Fig. 4.

Functional modifications of the Cys proteome. Protein Cys (RSH) undergoes a range of enzymatic and non-enzymatic modifications, often mediated by pH-dependent ionization to Cys thiolate (RS⁻; large yellow sphere). Interaction of RS⁻ with metal ions (blue) is common as a structural element, as a binding motif for nucleic acids and as a component of catalytic sites. RS⁻ is subject to oxidation ([O]) to Cys sulfenate (RSO⁻, yellow) by H₂O₂ and other 2-electron oxidants. Thiol (RSH) also undergoes exchange with disulfide (R₁S-SR₁) to generate different thiol (R₁SH) and disulfide (RS-SR₁) in a process termed thiol-disulfide exchange. Non-equilibrium steady-state oxidation of specific RSH occurs due to the presence of low nanomolar concentrations of H₂O₂ in cells. RSO⁻ reacts with RSH or GSH to produce the respective disulfides (RSSR, RSSG; dark yellow, top). Many RSO⁻ can undergo hyperoxidation to sulfinate (RSO₂⁻; orange, bottom) and sulfonate (RSO₃⁻; red) in the presence of excess oxidant. RS⁻ also reacts with hypothiocyanous acid (HOSCN) to produce sulfenyl thiocyanate (RSSCN; dark yellow, upper left), which rapidly hydrolyzes, and with nitric oxide through multiple means of nitronium ion transfer (NO⁺) to produce a corresponding nitrosothiol (RSNO; orange, bottom left). RSO⁻ can also react with hydrogen sulfide (HS⁻) to form a cysteinyl persulfide (RSS⁻, green), which can be oxidized to a cysteinyl thiosulfate (RSSO₃⁻). Alternatively, RSO⁻ can react with primary amines of neighboring amino acids or separate biomolecules to form sulfenamide (RSNHR) which can be further oxidized to sulfinamide (RS(O)NHR) and sulfonamide (RS(O)₂NHR), frequently resulting in cyclic intramolecular structures.