FIG. 6.

Hypothetical persulfidation-based thiol protection. a, In the unstressed state, Cys residues in proteins or metabolites will generally be in the reduced thiol form. b, Exposure to H₂O₂ yields the unstable sulfenic acid. c, Whereas this will typically react with another thiol to yield a disulfide, in the presence of H₂S, a persulfide can form, which will spontaneously ionize to the reactive perthiolate anion at physiological pH. d, The reactive perthiolate anion can react with H₂O₂, yielding persulfenylate anion. This might further react with H₂O₂, yielding persulfinylate and persulfonylate anions (in combination, these overoxidized forms designated “-SSOx”). e, Reduction of the disulfide bond in any of the -SSOx species by TRX1, TRP14, or GRX will regenerate the active thiol on the original substrate and liberate an oxidized inorganic S product, designated “SOx.” GRX, glutaredoxin; H₂O₂, hydrogen peroxide; H₂S, hydrogen sulfide; TRP14, thioredoxin-related protein of 14 kDa; TRX1, thioredoxin-1.