Thiol groups of cysteine residues in protein have long been known as vulnerable sites, prone to alkylation by electrophiles as well as to oxidation by prooxidant agents, with formation in the latter case of intra- and intermolecular disulfide bridges. A number of studies have shown that such modifications of protein thiols are responsible of the cytotoxic effects of several toxins and drugs (see, e.g., 1 – 3 . Recent experimental evidence has however documented that alterations in the redox status of cellular protein thiols can also mediate the nontoxic, physiological role exhibited by free radicals and other prooxidant species in modulating the function of growth factor receptors, protein kinases, and transcription factors ( 4 – 6 ). Also, the pathophysiological potential of reactions of S-thiolation and dethiolation in the modulation of several enzymatic activities has been established ( 7 , 8 ).Asimplified outline of the main factors involved in modification of redox status of protein thiols is reported in Fig. 1 . Fig. 1. Factors involved in reversible modification of protein sulfhydryl groups. [1] Protein thiols may be oxidized and form intra- and intermolecular disulfide bonds, due to the action of prooxidant agents (e.g., diamide, hydrogen peroxide, free radicals) as well as following the action of enzyme activities (protein disulfide isomerase). [2] Several reducing agents (e.g., dithiothreitol, 2-mercaptoethanol) can reduce disulfides back to free thiols; such action is enzymatically performed by thioredoxin as well.
