Abstract
The catalytic activity of peroxiredoxins (Prx) is determined by the conserved peroxidatic cysteine (CysP), which reacts with peroxides to form sulfenic acid (Cys-SOH). Under conditions of oxidative stress, CysP is oxidized to catalytically inactive sulfinic (Cys-SO2) and sulfonic (Cys-SO3) forms. The Cys-SO2 form can be reduced in a reaction catalyzed by sulfiredoxin (Srx). To explore the physiological significance of peroxiredoxin overoxidation, we investigated daily variations in the oxidation state of 2-Cys peroxiredoxins in flies of different ages, or under conditions when the pro-oxidative load is high. We found no statistically significant changes in the 2-Cys Prxs monomer:dimer ratio, which indirectly reflects changes in the Prx catalytic activity. However, we found daily variations in Prx-SO2/3 that were more pronounced in older flies as well as in flies lacking Srx. Unexpectedly, the srx mutant flies did not exhibit a diminished survivorship under normal or oxidative stress conditions. Moreover, the srx mutant was characterized by a higher physiological activity. In conclusion, catalytically inactive forms of Prx-SO2/3 serve not only as a marker of cellular oxidative burden, but may also play a role in an adaptive response, leading to a positive effect on the physiology of Drosophila melanogaster.
Highlights
The peroxiredoxin (Prx) protein family plays an important role in maintaining redox homeostasis and is functionally conserved in all kingdoms of life
73% and 71% identity with human PRDX1 and PRDX2, while CG6888 is considered more orthologous to Prx2 (60% and 57% identity to human PRDX2 and PRDX1, FlyBase data)
There was no negative effect of Srx underexpression on lifespan (Figure 5B). This underexpression of Srx produces a phenotype that is almost indistinguishable from control in terms of survival under normal or oxidative stress conditions. Another surprising finding from the study is that levels of physical activity were higher in flies underexpressing Srx, as we found a significant increase in the locomotor activity in the srx mutants (Figure 6 and Figure S7)
Summary
The peroxiredoxin (Prx) protein family plays an important role in maintaining redox homeostasis and is functionally conserved in all kingdoms of life. The most highly conserved region surrounds a key redox-active cysteine, termed the peroxidatic cysteine, CysP , which is reversibly oxidized by peroxides to a sulfenic acid (Cys-SOH). This peroxidatic Cys is present in all Prx subgroups, 1-Cys (Prx6), 2-Cys (Prxs 1–4) and atypical. In the case of the 2-Cys subgroup, Cys-SOH reacts with an additional conserved Cys residue termed the resolving cysteine, CysR , to form intra- or intermolecular disulfide bonds, that are in turn resolved through interaction with a variety of thiols to regenerate the fully reduced Prx. Under conditions of excess reactive oxygen species (ROS), the key cysteine can be selectively overoxidized to catalytically inactive sulfinic (Cys-SO2 ). To shed more light on the in vivo functions of overoxidized Prxs, we investigated the oxidation state variations of the Drosophla melanogaster
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