Selenoproteins and the Thioredoxin System

Abstract

The thioredoxin system, comprising NADPH, flavoprotein thioredoxin reductase (TrxR), and 12 kDa thioredoxin (Trx) with a catalytic dithiol/disulfide, is the ubiquitous biological cellular disulfide reduction system with major functions in DNA synthesis, defense against oxidative stress, and thiol redox control. In mammalian cells Trx system activity is controlled by the three TrxR isoenzymes which are large homodimeric selenoproteins. The availability of selenium affects not only the Trx system activity but also the existing form of TrxR. Selenium-deficient conditions cause the increase of a low activity form of TrxR, in which a cysteine residue substitutes for selenocysteine (Sec). On the other hand, the Trx system can reduce selenite into selenide, which is required for Sec residue synthesis in proteins. Trx system activity in turn may regulate the redox state and subcellular translocation of Sec insertion sequence element-binding protein 2 (SBP2) and Sec incorporation efficiency in all selenoproteins. The overall structure of TrxR is similar to that of glutathione reductase, but with a C-terminal elongation of 16 residues containing the conserved C-terminal active-site sequence –Gly–Cys–Sec–Gly. In oxidized TrxR, the active site is a selenenylsulfide, which is reduced to a catalytic selenolthiol by electrons from the redox-active disulfide/dithiol of the other subunit, as revealed by three-dimensional structures of the rat TrxR1 enzymes. The critical role of Sec in TrxR and its accessible location and reactivity in the C-terminal active site provide promising pharmaceutical drug targets for various human diseases such as malignant cancer and rheumatoid arthritis.