Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides

Abstract

Peroxiredoxins (Prxs) contain an active site cysteine that is sensitive to oxidation by H(2)O(2). Mammalian cells express six Prx isoforms that are localized to various cellular compartments. The oxidized active site cysteine of Prx can be reduced by a cellular thiol, thus enabling Prx to function as a locally constrained peroxidase. Regulation of Prx via phosphorylation in response to extracellular signals allows the local accumulation of H(2)O(2) and thereby enables its messenger function. The fact that the oxidation state of the active site cysteine of Prx can be transferred to other proteins that are less intrinsically susceptible to H(2)O(2) also allows Prx to function as an H(2)O(2) sensor.

FIGURE 1.

Reaction mechanisms of Prx enzymes. The reaction mechanisms of 2-Cys Prx (A), atypical 2-Cys Prx (B), and 1-Cys Prx (C) enzymes are shown. TrxR, Trx reductase.

FIGURE 2.

Antioxidant roles of Prx I, Prx III, and Srx in ethanol-fed mouse liver. EtOH feeding increases the abundance of CYP2E1 in the ER. A large proportion of Prx I is present at the cytosolic side of the ER membrane, where CYP2E1 is located. Prx I is therefore preferentially engaged in the reduction of ROS produced by CYP2E1 and becomes hyperoxidized. Reactivation of such hyperoxidized Prx I requires the action of Srx, the expression of which is greatly increased via an Nrf2- and antioxidant regulatory element (ARE)-dependent pathway in the livers of ethanol-fed mice. Ethanol feeding also increases the abundance of CYP2E1 and the production of ROS in mitochondria, likely resulting in hyperoxidation of Prx III that is reversed in part by translocation of Srx from the cytosol into mitochondria.

FIGURE 3.

Model for mechanism underlying H₂O₂ accumulation around lipid rafts and its role in intracellular signaling. See text for details.

FIGURE 4.

Role of Prx IV as H₂O₂ sensor for protein folding in ER. Oxidation of thiols to disulfide linkages during protein folding in the ER is achieved with the use of H₂O₂ produced by oxidant-generating sources such as Ero1, NADPH oxidase, and mitochondria. Ero1 produces H₂O₂ by transferring electrons from reduced PDI to O₂. In the proposed model, C_P–SH and C_R–SH of Prx IV are first oxidized by H₂O₂ to form a disulfide. The oxidized state of Prx IV is then transferred to PDI thiols, thereby converting them to a disulfide and finally resulting in the formation of a disulfide in the protein to be folded. Prx IV in the ER physically interacts with PDI. It is thus thought to function as a sensor of H₂O₂ in PDI-mediated protein folding.