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Antioxid Redox Signal. 2018 Mar 1;28(7):574-590. doi: 10.1089/ars.2017.7214. Epub 2017 Sep 8.

Hyperoxidation of Peroxiredoxins: Gain or Loss of Function?

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1 Institute for Cell and Molecular Biosciences, Newcastle University , Newcastle upon Tyne, United Kingdom .
2 Newcastle University Institute for Ageing, Newcastle University , Newcastle upon Tyne, United Kingdom .
3 School of Life Sciences, University of KwaZulu-Natal , Pietermartizburg, South Africa .



In 2003, structural studies revealed that eukaryotic 2-Cys peroxiredoxins (Prx) have evolved to be sensitive to inactivation of their thioredoxin peroxidase activity by hyperoxidation (sulfinylation) of their peroxide-reacting catalytic cysteine. This was accompanied by the unexpected discovery, that the sulfinylation of this cysteine was reversible in vivo and the identification of a new enzyme, sulfiredoxin, that had apparently co-evolved specifically to reduce hyperoxidized 2-Cys Prx, restoring their peroxidase activity. Together, these findings have provided the impetus for multiple studies investigating the purpose of this reversible, Prx hyperoxidation. Recent Advances: It has been suggested that inhibition of the thioredoxin peroxidase activity by hyperoxidation can both promote and inhibit peroxide signal transduction, depending on the context. Prx hyperoxidation has also been proposed to protect cells against reactive oxygen species (ROS)-induced damage, by preserving reduced thioredoxin and/or by increasing non-peroxidase chaperone or signaling activities of Prx.


Here, we will review the evidence in support of each of these proposed functions, in view of the in vivo contexts in which Prx hyperoxidation occurs, and the role of sulfiredoxin. Thus, we will attempt to explain the basis for seemingly contradictory roles for Prx hyperoxidation in redox signaling.


We provide a rationale, based on modeling and experimental studies, for why Prx hyperoxidation should be considered a suitable, early biomarker for damaging levels of ROS. We discuss the implications that this has for the role of Prx in aging and the detection of hyperoxidized Prx as a conserved feature of circadian rhythms. Antioxid. Redox Signal. 28, 574-590.


2-Cys peroxiredoxin; aging; chaperone; circadian rhythm; signaling; sulfiredoxin; thioredoxin

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