Reduction of Cysteine Sulfinic Acid in Eukaryotic, Typical 2-Cys Peroxiredoxins by Sulfiredoxin

Abstract

The eukaryotic, typical 2-Cys peroxiredoxins (Prxs) are inactivated by hyperoxidation of one of their active-site cysteine residues to cysteine sulfinic acid. This covalent modification is thought to enable hydrogen peroxidemediated cell signaling and to act as a functional switch between a peroxidase and a high-molecular-weight chaperone. Moreover, hyperoxidation has been implicated in a variety of disease states associated with oxidative stress, including cancer and aging-associated pathologies. A repair enzyme, sulfiredoxin (Srx), reduces the sulfinic acid moiety by using an unusual ATP-dependent mechanism. In this process, the Prx molecule undergoes dramatic structural rearrangements to facilitate repair. Structural, kinetic, mutational, and mass spectrometry-based approaches have been used to dissect the molecular basis for Srx catalysis. The available data support the direct formation of Cys sulfinic acid phosphoryl ester and protein-based thiosulfinate intermediates. This review discusses the role of Srx in the reversal of Prx hyperoxidation, the questions raised concerning the reductant required for human Srx regeneration, and the deglutathionylating activity of Srx. The complex interplay between Prx hyperoxidation, other forms of Prx covalent modification, and the oligomeric state also are discussed. Antioxid. Redox Signal. 15, 99-109.

Is Overoxidation of Peroxiredoxin Physiologically Significant?

“…Consistent with the very long lifetime of overoxidized C. elegans PRDX-2 was the finding that C. elegans, like many other organisms such as Xenopus laevis, Gallus gallus, and Neurospora crassa, do not encode any sulfiredoxin homologs, enzymes previously shown to reduce overoxidized peroxiredoxins (18). Further analysis of the C. elegans genome revealed, however, that C. elegans encodes the sestrin homolog Y74C9A.5.…”

“…This initial finding, combined with the discovery of sulfiredoxins, enzymes specialized to reduce sulfinic acid and regenerate peroxiredoxins, led to an attractive model, in which the rapid inactivation of peroxiredoxin would permit transient, potentially compartmentalized peroxide-mediated signaling events, critical to combat oxidative stress (15). This model left unexplained, however, the fact that many organisms lack sulfiredoxin, and raised the question how these organisms deal with overoxidation and inactivation of peroxiredoxins (18). One possible explanation was that sestrins, highly conserved Nrf2-dependent antioxidant proteins, take over the function of sulfiredoxins in those organisms.…”

“…It came thus as a surprise when genomic studies revealed that certain organisms, including C. elegans, lack sulfiredoxin homologs (18). One possible explanation was that these organisms might use sestrins, a family of antioxidant proteins recently shown to also reduce overoxidized peroxiredoxins (3,8), to regenerate the peroxidase-active state.…”

Nitration Transforms a Sensitive Peroxiredoxin 2 into a More Active and Robust Peroxidase

“…PTM of Prx that could affect their activity, redox state, oligomeric structure, or interaction with other proteins will undoubtedly affect redox signaling by H 2 O 2 , and it has been hypothesized that Prx inactivation via overoxidation is a way to accumulate H 2 O 2 to allow oxidation of other redox proteins (the floodgate hypothesis) (2). The presence of sulfiredoxin as an enzyme that specifically reduces typical 2-Cys Prx cysteine sulfinic acid supports the biological relevance of their peroxidase activity and the signaling role of their oxidative inactivation (16).…”

Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes

“…Given that PRXs are major intracellular antioxidants, inactivation by hyperoxidation would allow H 2 O 2 to accumulate and react with cysteines in proteins that are normally slower to react than PRXs, providing an alternative to the relay mechanism for redox regulation of signaling (11). Hyperoxidized PRXs, at least in the PRX-SO 2 H form, can be reduced by ATP-dependent sulfiredoxin; however, this reaction occurs at a much slower rate than thioredoxin reduction of PRX disulfides (16). If H 2 O 2 and other ROS rise to levels that overwhelm the antioxidant capacity of the cell, then oxidative stress occurs, which is associated with a disruption in normal physiologic signaling (9,13,17).…”