The Role of Peroxiredoxins in the Transduction of H2O2 Signals

Abstract

Hydrogen peroxide (H₂O₂) is produced on stimulation of many cell surface receptors and serves as an intracellular messenger in the regulation of diverse physiological events, mostly by oxidizing cysteine residues of effector proteins. Mammalian cells express multiple H₂O₂-eliminating enzymes, including catalase, glutathione peroxidase (GPx), and peroxiredoxin (Prx). A conserved cysteine in Prx family members is the site of oxidation by H₂O₂. Peroxiredoxins possess a high-affinity binding site for H₂O₂ that is lacking in catalase and GPx and which renders the catalytic cysteine highly susceptible to oxidation, with a rate constant several orders of magnitude greater than that for oxidation of cysteine in most H₂O₂ effector proteins. Moreover, Prxs are abundant and present in all subcellular compartments. The cysteines of most H₂O₂ effectors are therefore at a competitive disadvantage for reaction with H₂O₂. Recent Advances: Here we review intracellular sources of H₂O₂ as well as H₂O₂ target proteins classified according to biochemical and cellular function. We then highlight two strategies implemented by cells to overcome the kinetic disadvantage of most target proteins with regard to H₂O₂-mediated oxidation: transient inactivation of local Prx molecules via phosphorylation, and indirect oxidation of target cysteines via oxidized Prx. Critical Issues and Future Directions: Recent studies suggest that only a small fraction of the total pools of Prxs and H₂O₂ effector proteins localized in specific subcellular compartments participates in H₂O₂ signaling. Development of sensitive tools to selectively detect phosphorylated Prxs and oxidized effector proteins is needed to provide further insight into H₂O₂ signaling. Antioxid. Redox Signal. 28, 537-557.

Keywords: hydrogen peroxide; intracellular messenger; peroxiredoxin; thiol oxidation.