Figure 1.

The catalytic and regulatory cycles of 2-Cys peroxiredoxins (Prxs). Shown in brown is the normal Prx cycle with the structure of the peroxidatic Cys (C_P) residue shown for each redox state (carbons are colored gray, nitrogens blue, oxygens red, and sulfurs yellow; hydrogens are not shown for simplicity). The C_P thiolate (RS⁻) in the fully folded (FF) active site is first oxidized by the peroxide to form the sulfenic acid (R-SOH) or sulfenate (R-SO⁻) (computational approaches suggest stabilization of the C_P as the sulfenate, but the true protonation state is as yet uncertain). This sulfenate, which must undergo a conformational change to become locally unfolded (LU), then forms a disulfide bond with the resolving Cys (C_R) in 2-Cys Prxs. Reductive recycling by thioredoxin (Trx) or a Trx-like protein or domain (e.g., tryparedoxin or the N-terminal domain of bacterial AhpF) then restores the thiolate in the FF active site for another catalytic cycle. Shown in blue is the redox-linked regulatory cycle of predominantly eukaryotic Prxs, wherein the C_P sulfenate becomes further oxidized, in the presence of high peroxide levels, to the inactive sulfinate (R-SO₂⁻). In some organisms and Prx isoforms the active enzyme is restored by the ATP-dependent activity of sulfiredoxin (Srx).