Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewPeroxiredoxins as biomarkers of oxidative stress☆
Introduction
Peroxiredoxins (Prxs) are a class of thiol peroxidases that degrade hydroperoxides to water [1], [2]. Catalase and glutathione peroxidases also remove hydroperoxides, and these enzymes were considered to be the major enzymes responsible for protecting cells against hydroperoxides. However, recent data on the reactivity and abundance of the Prxs has revealed them to also be prominent members of the antioxidant defence network. There are indications that the role of Prxs in antioxidant defence is more complex than the removal of hydroperoxides. Prxs can be easily inactivated by hydrogen peroxide, disabling peroxidase activity and thereby limiting their ability to act as antioxidants [3]. Eukaryote Prxs are considerably more susceptible to oxidative inactivation than prokaryote family members, suggesting a gain-of-function that has been selected by evolution [4]. Prxs have complex oligomeric structures that are influenced by the redox state of the protein [5], [6], [7]. This combined knowledge has led to the hypothesis that Prxs act as redox sensors, regulating signal transduction pathways upon oxidation [8], [9].
Redox sensors detect disturbances in redox homeostasis, and as such, they are ideal entities to monitor for signs of oxidative stress. Many redox signalling models invoke transient and localized generation of reactive oxygen species. Markers of global protein and lipid oxidation associated with oxidative damage are insufficiently sensitive for detecting subtle modulations of redox homeostasis. To aid this endeavour, an array of redox reporter probes has become available for experimental use. An alternate approach is to specifically monitor endogenous redox-sensitive proteins. This review discusses the biochemical properties of the Prxs that make them suitable as sensitive biomarkers of oxidative stress, describes current methodology for measuring Prx oxidation in biological samples, and highlights studies where oxidation has been reported.
Section snippets
Biochemical properties of the Prxs
Prxs are highly conserved proteins that have been identified in all phyla. Many species contain more than one Prx; mammals have six different Prxs, with Prxs 1, 2 and 6 located in the cytosol, Prx 3 in the mitochondrial matrix, Prx 4 in the endoplasmic reticulum and Prx 5 in mitochondria, peroxisomes and the cytosol. Prx activity is characterised by a peroxidatic cysteine that is oxidized to a sulfenic acid by hydroperoxides including hydrogen peroxide, organic peroxides, peptide and protein
Prxs as markers of oxidative stress
The oxidized dimer of the typical 2-Cys Prxs accumulates during the breakdown of hydroperoxides, both because the rate of oxidation is faster than the rate of reduction and that Prxs are present at higher concentrations in cells than the major reductant thioredoxin. The extent of the bottleneck will vary depending on cell type and metabolic status, but monitoring the redox status of the 2-Cys Prxs could reveal subtle alterations in the rate of hydroperoxide generation, or impairment of the
Summary
Several features of the Prxs make measurement of their redox state a valuable biomarker of oxidative stress. They are abundant and highly reactive proteins, and oxidation has been observed where few if any other redox modifications are detectable. This enables detection of more subtle disturbances in redox homeostasis that could occur during signalling events, although sensitivity will vary between cell types depending on the robustness of their reduction systems. The varied intracellular
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This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.