Fig. 1.

Oxidative modifications of cysteine (A and B) and histidine (C) residues in proteins induced by H₂O₂. In cells, sulfhydryl (SH) groups of cysteine residues with low pKa may ionize forming thiolates. Thiolates are good nucleophiles and form a sulfenic acid (SOH) upon reaction with H₂O₂ (reaction 1). Once formed, the SOH can be reduced to a disulfide by a reaction with the SH group of another cysteine residue either in the same (reaction 7) or in a second protein (reaction 5). Alternatively, a SOH can react with the low molecular weight thiol glutathione (GSH) (reaction 4) to form a mixed disulfide in a reaction known as S-glutathionylation or S-thiolation. In an event where a neighboring cysteine residue or GSH is absent, the amide nitrogen of a neighboring amino acid residue can attack the SOH to form a sulfenamide (reaction 6). This reaction occurs in PTP1B. The SOH can also react further with H₂O₂ to generate more oxidized forms of sulfur, the sulfinic acid (SO₂H) (reaction 2) and sulfonic acid SO₃H (reaction 3). Disulfides can be reduced back to thiols using the thioredoxin/thioredoxin reductase and glutaredoxin/GSH/glutathione reductase systems. Sulfinic acids in 2-cys Prxs, but not other proteins, can be reduced to thiols using the enzyme sulfiredoxin [372]. No known enzyme is able to catalyze the reduction of sulfonic acids in proteins. In proteins containing iron metal centers such as PerR, histidine residues can be oxidized by H₂O₂ in a Fenton-like reaction possibly involving the formation of the hydroxyl radical as an intermediate, to form 2-oxo-histidine.