GO:0098625 methylselenol reductase activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0098625 methylselenol reductase activity catalyzes the NADPH-dependent reduction of methaneseleninic acid (CH3SeOH) to methylselenol (CH3SeH), producing NADP+ and water.
• Methylselenol is a central selenium metabolite that can be generated from Se-methylated selenocompounds via β-lyase and demethylase activities.
• Methylselenol is a superior substrate for thioredoxin and glutaredoxin systems compared to other selenium metabolites.
• Methylselenol induces toxic protein aggregation in yeast, linking this activity to proteostasis and cell death.
• Methylselenol and related selenometabolites modulate redox signaling, including regulation of protein kinase C and thioredoxin reductase.
• The enzyme activity is part of selenium metabolism and has implications for cancer chemoprevention and selenium toxicity.
Description
Methylselenol reductase activity (GO:0098625) is a molecular function that catalyzes the NADPH-dependent reduction of methaneseleninic acid (CH3SeOH) to methylselenol (CH3SeH), yielding NADP+ and water. This reaction is part of the broader metabolism of selenium compounds, where methylselenol serves as a key intermediate in the production of selenide and other selenium metabolites. The activity is essential for understanding how selenium, an essential micronutrient, is processed in cells and how its metabolites exert biological effects. Researchers study methylselenol reductase activity because methylselenol is a highly reactive selenium species that can influence redox signaling, protein function, and cell fate. Its production from Se-methylated selenocompounds has been linked to cancer chemoprevention, as methylselenol can inhibit tumor cell growth and induce apoptosis. Moreover, methylselenol can cause toxic protein aggregation in yeast, highlighting its potential to disrupt proteostasis. Thus, GO:0098625 represents a critical node in selenium metabolism with wide-ranging implications for health and disease.
methylselenol reductase activity At A Glance
| GO ID | GO:0098625 |
|---|---|
| GO term | methylselenol reductase activity |
| Ontology | molecular_function |
| Synonym | none |
| Major function | Catalyzes the NADPH-dependent reduction of methaneseleninic acid to methylselenol |
| Reaction | NADPH + H+ + CH3SeOH = NADP+ + CH3SeH + H2O |
| Cofactor | NADPH |
| Substrate | Methaneseleninic acid (CH3SeOH) |
| Product | Methylselenol (CH3SeH) |
What Is GO:0098625?
Methylselenol reductase activity is defined as the catalysis of the reaction: NADPH + H+ + CH3SeOH = NADP+ + CH3SeH + H2O. In other words, it is an oxidoreductase that uses NADPH to reduce methaneseleninic acid to methylselenol, releasing water and NADP+.
Why Is methylselenol reductase activity Important in Cell Biology?
Methylselenol reductase activity is important because it produces methylselenol, a key selenium metabolite with potent redox activity and anticancer properties. Methylselenol can modulate signaling pathways and induce cell death in cancer cells, making this activity a potential target for chemoprevention. Additionally, methylselenol can cause protein aggregation, linking selenium metabolism to proteotoxic stress.
• Produces methylselenol, a central metabolite in selenium metabolism.
• Methylselenol is a superior substrate for thioredoxin and glutaredoxin systems.
• Involved in cancer chemoprevention by selenium compounds.
• Methylselenol induces toxic protein aggregation in yeast.
• Modulates redox regulation of protein kinase C.
• Methylseleninate is a substrate for mammalian thioredoxin reductase.
• Se-methylselenocysteine is converted to methylselenol by β-lyase.
• Methylselenoesters show antiproliferative activity.
• Selenium metabolites influence epithelial and non-epithelial target cells.
• Potential target for selenium-based therapeutics.
Molecular Mechanism of methylselenol reductase activity
Substrate Binding and Cofactor Requirement
In simple terms: The enzyme grabs methaneseleninic acid and uses NADPH as a power source.
Methylselenol reductase activity requires NADPH as a cofactor to reduce methaneseleninic acid (CH3SeOH) to methylselenol (CH3SeH). The reaction consumes a proton and produces NADP+ and water.
Catalytic Reduction of Methaneseleninic Acid
In simple terms: The enzyme transfers electrons from NADPH to break the Se-OH bond, forming methylselenol.
The catalytic mechanism involves the reduction of the seleninic acid group, likely through a series of electron transfers from NADPH, resulting in the formation of methylselenol and water. This activity is part of the metabolic pathway that converts Se-methylated selenocompounds into selenide.
Role in Selenium Metabolism
In simple terms: This enzyme helps turn selenium compounds into usable forms.
Methylselenol reductase activity contributes to the metabolism of Se-methylated selenocompounds, such as Se-methylselenocysteine, which are converted to methylselenol by β-lyase and demethylase activities. Methylselenol can then be further metabolized to selenide, which is used for selenoprotein synthesis.
Interaction with Redox Systems
In simple terms: Methylselenol interacts with cellular redox proteins.
Methylselenol formed by this activity is a superior substrate for the thioredoxin and glutaredoxin systems, influencing cellular redox balance. It can also modulate protein kinase C and thioredoxin reductase, affecting redox signaling.
Key Genes Involved in GO:0098625 methylselenol reductase activity
The following genes and proteins are involved in methylselenol metabolism and related pathways.
| Gene | Major Role | Research Relevance |
|---|---|---|
| KYAT1 | β-lyase converting Se-methylselenocysteine to methylselenol | Assay development for methylselenol production |
| TXNRD1 | Thioredoxin reductase, reduces methylseleninate | Selenium metabolism and redox regulation |
| TXN | Thioredoxin, substrate for methylselenol | Redox regulation |
| GLRX | Glutaredoxin, interacts with methylselenol | Redox regulation |
| PRKC | Protein kinase C, regulated by selenometabolites | Redox signaling |
| SELENOP | Selenoprotein P, selenium transport | Selenium metabolism |
| GPX1 | Glutathione peroxidase, antioxidant | Selenium metabolism |
| SEPHS2 | Selenophosphate synthetase, selenoprotein synthesis | Selenium metabolism |
| SLC7A11 | Cystine/glutamate transporter, affects selenium uptake | Selenium metabolism |
| GCLC | Glutamate-cysteine ligase, glutathione synthesis | Redox regulation |
| GCLM | Glutamate-cysteine ligase modifier | Redox regulation |
| NFE2L2 | Nrf2, regulates antioxidant response | Selenium and redox signaling |
| MAPK1 | ERK2, signaling kinase | Selenium effects on signaling |
| AKT1 | Akt, survival kinase | Selenium effects on signaling |
| CASP3 | Caspase-3, apoptosis executioner | Selenium-induced apoptosis |
| TP53 | p53, tumor suppressor | Selenium and cancer |
| BAX | Pro-apoptotic Bcl-2 family member | Selenium-induced apoptosis |
| BCL2 | Anti-apoptotic Bcl-2 family member | Selenium and apoptosis |
How Is methylselenol reductase activity Regulated?
Methylselenol reductase activity is regulated by the availability of its substrate methaneseleninic acid and cofactor NADPH, as well as by the expression and activity of enzymes involved in selenium metabolism, such as β-lyase and demethylase. Additionally, redox status and the presence of other selenium metabolites can influence the flux through this pathway.
methylselenol reductase activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TXNRD1 | Cancer, redox regulation | Knockout in cancer cell lines |
| KYAT1 | Selenium metabolism, cancer | Overexpression in HEK293 |
| PRKC | Cancer, redox signaling | Point mutation in PKC |
| TP53 | Cancer, apoptosis | Knock-in of p53 mutants |
| NFE2L2 | Cancer, antioxidant response | Knockout in A549 |
Cancer Chemoprevention
Methylselenol produced by methylselenol reductase activity has been implicated in cancer chemoprevention. Selenium compounds that generate methylselenol can inhibit tumor cell growth and induce apoptosis. Methylselenoesters, which can release methylselenol, show antiproliferative activity against cancer cells.
Neurodegeneration and Proteotoxicity
Methylselenol can induce toxic protein aggregation, as shown in Saccharomyces cerevisiae, suggesting that dysregulation of methylselenol production may contribute to proteotoxic stress and neurodegeneration.
Redox Signaling and Inflammation
Methylselenol modulates redox-sensitive signaling pathways, including protein kinase C and thioredoxin reductase, which are involved in inflammation and cancer. Thus, methylselenol reductase activity may influence inflammatory responses and redox homeostasis.
From methylselenol reductase activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does KO of KYAT1 reduce methylselenol production? | KYAT1 knockout cell line |
| Does point mutation in TXNRD1 affect methylseleninate reduction? | TXNRD1 point mutant knock-in |
| Can overexpression of methylselenol reductase increase methylselenol? | Overexpression cell line |
| Does tagged methylselenol reductase localize to mitochondria? | Tagged knock-in |
| Does KO of GLRX affect methylselenol toxicity? | GLRX knockout |
| Does knock-in of PRKC mutant alter redox regulation? | PRKC point mutant knock-in |
How to Study the methylselenol reductase activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| NADPH consumption assay | Enzyme activity | In vitro kinetics |
| HPLC | Methylselenol production | Metabolite quantification |
| LC-MS | Selenium metabolites | Metabolomics |
| CRISPR knockout | Gene function | Loss-of-function studies |
| CRISPR knock-in | Mutant expression | Gain-of-function studies |
| Fluorescence microscopy | Protein aggregation | Proteostasis |
| ROS probes | Redox status | Oxidative stress |
Enzymatic Assays
Methylselenol reductase activity can be measured using NADPH consumption assays or by detecting methylselenol production via HPLC or mass spectrometry.
Genetic Knockout and Knock-in
CRISPR-Cas9 can be used to generate knockout or knock-in cell lines to study the role of specific genes in methylselenol metabolism.
Redox Status Measurement
The impact of methylselenol on cellular redox can be assessed using probes for reactive oxygen species and glutathione levels.
Protein Aggregation Assays
Methylselenol-induced protein aggregation can be monitored using fluorescence microscopy or filter trap assays.
How CRISPR Can Be Used to Study GO:0098625 methylselenol reductase activity
Knockout
CRISPR knockout of genes involved in methylselenol metabolism, such as KYAT1 or TXNRD1, can reveal their contribution to methylselenol reductase activity and downstream effects.
Point Mutation
Introducing point mutations in candidate genes can help dissect catalytic residues or regulatory sites important for methylselenol reductase activity.
Knock-in
Knock-in of tagged versions of enzymes can facilitate localization and interaction studies.
Overexpression
Overexpression of methylselenol reductase or related enzymes can increase methylselenol production and enhance its biological effects.
How EDITGENE Supports methylselenol reductase activity Research
Researchers studying methylselenol reductase activity-related genes often need to determine whether a candidate gene is causally involved in selenium metabolism, redox regulation, or cancer cell growth. EDITGENE provides comprehensive CRISPR services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for methylselenol reductase activity research.
Frequently Asked Questions About methylselenol reductase activity
What is methylselenol reductase activity?
Methylselenol reductase activity (GO:0098625) is a molecular function that catalyzes the NADPH-dependent reduction of methaneseleninic acid to methylselenol, producing NADP+ and water.
What genes are involved in methylselenol reductase activity?
Genes such as KYAT1, TXNRD1, and GLRX are involved in methylselenol metabolism and related redox pathways.
What is the reaction catalyzed by methylselenol reductase?
The reaction is: NADPH + H+ + CH3SeOH = NADP+ + CH3SeH + H2O.
Why is methylselenol important?
Methylselenol is a key selenium metabolite with anticancer and redox-modulating properties.
How is methylselenol produced?
Methylselenol is produced from Se-methylated selenocompounds by β-lyase and demethylase activities, and by methylselenol reductase activity.
What diseases are associated with methylselenol reductase activity?
It is linked to cancer chemoprevention and proteotoxic stress.
Can CRISPR be used to study methylselenol reductase activity?
Yes, CRISPR knockout, knock-in, and point mutation models can be used to study genes involved in this activity.
What are the substrates and products of methylselenol reductase?
Substrate: methaneseleninic acid; products: methylselenol, NADP+, and water.
What cofactor does methylselenol reductase require?
NADPH is required as a cofactor.
How can I measure methylselenol reductase activity?
Activity can be measured by NADPH consumption assays or by detecting methylselenol via HPLC or mass spectrometry.
Conclusion
Methylselenol reductase activity (GO:0098625) is a critical enzymatic function in selenium metabolism, producing methylselenol, a metabolite with significant redox and anticancer properties. Understanding its mechanism and regulation can provide insights into cancer chemoprevention and proteotoxic stress. EDITGENE offers advanced CRISPR solutions to study this activity and its related genes.
References
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- 2. Díaz-Argelich N et al.. 2017. Novel Methylselenoesters as Antiproliferative Agents.. Molecules 22(8) PMID: 28767087
- 3. Dauplais M et al.. 2021. Methylselenol Produced In Vivo from Methylseleninic Acid or Dimethyl Diselenide Induces Toxic Protein Aggregation in Saccharomyces cerevisiae.. Int J Mol Sci 22(5) PMID: 33668124
- 4. Selvam AK et al.. 2020. A Novel Assay Method to Determine the β-Elimination of Se-Methylselenocysteine to Monomethylselenol by Kynurenine Aminotransferase 1.. Antioxidants (Basel) 9(2) PMID: 32033380
- 5. Gopalakrishna R et al.. 2018. Redox regulation of protein kinase C by selenometabolites and selenoprotein thioredoxin reductase limits cancer prevention by selenium.. Free Radic Biol Med 127:55-61 PMID: 29775743
- 6. Lü J et al.. 2005. Selenium and cancer chemoprevention: hypotheses integrating the actions of selenoproteins and selenium metabolites in epithelial and non-epithelial target cells.. Antioxid Redox Signal 7(11-12):1715-27 PMID: 16356132
- 7. Fernandes AP et al.. 2012. Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems.. PLoS One 7(11):e50727 PMID: 23226364
- 8. Gromer S et al.. 2002. Methylseleninate is a substrate rather than an inhibitor of mammalian thioredoxin reductase. Implications for the antitumor effects of selenium.. J Biol Chem 277(12):9701-6 PMID: 11782468
