Irreversible Inactivation of Glutaredoxins 1 and 2 by Peroxynitrite

Formation of a mixed disulfide between a protein thiol and glutathione, i.e. S-glutathionylation (or S-glutathiolation), is considered a potential regulatory mechanism especially under oxidative stress.1-3 Most enzymes with an active site cysteine lose activity upon S-glutathionylation and regain activity when reduced by thiols. While the cellular mech-anism of S-glutathionylation remains unresolved, degluta-thionylation is known to be catalyzed by glutaredoxins.3 Glutaredoxins 1 and 2 are disulfide-dithiol oxidoreduc-tases localized in cytosol and mitochondrial matrix, respec-tively.4 They catalyze the transfer of a glutathione moiety from an S-glutathionylated protein to glutathione. Gluta-redoxin 1 (Grx1) contains a conserved CPYC sequence with the N-terminal cysteine having a very low pKa. A similar CSYC motif is found in Grx2. As expected, down-regulatio