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Review
, 39 (1), 31-9

Microbial 2-Cys Peroxiredoxins: Insights Into Their Complex Physiological Roles

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Review

Microbial 2-Cys Peroxiredoxins: Insights Into Their Complex Physiological Roles

Michel B Toledano et al. Mol Cells.

Abstract

The peroxiredoxins (Prxs) constitute a very large and highly conserved family of thiol-based peroxidases that has been discovered only very recently. We consider here these enzymes through the angle of their discovery, and of some features of their molecular and physiological functions, focusing on complex phenotypes of the gene mutations of the 2-Cys Prxs subtype in yeast. As scavengers of the low levels of H2O2 and as H2O2 receptors and transducers, 2-Cys Prxs have been highly instrumental to understand the biological impact of H2O2, and in particular its signaling function. 2-Cys Prxs can also become potent chaperone holdases, and unveiling the in vivo relevance of this function, which is still not established, should further increase our knowledge of the biological impact and toxicity of H2O2. The diverse molecular functions of 2-Cys Prx explain the often-hard task of relating them to peroxiredoxin genes phenotypes, which underscores the pleiotropic physiological role of these enzymes and complex biologic impact of H2O2.

Keywords: H2O2 scavenging; H2O2 signaling; chaperone; peroxiredoxins.

Figures

Fig. 1.
Fig. 1.
The two catalytic cycles of 2-Cys Prxs (Noichri et al., 2015). 2-Cys Prx are obligate head-to-tail B-type homodimers, each with two catalytic Cys residues. In the peroxidatic cycle, the N-terminal Cys, named CP for peroxidatic Cys, reduces H2O2 by direct reaction with release of one H2O molecule, and is in turn oxidized to a sulfenic acid (CP-SOH) (Wood et al., 2003). The Cys-sulfenic acid moiety then condenses with the C-terminal catalytic Cys residue of the other subunit, or resolving Cys (CR) into an intermolecular disulfide, with release of the second H2O molecule. Disulfide formation causes an important structural remodeling both at the CP-active site pocket and CR-containing C-terminal domain, which switches the enzyme structure form a fully folded (FF) to a locally unfolded (LU) conformation (Hall et al., 2011; Wood et al., 2003). Karplus and coworkers have elegantly shown that the enzyme FF conformation both stabilizes the deprotonated reactive form of CP and provides a steric and electrostatic environment that activates H2O2, hence establishing the observed CP extraordinary high reactivity for H2O2 (Hall et al., 2010; Karplus, 2015). The catalytic intermolecular disulfide is subsequently reduced by thioredoxin, which completes the catalytic cycle, returning the enzyme to the FF conformation. In the sulfinic acid cycle however, the CP-SOH further reacts with H2O2 instead of condensing with CR, thus becoming oxidized to the corresponding sulfinic acid (−SO2H), which exit the enzyme from the peroxidatic cycle. Sulfinylated Prx undergoes a slow ATP-dependent reduction by the enzyme sulfiredoxin (Srx), which returns the enzyme into the peroxidatic cycle (Biteau et al., 2003; Woo et al., 2003). Sensitivity of eukaryotic enzymes to hyperoxidation is linked to the presence of two sequence fingerprints absent in other family enzymes, an insertion in the loop between α4 and β5 carrying the conserved GGLG motif, and an additional helix (α7) occurring as a C-terminal extension and containing the conserved YF motif (Wood et al., 2003). Such a structural configuration is thought to slow down the FF to LU transition rate, thereby favoring hyperoxidation.
Fig. 2.
Fig. 2.
2-Cys Prxs enzymatic cycling involves dramatic changes in quaternary structure (Noichri et al., 2015). See the text.
Fig. 3.
Fig. 3.
Loss-of function mutations of cytosolic thioredoxin reductase-encoding TRR1 suppress defects in H2O2 scavenging and protein quality control linked to the loss of TSA1 (MacDiarmid et al., 2013; Ragu et al., 2014). Suppression is indicated in red arrows (see text).

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