TMT1B

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.

1. 2021 High

   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

   PMID:33649426

   Open questions at the time

   • Full endogenous physiological substrate spectrum beyond tested thiols not delineated
   • Structural basis of substrate selectivity not resolved
2. 2023 High

   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

   PMID:37137720

   Open questions at the time

   • Relative contribution of each paralog to specific substrates not quantified
   • Tissue distribution of activity beyond liver not defined
3. 2022 Medium

   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

   PMID:35397445

   Open questions at the time

   • Direct in vitro methylation of methanethiol by purified enzyme not shown in this work
   • In vivo relevance of methanethiol bioactivation not established
4. 2024 Medium

   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

   PMID:38151817

   Open questions at the time

   • Clinical relevance of enzyme-mediated resistance not tested
   • Stoichiometry of drug methylation in cells not quantified
5. 2017 Medium

   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

   PMID:28219369

   Open questions at the time

   • Molecular mechanism by which TMT1B preserves Golgi structure unknown
   • Whether catalytic activity is required for the Golgi role not tested
6. 2025 Medium

   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

   PMID:40045399 PMID:40068772

   Open questions at the time

   • Direct biochemical demonstration that TMT1B writes m6A is not reconstituted
   • How a thiol methyltransferase would act as an RNA m6A writer mechanistically unresolved
7. 2026 Low

   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

   PMID:38848215 PMID:41644777 PMID:41652972 PMID:42122180

   Open questions at the time

   • 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

• 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.
• 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