Overview of peroxiredoxins in oxidant defense and redox regulation

Abstract

Peroxiredoxins are important hydroperoxide detoxification enzymes, yet have only come to the fore in recent years relative to the other major players in peroxide detoxification, heme-containing catalases and peroxidases and glutathione peroxidases. These cysteine-dependent peroxidases exhibit high reactivity with hydrogen peroxide, organic hydroperoxides, and peroxynitrite and play major roles not only in peroxide defense, but also in regulating peroxide-mediated cell signaling. This overview focuses on important peroxiredoxin features that have emerged over the past several decades with an emphasis on catalytic mechanism, regulation, and biological function.

Figure 1

The catalytic cycle of Prx. The three main chemical steps of catalysis are (1) peroxidation, forming the sulfenic acid at the peroxidatic cysteine (S_pOH), (2) resolution which generates a disulfide bond, and (3) recycling by reduction to return the enzyme to its peroxide-reactive state. The cycle requires two conformational states; the fully folded (FF), intact active site is needed for peroxidation, whereas a structural rearrangement to generate the locally unfolded (LU) form is required for resolution. Redox-dependent regulation of Prxs may occur through a second step of peroxide-mediated oxidation of the sulfenic acid when peroxide concentrations are high, and the inactivated enzyme may be rescued through an ATP-dependent reaction catalyzed by sulfiredoxin (Srx). This generic Prx emphasizes the chemistry at the peroxidatic cysteine, with the resolving thiol group (R’S_rH) coming either from the Prx itself or another molecule. R” in the recycling step typically represents disulfide-reducing proteins such as Trx and AhpF.

Figure 2

Oligomeric interfaces and quanternary structures of Prxs. Dimerization of Prx subunits can occur through two different types of interfaces, the A-type interface (as observed for Tpx and Prx5 subfamily members), or the B-type interface which brings the β sheets together to form an extended sheet (as observed for PrxI/AhpC and Prx6 subfamilies). Some members of the PrxI/AhpC and Prx6 subfamilies also form decameric, or less commonly dodecameric or octameric, structures built from B-type dimers through interaction at their A-type interfaces.

Figure 3

Interactions around the Prx active site with bound hydroperoxide substrate. The stabilizing hydrogen bonding interactions (dotted lines) between key atoms from the backbone and the four conserved residues, and with the ROOH substrate, are indicated. The geometry of the active site is ideal for stabilizing the larger distance between O_A and O_B atoms as the bond is broken. Adapted from (Hall, et al., 2010).