GO:0018708 thiol S-methyltransferase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0018708 thiol S-methyltransferase activity catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a thiol substrate, producing S-adenosyl-L-homocysteine and a thioether.
• The enzymes METTL7A (TMT1A) and METTL7B (TMT1B) are responsible for alkyl S-thiol methyltransferase activity in liver.
• Thiol S-methyltransferase activity is present in human erythrocyte membranes, colonocytes, intestine, and liver, where it metabolizes drugs such as captopril, N-acetylcysteine, and penicillamine [2,3,4,6,7,8].
• Altered thiol S-methyltransferase activity has been observed in inflammatory bowel disease, suggesting a role in intestinal pathophysiology.
• Studying this activity requires careful distinction from thiopurine methyltransferase (TPMT), as both can methylate overlapping substrates.
• CRISPR-based knockout, point mutation, and overexpression models are essential to dissect the contribution of METTL7A/METTL7B and other candidate genes to thiol S-methyltransferase activity.
Description
Thiol S-methyltransferase activity (GO:0018708) is a molecular function that catalyzes the S-adenosyl-L-methionine-dependent methylation of thiol compounds to their corresponding thioethers. This activity is widely distributed in mammalian tissues, including erythrocyte membranes, colonocytes, intestine, and liver, and plays a key role in the metabolism of endogenous thiols and xenobiotic thiol drugs [2,3,6,7]. The reaction consumes S-adenosyl-L-methionine (SAM) and produces S-adenosyl-L-homocysteine (SAH) and a thioether product. Researchers study this activity to understand drug detoxification, sulfur metabolism, and disease-associated changes in methylation capacity [4,5]. The recent identification of METTL7A (TMT1A) and METTL7B (TMT1B) as the principal enzymes responsible for alkyl S-thiol methyltransferase activity in liver has reinvigorated interest in this GO term. These enzymes are distinct from thiopurine methyltransferase (TPMT), although both can methylate certain thiol substrates, necessitating careful experimental design.
thiol S-methyltransferase activity At A Glance
| GO ID | GO:0018708 |
|---|---|
| GO term | thiol S-methyltransferase activity |
| Ontology | molecular_function |
| Synonym | S-adenosyl-L-methionine:thiol S-methyltransferase activity; thiol methyltransferase activity; TMT |
| Definition | Catalysis of the reaction: S-adenosyl-L-methionine + a thiol = S-adenosyl-L-homocysteine + a thioether. |
| Major function | Methylation of thiol compounds using SAM as the methyl donor, producing thioethers and SAH. |
| Key enzymes | METTL7A (TMT1A), METTL7B (TMT1B) |
| Tissue distribution | Erythrocyte membranes, colonocytes, intestine, liver |
| Substrates | Captopril, N-acetylcysteine, penicillamine, diethyldithiocarbamate, 7 alpha-thio-spirolactone |
What Is GO:0018708?
Thiol S-methyltransferase activity is defined as the catalysis of the reaction: S-adenosyl-L-methionine + a thiol = S-adenosyl-L-homocysteine + a thioether. In other words, it transfers a methyl group from SAM to a sulfur atom of a thiol substrate, forming a methylated thioether product and releasing SAH. This activity is synonymous with S-adenosyl-L-methionine:thiol S-methyltransferase activity, thiol methyltransferase activity, and TMT.
Why Is thiol S-methyltransferase activity Important in Cell Biology?
Thiol S-methyltransferase activity is important because it modulates the pharmacokinetics and toxicity of thiol-containing drugs and endogenous thiols [3,6,8]. By methylating captopril, N-acetylcysteine, and penicillamine, this activity can alter drug efficacy and clearance [3,6,8]. In addition, changes in thiol S-methyltransferase activity have been linked to inflammatory bowel disease, suggesting a role in intestinal inflammation and sulfur metabolism. The identification of METTL7A and METTL7B as the enzymes responsible for this activity in liver provides a molecular handle to study its regulation and contribution to disease. Understanding this activity is also critical for interpreting methylation assays, as thiopurine methyltransferase (TPMT) can methylate overlapping substrates, leading to potential confounding.
• Metabolizes thiol drugs such as captopril, N-acetylcysteine, and penicillamine, affecting their pharmacokinetics [3,6,8].
• Contributes to the S-methylation of diethyldithiocarbamate in human liver.
• Shows altered activity in inflammatory bowel disease, linking it to intestinal pathophysiology.
• Is present in erythrocyte membranes, providing an accessible biomarker for enzyme activity [2,6].
• Distinct from but overlapping with thiopurine methyltransferase (TPMT) in substrate specificity.
• Enzymes METTL7A (TMT1A) and METTL7B (TMT1B) are the major alkyl S-thiol methyltransferases in liver.
• Important for sulfur metabolism and detoxification of reactive thiols.
• Potential target for modulating drug metabolism and toxicity [3,4].
• Relevant to colonocyte and intestinal function [2,7].
• Provides a model system to study SAM-dependent methylation reactions.
What Happens During thiol S-methyltransferase activity?
Substrate binding and methyl transfer
In simple terms: The enzyme grabs a thiol molecule and a methyl donor, then moves the methyl group onto the thiol.
Thiol S-methyltransferase activity begins with the binding of S-adenosyl-L-methionine (SAM) and a thiol substrate to the enzyme active site. The enzyme facilitates the transfer of the methyl group from SAM to the sulfur atom of the thiol, forming a thioether product and S-adenosyl-L-homocysteine (SAH). This reaction has been demonstrated with substrates such as captopril, N-acetylcysteine, and penicillamine in human erythrocyte membranes [3,6,8].
Tissue-specific distribution and isoforms
In simple terms: Different tissues have different amounts of this enzyme activity.
Thiol S-methyltransferase activity is differentially distributed across human tissues. It is present in erythrocyte membranes, colonocytes, and along the human bowel, with microsomal and cytosolic forms showing distinct distributions [2,7]. In the liver, METTL7A (TMT1A) and METTL7B (TMT1B) are responsible for alkyl S-thiol methyltransferase activity. This tissue-specific expression pattern influences local drug metabolism and thiol homeostasis [1,7].
Substrate specificity and overlap with TPMT
In simple terms: This enzyme can act on several thiol drugs, but another enzyme called TPMT can also act on some of the same molecules.
Thiol S-methyltransferase activity can methylate a range of thiol substrates, including captopril, N-acetylcysteine, D- and L-penicillamine, and 7 alpha-thio-spirolactone [3,6,8]. However, thiopurine methyltransferase (TPMT) can also catalyze the S-methylation of certain thiols such as diethyldithiocarbamate, leading to potential overlap in substrate specificity. Therefore, distinguishing between these activities requires careful biochemical assays and genetic models.
Role in drug metabolism and disease
In simple terms: This enzyme helps process thiol drugs and its activity changes in some diseases.
By methylating thiol-containing drugs, thiol S-methyltransferase activity can influence drug half-life and toxicity [3,6,8]. In inflammatory bowel disease, thiol S-methyltransferase activity is altered in colonocytes, suggesting a link between this activity and intestinal inflammation. These findings highlight the clinical relevance of this molecular function.
Key Genes Involved in GO:0018708 thiol S-methyltransferase activity
The following genes and proteins are directly implicated in thiol S-methyltransferase activity or are closely related to its study.
| Gene | Major Role | Research Relevance |
|---|---|---|
| METTL7A (TMT1A) | Alkyl S-thiol methyltransferase in liver | Responsible for thiol S-methyltransferase activity; knockout models can abolish activity |
| METTL7B (TMT1B) | Alkyl S-thiol methyltransferase in liver | Contributes to thiol S-methyltransferase activity; potential redundancy with METTL7A |
| TPMT | Thiopurine methyltransferase | Can methylate overlapping thiol substrates; important for distinguishing activities |
| GSTP1 | Glutathione S-transferase | Indirectly related to thiol metabolism; not a thiol S-methyltransferase but often studied together |
| COMT | Catechol-O-methyltransferase | Methylates catechols, not thiols; used as a negative control in specificity studies |
| MAT1A | Methionine adenosyltransferase | Produces SAM, the methyl donor for thiol S-methyltransferase activity |
| MAT2A | Methionine adenosyltransferase | Alternative SAM producer; affects methyl donor availability |
| AHCY | S-adenosylhomocysteine hydrolase | Metabolizes SAH, the product of the reaction |
| MTR | Methionine synthase | Regenerates methionine from homocysteine, linking to methylation cycle |
| CBS | Cystathionine beta-synthase | Transsulfuration pathway, affects thiol pools |
| CTH | Cystathionine gamma-lyase | Produces cysteine and thiols, potential substrates |
| GCLC | Glutamate-cysteine ligase | Glutathione synthesis, affects thiol substrate availability |
| GCLM | Glutamate-cysteine ligase modifier | Regulates glutathione synthesis |
| NQO1 | NAD(P)H quinone dehydrogenase | Not directly related; often used as a control in liver studies |
| ABCB1 | Multidrug resistance protein | Transports thiol drugs; indirect relevance |
| SLCO1B1 | Organic anion transporting polypeptide | Uptake of thiol drugs; indirect relevance |
| UGT1A1 | UDP-glucuronosyltransferase | Competing drug metabolism pathway |
| SULT1A1 | Sulfotransferase | Competing conjugation pathway for thiols |
How Is thiol S-methyltransferase activity Regulated?
Thiol S-methyltransferase activity is regulated at multiple levels. The expression of METTL7A and METTL7B, the enzymes responsible for this activity in liver, is likely controlled by transcriptional and post-transcriptional mechanisms, although specific regulators are not fully defined. The availability of the methyl donor SAM, produced by methionine adenosyltransferases (MAT1A, MAT2A), directly influences reaction rate. In addition, the product SAH is hydrolyzed by AHCY, and the ratio of SAM to SAH can affect methyltransferase activity. Tissue-specific distribution, as seen in intestine and erythrocytes, suggests developmental or tissue-specific regulatory programs [2,7]. Disease states such as inflammatory bowel disease may alter activity, but the underlying regulatory changes remain to be elucidated.
thiol S-methyltransferase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| METTL7A (TMT1A) | Liver detoxification and drug metabolism | Knockout HepG2 or primary hepatocytes |
| METTL7B (TMT1B) | Liver detoxification and drug metabolism | Knockout or double knockout with METTL7A |
| TPMT | Thiopurine drug toxicity | Point mutation models to distinguish from thiol S-methyltransferase |
| Not specified | Inflammatory bowel disease | Patient-derived colonocytes or intestinal organoids |
| Not specified | Captopril and penicillamine metabolism | Erythrocyte membrane assays or overexpression in cell lines [3,6,8] |
Inflammatory bowel disease
Thiol S-methyltransferase activity is altered in colonocytes from patients with inflammatory bowel disease, suggesting a role in the pathogenesis or response to intestinal inflammation. The mechanism may involve changes in thiol metabolism and detoxification capacity in the gut.
Drug metabolism and toxicity
Variations in thiol S-methyltransferase activity can affect the metabolism of thiol drugs such as captopril, N-acetylcysteine, and penicillamine, potentially influencing drug efficacy and toxicity [3,6,8]. This has implications for personalized medicine and drug dosing.
Liver function and detoxification
In the liver, METTL7A and METTL7B mediate alkyl S-thiol methyltransferase activity, which contributes to the detoxification of thiol compounds. Dysregulation of this activity could impact liver function and susceptibility to xenobiotic injury.
From thiol S-methyltransferase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does METTL7A knockout abolish thiol S-methyltransferase activity? | METTL7A knockout cell line (e.g., HepG2) |
| Does METTL7B compensate for METTL7A loss? | Double knockout of METTL7A and METTL7B |
| Can a point mutation in the active site eliminate activity? | Point mutation knock-in of catalytic residues in METTL7A |
| Does overexpression increase thiol drug methylation? | Overexpression of METTL7A or METTL7B in HEK293 cells |
| Can we tag METTL7A to study localization? | Tagged knock-in of METTL7A with FLAG or GFP |
| Does TPMT contribute to thiol S-methyltransferase activity? | TPMT knockout or point mutation models |
How to Study the thiol S-methyltransferase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Radiolabeled SAM assay | Thioether product formation | Enzyme activity in tissue homogenates |
| HPLC-UV | Substrate depletion or product formation | Kinetic analysis of thiol methylation |
| LC-MS/MS | Thioether metabolites | Drug metabolism studies |
| CRISPR knockout screen | Genes required for activity | Identification of METTL7A/METTL7B |
| Western blot | Protein expression | Validation of knockout or overexpression |
| RNA-seq | Transcript levels | Tissue distribution and regulation |
| Immunofluorescence | Subcellular localization | Tagged knock-in models |
| Co-immunoprecipitation | Protein-protein interactions | Discovery of regulatory partners |
Biochemical assays for thiol S-methyltransferase activity
Classic assays measure the formation of radiolabeled thioether products from 14C-SAM or the disappearance of thiol substrates using HPLC or mass spectrometry [3,6,8]. These assays can be performed on tissue homogenates, erythrocyte membranes, or recombinant enzymes [2,6].
CRISPR-based genetic screens
Genome-wide CRISPR knockout screens can identify genes required for thiol S-methyltransferase activity, as demonstrated by the identification of METTL7A and METTL7B. Such screens use a functional readout, such as thioether production or cell survival in the presence of thiol drugs.
Proteomics and interactomics
Affinity purification coupled with mass spectrometry can identify proteins interacting with METTL7A or METTL7B, revealing potential regulatory subunits or substrate adaptors. Quantitative proteomics can also measure changes in enzyme abundance across tissues or disease states.
Expression profiling and transcriptomics
RNA-seq can quantify METTL7A and METTL7B expression across tissues and conditions, helping to correlate expression with activity. Single-cell RNA-seq can reveal cell-type-specific expression in complex tissues like intestine.
How CRISPR Can Be Used to Study GO:0018708 thiol S-methyltransferase activity
Knockout
CRISPR knockout of METTL7A or METTL7B can abolish thiol S-methyltransferase activity in liver-derived cell lines, providing causal evidence for their role. Double knockout can reveal redundancy or compensatory mechanisms.
Point Mutation
Introducing point mutations in the catalytic domain of METTL7A or METTL7B can dissect the enzymatic mechanism and identify essential residues. Such models are useful for separating methyltransferase activity from other functions.
Knock-in
Knock-in of tagged versions (e.g., FLAG, GFP) of METTL7A or METTL7B allows for localization and interaction studies without altering endogenous regulation. Knock-in of disease-associated variants can model altered activity.
Overexpression
Overexpression of METTL7A or METTL7B in cell lines such as HEK293 can increase thiol S-methyltransferase activity, enabling substrate specificity studies and drug metabolism assays.
How EDITGENE Supports thiol S-methyltransferase activity Research
Researchers studying thiol S-methyltransferase activity-related genes often need to determine whether a candidate gene is causally involved in the enzymatic reaction or its regulation. This requires precise genetic models that can knockout, mutate, or overexpress the gene of interest in relevant cell types.
Contact EDITGENE today to design your custom CRISPR model for thiol S-methyltransferase activity research.
Frequently Asked Questions About thiol S-methyltransferase activity
What is thiol S-methyltransferase activity?
Thiol S-methyltransferase activity (GO:0018708) is a molecular function that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to a thiol substrate, producing S-adenosyl-L-homocysteine and a thioether.
What genes are involved in thiol S-methyltransferase activity?
The main genes are METTL7A (TMT1A) and METTL7B (TMT1B), which are responsible for alkyl S-thiol methyltransferase activity in liver. TPMT can also methylate some overlapping substrates.
Which drugs are metabolized by thiol S-methyltransferase?
Captopril, N-acetylcysteine, penicillamine, and diethyldithiocarbamate are known substrates [3,4,6,8].
Where is thiol S-methyltransferase activity found in the body?
It is present in erythrocyte membranes, colonocytes, intestine, and liver [2,3,6,7].
How is thiol S-methyltransferase activity measured?
It is measured using radiolabeled SAM assays, HPLC, or LC-MS/MS to detect thioether products or substrate depletion [3,6].
What is the difference between thiol S-methyltransferase and thiopurine methyltransferase?
Thiol S-methyltransferase (TMT) and thiopurine methyltransferase (TPMT) are distinct enzymes, but both can methylate certain thiol substrates, requiring careful assay design to distinguish them.
Is thiol S-methyltransferase activity altered in disease?
Yes, altered activity has been observed in inflammatory bowel disease.
Can CRISPR be used to study thiol S-methyltransferase activity?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect the function of METTL7A, METTL7B, and other genes.
What is the reaction catalyzed by thiol S-methyltransferase?
S-adenosyl-L-methionine + a thiol = S-adenosyl-L-homocysteine + a thioether.
What are the synonyms for thiol S-methyltransferase activity?
Synonyms include S-adenosyl-L-methionine:thiol S-methyltransferase activity, thiol methyltransferase activity, and TMT.
Conclusion
Thiol S-methyltransferase activity (GO:0018708) is a key molecular function involved in the methylation of thiol compounds, with important roles in drug metabolism and intestinal disease [1,5]. The identification of METTL7A and METTL7B as the principal enzymes has advanced our understanding of this activity. Researchers can leverage CRISPR-based models to further dissect its regulation and contribution to human health.
References
- 1. Russell DA et al.. 2023. METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver.. Drug Metab Dispos 51(8):1024-1034 PMID: 37137720
- 2. Babidge WJ et al.. 1995. Thiol methyltransferase activity in colonocytes and erythrocyte membranes.. J Clin Pathol 48(7):641-4 PMID: 7560171
- 3. Drummer OH et al.. 1983. S-methylation of captopril. Demonstration of captopril thiol methyltransferase activity in human erythrocytes and enzyme distribution in rat tissues.. Biochem Pharmacol 32(10):1557-62 PMID: 6344869
- 4. Glauser TA et al.. 1993. Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase.. J Pharmacol Exp Ther 266(1):23-32 PMID: 8392551
- 5. Roediger WE et al.. 2000. Thiol methyltransferase activity in inflammatory bowel disease.. Gut 47(2):206-10 PMID: 10896911
- 6. Keith RA et al.. 1984. Human erythrocyte membrane thiol methyltransferase. S-methylation of captopril, N-acetylcysteine, and 7 alpha-thio-spirolactone.. Drug Metab Dispos 12(6):717-24 PMID: 6150821
- 7. Pacifici GM et al.. 1993. S-methyltransferases in human intestine: differential distribution of the microsomal thiol methyltransferase and cytosolic thiopurine methyltransferase along the human bowel.. Xenobiotica 23(6):671-9 PMID: 8212740
- 8. Keith RA et al.. 1985. S-Methylation of D- and L-penicillamine by human erythrocyte membrane thiol methyltransferase.. Drug Metab Dispos 13(6):669-76 PMID: 2867869
