Selenium in Thioredoxin Reductase is Critical for Catalysis

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(Last Updated On: April 2, 2020)
selenocysteine in thioredoxin reductase acts as an electron carrier
Selenocysteine present in the Thioredoxin Reductase is a critical part of catalysis during which it acts as an electron carrier. Image: (Lothrop et al.; 2014)

Mammalian thioredoxin reductase is a selenium-containing selenoenzyme. It contains selenocysteine instead of cysteine and selenium of selenocysteine acts as an electron acceptor during the catalysis. Selenium in the thioredoxin reductase is critical for catalysis because it has some important properties as it acts as a better nucleophile than a thiolate. It also acts as a better electrophile in the form of selenosulfide than a sulfide group. It is a better leaving group and more reactive than that of the thiolate/disulfide group.


Selenoenzymes, such as thioredoxin reductase is involved in thiol/disulfide exchange reactions in which selenocysteine of the enzyme replaces the cysteine of the substrate to create selenosulfide linkage. First, selenolate of the selenocysteine in then Cys497-Sec498 dyad acts as the donor of electrons, donating electrons to the thiol group of the substrate. In the second step, it acts as an electron acceptor, accepting electrons from the N-terminal redox center of the enzyme thioredoxin reductase. NADPH is the ultimate source of electron donor to the enzyme’s N-terminal redox center.

To confirm that selenium acts as an electron acceptor in the selenoenzyme thioredoxin reductase, a team of researchers from the Department of Biochemistry, University of Vermont, College, USA and Department of Chemistry and Biochemistry, Florida International University, USA performed mutagenesis in the enzyme.

They created a mutated enzyme in whichCys497-Sec498 dyad was replaced by the Ser497-Cys498 dyad. Mutated thioredoxin reductase was incubated with the C35S/C73S mutant human thioredoxin-1 substrate. Researchers found a mixed disulfide-bonded complex between Cys498 of thioredoxin reductase and Cys32 of the human thioredoxin-1 substrate indicating that Sec498 of the enzyme in the wild type is the attacking nucleophile in the thiol/disulfide exchange reaction.

After reducing the substrate, the C-terminal of the enzyme Cys497-Sec498 dyad becomes oxidized forming 8 membered ring containing selenosulfide linkages. This selenosulfide bridge undergoes another thiol/disulfide exchange reaction with the N-terminal redox center as mentioned earlier.

A similar result was obtained when researchers carried out a mutation in the enzyme by replacing selenocysteine with homocysteine. All these findings reveal that only if selenocysteine is present next to the cysteine in the 498th position of the polypeptide chain, the enzyme is catalytically active.

Reference: American Chemical Society (Selenium as an Electron Acceptor during the Catalytic Mechanism of Thioredoxin Reductase)
Article DOI: 10.1021/bi400658g

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