FIG. 3.
Multiple chemical roles for selenium in the catalytic mechanism of thioredoxin reductase (TR). (A) Nucleophilic attack–Selenium acts as a nucleophile to attack the disulfide bond of thioredoxin (Trx). (B) Resolution step–Selenium acts as an electrophile so that the mixed selenosulfide bond between TR and Trx is resolved to release the reduced product. (C) Ring opening step–The interchange Cys residue (CysIC) has the choice of either: (1) attacking the selenium atom of the eight-membered ring (electrophile), or (2) attacking the sulfur atom of the ring (leaving group). (D) Regeneration of selenolate: If path (1) is used in (C), then the selenosulfide bond between the N-terminal and C-terminal redox center must be resolved. In this case, selenium would be in the leaving group position.