transcriptional target of RhoBTB1 and is required for Golgi integrity. RhoBTB1 regulates the integrity of the Golgi complex through METTL7B; silencing of either RhoBTB1 or METTL7B leads to Golgi fragmentation in breast cancer cells.","method":"Transcriptome analysis, Q-PCR, gene silencing (siRNA), cell imaging of Golgi morphology, rescue experiments with RhoBTB1 re-expression","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene silencing with defined cellular phenotype (Golgi fragmentation) and epistatic rescue; single lab, two orthogonal methods","pmids":["28219369"],"is_preprint":false},{"year":2016,"finding":"METTL7B (TMT1B) is localized to the endoplasmic reticulum as well as to stacked Golgi and lipid droplets, consistent with its membrane-associated biochemical properties.","method":"Cell imaging, subcellular fractionation (reviewed in Denford & Wilhelm 2023, citing prior localization data)","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data reported in a review without primary experimental details; single indirect citation","pmids":["37456227"],"is_preprint":false},{"year":2022,"finding":"METTL7B (TMT1B) methylates methanethiol in 16HBE human bronchial epithelial cells, converting it partially to dimethyl sulfide. Gene silencing of METTL7B significantly alleviated methanethiol-induced cytotoxicity, reactive oxygen species production, TNF signaling pathway activation, loss of mitochondrial membrane potential, and cell necrosis, demonstrating that METTL7B-mediated S-methylation bioactivates methanethiol to a toxic product.","method":"Gene silencing of METTL7B, metabolite measurement (dimethyl sulfide detection), ROS assay, cell viability assay, mitochondrial membrane potential assay, non-target metabolomics","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene silencing with defined metabolic and cytotoxic phenotype plus metabolite detection; single lab, multiple orthogonal readouts","pmids":["35397445"],"is_preprint":false},{"year":2025,"finding":"METTL7B suppresses USP38 expression via m6A-dependent mRNA degradation, leading to increased ubiquitylation of HDAC3 (a histone lysine delactylase), thereby maintaining histone lactylation levels. This pathway ameliorates cardiac remodelling. These mechanistic links were demonstrated by immunoprecipitation and RNA pull-down assays.","method":"Immunofluorescence, immunoprecipitation, RNA pull-down assay, transverse aortic constriction (TAC) mouse model, qRT-PCR, western blotting","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunoprecipitation and RNA pull-down demonstrate direct interactions; in vivo model used; single lab","pmids":["40068772"],"is_preprint":false},{"year":2025,"finding":"HOXB4 binds to the METTL7B promoter and inhibits its mRNA expression, as demonstrated by dual-luciferase reporter, ChIP, and DNA pulldown assays. METTL7B in turn controls mRNA decay of TKT via m6A methylation, as shown by methylated RNA immunoprecipitation assay.","method":"Dual-luciferase reporter assay, ChIP assay, DNA pulldown, methylated RNA immunoprecipitation (MeRIP), gain- and loss-of-function experiments","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding of HOXB4 to METTL7B promoter shown by ChIP and pulldown, and m6A-dependent mRNA decay shown by MeRIP; single lab, multiple orthogonal methods","pmids":["40045399"],"is_preprint":false},{"year":2024,"finding":"METTL7B downregulates expression of key neuronal differentiation players including SALL2 via post-translational modifications of histone marks, regulating neural stem cell-to-astrocyte differentiation trajectory in glioblastoma.","method":"Single-cell transcriptomic analysis of glioblastoma tumors and cerebral organoids derived from expanded potential stem cells overexpressing METTL7B","journal":"Cell reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic claim (histone mark modification) is stated but only supported by transcriptomic analysis without direct biochemical demonstration of histone modification by METTL7B; single lab","pmids":["38848215"],"is_preprint":false},{"year":2026,"finding":"METTL7B promotes m6A methylation and stability of lncRNA-MIR22HG, prolonging its transcript half-life. Stabilized lncRNA-MIR22HG suppresses ubiquitin-mediated degradation of JARID2, which then promotes assembly of the p53/p300/MDM2 transcriptional complex to up-regulate pro-apoptotic genes, driving neuronal apoptosis in cerebral ischemia/reperfusion injury.","method":"In vivo MCAO/R mouse model, in vitro OGD/R N2a cell model, m6A methylation quantification, transcript half-life measurement, overexpression and knockdown experiments, functional rescue assays","journal":"Cell biology and toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement supported by cell/animal models and m6A quantification but biochemical reconstitution of METTL7B's direct methylation of lncRNA-MIR22HG is not demonstrated; single lab","pmids":["41644777"],"is_preprint":false},{"year":2026,"finding":"METTL7B knockdown promotes ferroptosis in NSCLC cells by reducing m6A modification on LINC02159, decreasing its expression. LINC02159 recruits KAT2A to enhance H3K27ac enrichment on the ARNTL2 promoter, promoting ARNTL2 expression, which suppresses ferroptosis. Overexpression of LINC02159 or ARNTL2 partially reverses the pro-ferroptotic effects of METTL7B knockdown.","method":"METTL7B knockdown, m6A quantification, lncRNA expression measurement, functional rescue experiments with LINC02159 and ARNTL2 overexpression, MTT cell viability assay, ferroptosis marker measurements","journal":"Free radical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement via genetic rescue experiments; direct m6A writing on LINC02159 by METTL7B not biochemically reconstituted; single lab","pmids":["41652972"],"is_preprint":false},{"year":2024,"finding":"METTL7B enhances tumor cell migration and invasion through integrin-associated pathways, with Integrin Alpha 3 (ITGA3) identified as a conserved downstream effector. Gain- and loss-of-function experiments in LUAD and glioblastoma cell lines confirmed that METTL7B modulates ITGA3 expression and invasive behavior.","method":"Single-cell RNA sequencing analysis, TCGA transcriptomic analysis, gain- and loss-of-function experiments, immunofluorescence, transwell invasion/migration assays","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional perturbation with cellular phenotype (invasion) and downstream effector identification, but molecular mechanism linking METTL7B to ITGA3 regulation not biochemically defined; single lab","pmids":["42122180"],"is_preprint":false}],"current_model":"TMT1B (METTL7B) is an S-adenosyl-L-methionine (SAM)-dependent alkyl thiol methyltransferase, localized to the endoplasmic reticulum and Golgi, that catalyzes S-methylation of small molecule thiols including hydrogen sulfide and thiol-containing drugs such as captopril and romidepsin (via a conserved active-site aspartate D98A essential for catalysis); together with its paralog METTL7A (TMT1A), it accounts for microsomal TMT activity in human liver, and it also influences Golgi integrity downstream of RhoBTB1, modulates histone lactylation through m6A-dependent suppression of USP38/HDAC3, and participates in multiple cancer-relevant signaling axes—including regulation of cell cycle, glycolysis, and invasiveness—though many of these broader cellular roles remain mechanistically incompletely defined."},"narrative":{"mechanistic_narrative":"TMT1B (METTL7B) is an S-adenosyl-L-methionine (SAM)-dependent alkyl thiol methyltransferase that catalyzes S-methylation of hydrogen sulfide and a range of exogenous thiol-containing small molecules, including captopril, 7α-thiospironolactone, and L-penicillamine; catalysis depends on the conserved active-site aspartate D98, mutation of which abolishes activity, and the enzyme is competitively inhibited by S-adenosyl-L-homocysteine [PMID:33649426]. Together with its paralog METTL7A (TMT1A), it accounts for the microsomal thiol methyltransferase (TMT) activity of human liver, where TMT activity correlates with the protein levels of both enzymes; unlike METTL7A, TMT1B is not inhibited by the classic TMT inhibitor DCMB [PMID:37137720]. This thiol-methylating activity has direct pharmacological and toxicological consequences: TMT1B methylates and inactivates the zinc-binding thiol of thiol-based HDAC inhibitors such as romidepsin to confer selective drug resistance [PMID:38151817], and it bioactivates methanethiol toward a cytotoxic product in bronchial epithelial cells [PMID:35397445]. TMT1B is also a downstream transcriptional target of RhoBTB1 required to maintain Golgi integrity, with loss of either factor causing Golgi fragmentation [PMID:28219369]. Beyond these directly demonstrated thiol-methyltransferase and Golgi roles, TMT1B has been linked to m6A-dependent regulation of target transcripts and to various cancer-relevant phenotypes, but these broader roles are supported only by lower-confidence, model-based evidence in the available corpus.","teleology":[{"year":2021,"claim":"Establishing what TMT1B does enzymatically: it was defined as a SAM-dependent alkyl thiol methyltransferase acting on H2S and exogenous thiol drugs, with a mapped catalytic residue.","evidence":"Recombinant enzyme in vitro methylation assays with AdoHcy competitive inhibition and D98A active-site mutagenesis, plus knockdown/overexpression in HepG2 and HeLa cells","pmids":["33649426"],"confidence":"High","gaps":["Full endogenous physiological substrate spectrum beyond tested thiols not delineated","Structural basis of substrate selectivity not resolved"]},{"year":2023,"claim":"Placing TMT1B in human drug metabolism: it and paralog METTL7A jointly account for hepatic microsomal TMT activity, and a differential inhibitor profile distinguishes the two enzymes.","evidence":"Quantitative proteomics of human liver microsomes correlated with activity, recombinant enzyme assays, and DCMB IC50 determination","pmids":["37137720"],"confidence":"High","gaps":["Relative contribution of each paralog to specific substrates not quantified","Tissue distribution of activity beyond liver not defined"]},{"year":2022,"claim":"Connecting the methyltransferase activity to toxicology: TMT1B bioactivates methanethiol to dimethyl sulfide, driving cytotoxic stress responses.","evidence":"METTL7B silencing in 16HBE cells with metabolite detection, ROS, mitochondrial membrane potential, and viability readouts","pmids":["35397445"],"confidence":"Medium","gaps":["Direct in vitro methylation of methanethiol by purified enzyme not shown in this work","In vivo relevance of methanethiol bioactivation not established"]},{"year":2024,"claim":"Linking thiol methylation to drug resistance: TMT1B methylates and inactivates thiol-based HDAC inhibitors, conferring selective resistance.","evidence":"Romidepsin-resistance selection in MCF-7, overexpression, in vitro methylation of HDACi substrates, and pharmacological profiling across an HDACi panel","pmids":["38151817"],"confidence":"Medium","gaps":["Clinical relevance of enzyme-mediated resistance not tested","Stoichiometry of drug methylation in cells not quantified"]},{"year":2017,"claim":"Identifying a non-catalytic cellular role: TMT1B acts downstream of RhoBTB1 to maintain Golgi integrity.","evidence":"Transcriptome analysis, siRNA silencing with Golgi morphology imaging, and RhoBTB1 re-expression rescue in breast cancer cells","pmids":["28219369"],"confidence":"Medium","gaps":["Molecular mechanism by which TMT1B preserves Golgi structure unknown","Whether catalytic activity is required for the Golgi role not tested"]},{"year":2025,"claim":"Proposing an m6A-writing role: TMT1B was reported to regulate target transcript stability/decay (USP38, TKT) via m6A, linking it to histone lactylation and metabolic regulation.","evidence":"Immunoprecipitation, RNA pull-down, MeRIP, ChIP, and in vivo/cell models","pmids":["40068772","40045399"],"confidence":"Medium","gaps":["Direct biochemical demonstration that TMT1B writes m6A is not reconstituted","How a thiol methyltransferase would act as an RNA m6A writer mechanistically unresolved"]},{"year":2026,"claim":"Extending TMT1B to neuronal injury and cancer phenotypes through proposed m6A-dependent regulation of lncRNAs and downstream effectors.","evidence":"MCAO/R and OGD/R models, NSCLC ferroptosis assays, single-cell transcriptomics, m6A quantification, and genetic rescue experiments","pmids":["41644777","41652972","38848215","42122180"],"confidence":"Low","gaps":["Direct m6A methylation of named lncRNA/mRNA targets by TMT1B not biochemically reconstituted","Pathway placements rely on correlative and rescue data in single labs","Histone-mark modification claims lack direct biochemical demonstration"]},{"year":null,"claim":"Whether TMT1B possesses a genuine catalytic RNA m6A-writing activity distinct from its established thiol methyltransferase function, and how its catalytic versus structural roles partition across drug metabolism, Golgi maintenance, and disease phenotypes, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro reconstitution of TMT1B as an RNA m6A methyltransferase","No structural model linking the thiol active site to proposed RNA activity","Endogenous physiological substrates of the thiol activity not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,5]}],"complexes":[],"partners":["METTL7A","RHOBTB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UX53","full_name":"Thiol S-methyltransferase TMT1B","aliases":["Methyltransferase-like protein 7B","Thiol S-methyltransferase METTL7B"],"length_aa":244,"mass_kda":27.8,"function":"Thiol S-methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to alkyl and phenolic thiol-containing acceptor substrates. Together with TMT1B accounts for most of S-thiol methylation activity in the endoplasmic reticulum of hepatocytes. Selectively methylates S-centered nucleophiles from metabolites such as hydrogen sulfide and dithiothreitol","subcellular_location":"Endoplasmic reticulum membrane; Lipid droplet; Microsome; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q6UX53/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMT1B","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMT1B","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"METTL7B","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":126.1},{"tissue":"heart muscle","ntpm":136.0},{"tissue":"liver","ntpm":267.4}],"url":"https://www.proteinatlas.org/search/METTL7B"},"hgnc":{"alias_symbol":["MGC17301","ALDI"],"prev_symbol":["METTL7B"]},"alphafold":{"accession":"Q6UX53","domains":[{"cath_id":"3.40.50.150","chopping":"2-61_71-80_90-242","consensus_level":"high","plddt":95.5877,"start":2,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX53","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX53-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UX53-F1-predicted_aligned_error_v6.png","plddt_mean":94.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMT1B","jax_strain_url":"https://www.jax.org/strain/search?query=TMT1B"},"sequence":{"accession":"Q6UX53","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UX53.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UX53/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UX53"}},"corpus_meta":[{"pmid":"28219369","id":"PMC_28219369","title":"The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B.","date":"2017","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28219369","citation_count":70,"is_preprint":false},{"pmid":"32180726","id":"PMC_32180726","title":"METTL7B Is Required for Cancer Cell Proliferation and Tumorigenesis in Non-Small Cell Lung Cancer.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32180726","citation_count":46,"is_preprint":false},{"pmid":"33649426","id":"PMC_33649426","title":"Human METTL7B is an alkyl thiol methyltransferase that metabolizes hydrogen sulfide and captopril.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33649426","citation_count":46,"is_preprint":false},{"pmid":"31121562","id":"PMC_31121562","title":"METTL7B promotes migration and invasion in thyroid cancer through epithelial-mesenchymal transition.","date":"2019","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/31121562","citation_count":34,"is_preprint":false},{"pmid":"37137720","id":"PMC_37137720","title":"METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.","date":"2023","source":"Drug metabolism and disposition: the biological fate of chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/37137720","citation_count":19,"is_preprint":false},{"pmid":"33718220","id":"PMC_33718220","title":"Downregulation of METTL7B Inhibits Proliferation of Human Clear Cell Renal Cancer Cells In Vivo and In Vitro.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33718220","citation_count":18,"is_preprint":false},{"pmid":"38151817","id":"PMC_38151817","title":"The Methyltransferases METTL7A and METTL7B Confer Resistance to Thiol-Based Histone Deacetylase Inhibitors.","date":"2024","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38151817","citation_count":16,"is_preprint":false},{"pmid":"33858297","id":"PMC_33858297","title":"circ-PSD3 promoted proliferation and invasion of papillary thyroid cancer cells via regulating the miR-7-5p/METTL7B axis.","date":"2021","source":"Journal of receptor and signal transduction research","url":"https://pubmed.ncbi.nlm.nih.gov/33858297","citation_count":16,"is_preprint":false},{"pmid":"33240979","id":"PMC_33240979","title":"METTL7B (methyltransferase-like 7B) identification as a novel biomarker for lung adenocarcinoma.","date":"2020","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33240979","citation_count":13,"is_preprint":false},{"pmid":"33484445","id":"PMC_33484445","title":"Low Molecular Pectin Inhibited the Lipid Accumulation by Upregulation of METTL7B.","date":"2021","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33484445","citation_count":11,"is_preprint":false},{"pmid":"35254598","id":"PMC_35254598","title":"METTL7B contributes to the malignant progression of glioblastoma by inhibiting EGR1 expression.","date":"2022","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/35254598","citation_count":10,"is_preprint":false},{"pmid":"40068772","id":"PMC_40068772","title":"METTL7B-induced histone lactylation prevents heart failure by ameliorating cardiac remodelling.","date":"2025","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/40068772","citation_count":9,"is_preprint":false},{"pmid":"35397445","id":"PMC_35397445","title":"Potent necrosis effect of methanethiol mediated by METTL7B enzyme bioactivation mechanism in 16HBE cell.","date":"2022","source":"Ecotoxicology and environmental 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Adenocarcinoma by Targeting the METTL7B Gene.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35646115","citation_count":4,"is_preprint":false},{"pmid":"38294636","id":"PMC_38294636","title":"Glycolysis Modulation by METTL7B Shapes Acute Lymphoblastic Leukemia Cell Proliferation and Chemotherapy Response.","date":"2024","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/38294636","citation_count":2,"is_preprint":false},{"pmid":"37151605","id":"PMC_37151605","title":"lncRNA PDCD4-AS1 Promotes the Progression of Glioma by Regulating miR-30b-3p/METTL7B Signaling.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/37151605","citation_count":2,"is_preprint":false},{"pmid":"40750092","id":"PMC_40750092","title":"Correlation between methyltransferase METTL7B and atherosclerosis.","date":"2025","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40750092","citation_count":0,"is_preprint":false},{"pmid":"42122180","id":"PMC_42122180","title":"Single-Cell Dissection Identifies METTL7B as Associated with Cell Adhesion-Mediated Tumor Invasion in Lung Adenocarcinoma and Glioblastoma.","date":"2026","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/42122180","citation_count":0,"is_preprint":false},{"pmid":"41652972","id":"PMC_41652972","title":"Molecular mechanism of METTL7B-mediated m6A modification in ferroptosis of non-small cell lung cancer cells.","date":"2026","source":"Free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/41652972","citation_count":0,"is_preprint":false},{"pmid":"41644777","id":"PMC_41644777","title":"METTL7B-stabilized lncRNA-MIR22HG to drive p53-mediated neuronal apoptosis via the ubiquitinating JARID2 in cerebral ischemia/reperfusion injury.","date":"2026","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41644777","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14683,"output_tokens":3572,"usd":0.048814,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11137,"output_tokens":2856,"usd":0.063543,"stage2_stop_reason":"end_turn"},"total_usd":0.112357,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL7B (TMT1B) encodes an alkyl thiol methyltransferase that catalyzes transfer of a methyl group from S-adenosyl-L-methionine (AdoMet) to hydrogen sulfide (H2S) and other exogenous thiol small molecules including captopril, 7α-thiospironolactone, and L-penicillamine. Gene knockdown in HepG2 cells and overexpression in HeLa cells directly alter captopril methylation. Recombinantly expressed enzyme methylates substrates in a time- and concentration-dependent manner. S-adenosyl-L-homocysteine (AdoHcy) competitively inhibits activity. Mutation of the conserved active-site aspartate D98A abolishes methylation activity.\",\n      \"method\": \"Gene knockdown (shRNA) in HepG2 cells, overexpression in HeLa cells, recombinant protein expression and purification, in vitro methylation assays, active-site mutagenesis (D98A), competitive inhibition assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant enzyme, active-site mutagenesis, and cell-based knockdown/overexpression; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"33649426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Both METTL7B (TMT1B) and its paralog METTL7A (TMT1A) are responsible for microsomal alkyl thiol methyltransferase (TMT) activity in human liver. Quantitative proteomics of human liver microsomes shows TMT activity correlates with METTL7A and METTL7B protein levels. Purified recombinant METTL7A methylates exogenous thiol substrates including 7α-thiospironolactone, dithiothreitol, 4-chlorothiophenol, and mertansine. The classic TMT inhibitor DCMB inhibits METTL7A (IC50 = 1.17 μM) but does not inhibit METTL7B, indicating both enzymes contribute to total TMT activity.\",\n      \"method\": \"Quantitative proteomics of human liver microsomes, recombinant protein purification, in vitro enzyme activity assays, gene modulation in HepG2 and HeLa cells, inhibitor IC50 determination\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with purified recombinant protein, quantitative proteomics, cell-based gene modulation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"37137720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL7B (TMT1B) and METTL7A confer resistance to thiol-based histone deacetylase inhibitors (romidepsin and other thiol-HDACis) by methylating and inactivating the zinc-binding thiol moiety of these drugs. Expression of either enzyme in MCF-7 cells selected for romidepsin resistance confers selective resistance to thiol-based HDACis but not to non-thiol HDACis (belinostat, panobinostat, vorinostat). Both enzymes were shown capable of methylating thiol-containing HDACis in vitro.\",\n      \"method\": \"Drug-selection resistance model, RNA-sequencing, overexpression, in vitro methylation of HDACi substrates, pharmacological profiling across HDACi drug panel\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro enzyme activity on drug substrates plus cell-based resistance phenotype; single lab but two orthogonal approaches\",\n      \"pmids\": [\"38151817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"METTL7B is a downstream transcriptional target of RhoBTB1 and is required for Golgi integrity. RhoBTB1 regulates the integrity of the Golgi complex through METTL7B; silencing of either RhoBTB1 or METTL7B leads to Golgi fragmentation in breast cancer cells.\",\n      \"method\": \"Transcriptome analysis, Q-PCR, gene silencing (siRNA), cell imaging of Golgi morphology, rescue experiments with RhoBTB1 re-expression\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene silencing with defined cellular phenotype (Golgi fragmentation) and epistatic rescue; single lab, two orthogonal methods\",\n      \"pmids\": [\"28219369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"METTL7B (TMT1B) is localized to the endoplasmic reticulum as well as to stacked Golgi and lipid droplets, consistent with its membrane-associated biochemical properties.\",\n      \"method\": \"Cell imaging, subcellular fractionation (reviewed in Denford & Wilhelm 2023, citing prior localization data)\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data reported in a review without primary experimental details; single indirect citation\",\n      \"pmids\": [\"37456227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"METTL7B (TMT1B) methylates methanethiol in 16HBE human bronchial epithelial cells, converting it partially to dimethyl sulfide. Gene silencing of METTL7B significantly alleviated methanethiol-induced cytotoxicity, reactive oxygen species production, TNF signaling pathway activation, loss of mitochondrial membrane potential, and cell necrosis, demonstrating that METTL7B-mediated S-methylation bioactivates methanethiol to a toxic product.\",\n      \"method\": \"Gene silencing of METTL7B, metabolite measurement (dimethyl sulfide detection), ROS assay, cell viability assay, mitochondrial membrane potential assay, non-target metabolomics\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene silencing with defined metabolic and cytotoxic phenotype plus metabolite detection; single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"35397445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL7B suppresses USP38 expression via m6A-dependent mRNA degradation, leading to increased ubiquitylation of HDAC3 (a histone lysine delactylase), thereby maintaining histone lactylation levels. This pathway ameliorates cardiac remodelling. These mechanistic links were demonstrated by immunoprecipitation and RNA pull-down assays.\",\n      \"method\": \"Immunofluorescence, immunoprecipitation, RNA pull-down assay, transverse aortic constriction (TAC) mouse model, qRT-PCR, western blotting\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunoprecipitation and RNA pull-down demonstrate direct interactions; in vivo model used; single lab\",\n      \"pmids\": [\"40068772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXB4 binds to the METTL7B promoter and inhibits its mRNA expression, as demonstrated by dual-luciferase reporter, ChIP, and DNA pulldown assays. METTL7B in turn controls mRNA decay of TKT via m6A methylation, as shown by methylated RNA immunoprecipitation assay.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP assay, DNA pulldown, methylated RNA immunoprecipitation (MeRIP), gain- and loss-of-function experiments\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding of HOXB4 to METTL7B promoter shown by ChIP and pulldown, and m6A-dependent mRNA decay shown by MeRIP; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40045399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL7B downregulates expression of key neuronal differentiation players including SALL2 via post-translational modifications of histone marks, regulating neural stem cell-to-astrocyte differentiation trajectory in glioblastoma.\",\n      \"method\": \"Single-cell transcriptomic analysis of glioblastoma tumors and cerebral organoids derived from expanded potential stem cells overexpressing METTL7B\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic claim (histone mark modification) is stated but only supported by transcriptomic analysis without direct biochemical demonstration of histone modification by METTL7B; single lab\",\n      \"pmids\": [\"38848215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL7B promotes m6A methylation and stability of lncRNA-MIR22HG, prolonging its transcript half-life. Stabilized lncRNA-MIR22HG suppresses ubiquitin-mediated degradation of JARID2, which then promotes assembly of the p53/p300/MDM2 transcriptional complex to up-regulate pro-apoptotic genes, driving neuronal apoptosis in cerebral ischemia/reperfusion injury.\",\n      \"method\": \"In vivo MCAO/R mouse model, in vitro OGD/R N2a cell model, m6A methylation quantification, transcript half-life measurement, overexpression and knockdown experiments, functional rescue assays\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement supported by cell/animal models and m6A quantification but biochemical reconstitution of METTL7B's direct methylation of lncRNA-MIR22HG is not demonstrated; single lab\",\n      \"pmids\": [\"41644777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL7B knockdown promotes ferroptosis in NSCLC cells by reducing m6A modification on LINC02159, decreasing its expression. LINC02159 recruits KAT2A to enhance H3K27ac enrichment on the ARNTL2 promoter, promoting ARNTL2 expression, which suppresses ferroptosis. Overexpression of LINC02159 or ARNTL2 partially reverses the pro-ferroptotic effects of METTL7B knockdown.\",\n      \"method\": \"METTL7B knockdown, m6A quantification, lncRNA expression measurement, functional rescue experiments with LINC02159 and ARNTL2 overexpression, MTT cell viability assay, ferroptosis marker measurements\",\n      \"journal\": \"Free radical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement via genetic rescue experiments; direct m6A writing on LINC02159 by METTL7B not biochemically reconstituted; single lab\",\n      \"pmids\": [\"41652972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL7B enhances tumor cell migration and invasion through integrin-associated pathways, with Integrin Alpha 3 (ITGA3) identified as a conserved downstream effector. Gain- and loss-of-function experiments in LUAD and glioblastoma cell lines confirmed that METTL7B modulates ITGA3 expression and invasive behavior.\",\n      \"method\": \"Single-cell RNA sequencing analysis, TCGA transcriptomic analysis, gain- and loss-of-function experiments, immunofluorescence, transwell invasion/migration assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional perturbation with cellular phenotype (invasion) and downstream effector identification, but molecular mechanism linking METTL7B to ITGA3 regulation not biochemically defined; single lab\",\n      \"pmids\": [\"42122180\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMT1B (METTL7B) is an S-adenosyl-L-methionine (SAM)-dependent alkyl thiol methyltransferase, localized to the endoplasmic reticulum and Golgi, that catalyzes S-methylation of small molecule thiols including hydrogen sulfide and thiol-containing drugs such as captopril and romidepsin (via a conserved active-site aspartate D98A essential for catalysis); together with its paralog METTL7A (TMT1A), it accounts for microsomal TMT activity in human liver, and it also influences Golgi integrity downstream of RhoBTB1, modulates histone lactylation through m6A-dependent suppression of USP38/HDAC3, and participates in multiple cancer-relevant signaling axes—including regulation of cell cycle, glycolysis, and invasiveness—though many of these broader cellular roles remain mechanistically incompletely defined.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMT1B (METTL7B) is an S-adenosyl-L-methionine (SAM)-dependent alkyl thiol methyltransferase that catalyzes S-methylation of hydrogen sulfide and a range of exogenous thiol-containing small molecules, including captopril, 7α-thiospironolactone, and L-penicillamine; catalysis depends on the conserved active-site aspartate D98, mutation of which abolishes activity, and the enzyme is competitively inhibited by S-adenosyl-L-homocysteine [#0]. Together with its paralog METTL7A (TMT1A), it accounts for the microsomal thiol methyltransferase (TMT) activity of human liver, where TMT activity correlates with the protein levels of both enzymes; unlike METTL7A, TMT1B is not inhibited by the classic TMT inhibitor DCMB [#1]. This thiol-methylating activity has direct pharmacological and toxicological consequences: TMT1B methylates and inactivates the zinc-binding thiol of thiol-based HDAC inhibitors such as romidepsin to confer selective drug resistance [#2], and it bioactivates methanethiol toward a cytotoxic product in bronchial epithelial cells [#5]. TMT1B is also a downstream transcriptional target of RhoBTB1 required to maintain Golgi integrity, with loss of either factor causing Golgi fragmentation [#3]. Beyond these directly demonstrated thiol-methyltransferase and Golgi roles, TMT1B has been linked to m6A-dependent regulation of target transcripts and to various cancer-relevant phenotypes, but these broader roles are supported only by lower-confidence, model-based evidence in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Establishing what TMT1B does enzymatically: it was defined as a SAM-dependent alkyl thiol methyltransferase acting on H2S and exogenous thiol drugs, with a mapped catalytic residue.\",\n      \"evidence\": \"Recombinant enzyme in vitro methylation assays with AdoHcy competitive inhibition and D98A active-site mutagenesis, plus knockdown/overexpression in HepG2 and HeLa cells\",\n      \"pmids\": [\"33649426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full endogenous physiological substrate spectrum beyond tested thiols not delineated\", \"Structural basis of substrate selectivity not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing TMT1B in human drug metabolism: it and paralog METTL7A jointly account for hepatic microsomal TMT activity, and a differential inhibitor profile distinguishes the two enzymes.\",\n      \"evidence\": \"Quantitative proteomics of human liver microsomes correlated with activity, recombinant enzyme assays, and DCMB IC50 determination\",\n      \"pmids\": [\"37137720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each paralog to specific substrates not quantified\", \"Tissue distribution of activity beyond liver not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connecting the methyltransferase activity to toxicology: TMT1B bioactivates methanethiol to dimethyl sulfide, driving cytotoxic stress responses.\",\n      \"evidence\": \"METTL7B silencing in 16HBE cells with metabolite detection, ROS, mitochondrial membrane potential, and viability readouts\",\n      \"pmids\": [\"35397445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro methylation of methanethiol by purified enzyme not shown in this work\", \"In vivo relevance of methanethiol bioactivation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linking thiol methylation to drug resistance: TMT1B methylates and inactivates thiol-based HDAC inhibitors, conferring selective resistance.\",\n      \"evidence\": \"Romidepsin-resistance selection in MCF-7, overexpression, in vitro methylation of HDACi substrates, and pharmacological profiling across an HDACi panel\",\n      \"pmids\": [\"38151817\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical relevance of enzyme-mediated resistance not tested\", \"Stoichiometry of drug methylation in cells not quantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying a non-catalytic cellular role: TMT1B acts downstream of RhoBTB1 to maintain Golgi integrity.\",\n      \"evidence\": \"Transcriptome analysis, siRNA silencing with Golgi morphology imaging, and RhoBTB1 re-expression rescue in breast cancer cells\",\n      \"pmids\": [\"28219369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which TMT1B preserves Golgi structure unknown\", \"Whether catalytic activity is required for the Golgi role not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposing an m6A-writing role: TMT1B was reported to regulate target transcript stability/decay (USP38, TKT) via m6A, linking it to histone lactylation and metabolic regulation.\",\n      \"evidence\": \"Immunoprecipitation, RNA pull-down, MeRIP, ChIP, and in vivo/cell models\",\n      \"pmids\": [\"40068772\", \"40045399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical demonstration that TMT1B writes m6A is not reconstituted\", \"How a thiol methyltransferase would act as an RNA m6A writer mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending TMT1B to neuronal injury and cancer phenotypes through proposed m6A-dependent regulation of lncRNAs and downstream effectors.\",\n      \"evidence\": \"MCAO/R and OGD/R models, NSCLC ferroptosis assays, single-cell transcriptomics, m6A quantification, and genetic rescue experiments\",\n      \"pmids\": [\"41644777\", \"41652972\", \"38848215\", \"42122180\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct m6A methylation of named lncRNA/mRNA targets by TMT1B not biochemically reconstituted\", \"Pathway placements rely on correlative and rescue data in single labs\", \"Histone-mark modification claims lack direct biochemical demonstration\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether TMT1B possesses a genuine catalytic RNA m6A-writing activity distinct from its established thiol methyltransferase function, and how its catalytic versus structural roles partition across drug metabolism, Golgi maintenance, and disease phenotypes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro reconstitution of TMT1B as an RNA m6A methyltransferase\", \"No structural model linking the thiol active site to proposed RNA activity\", \"Endogenous physiological substrates of the thiol activity not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"METTL7A\", \"RhoBTB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}