Role of Different Residues in Peroxiredoxin for Redox Signaling Via Mediator proteins

Abstract

Abstract newlinePeroxiredoxins belong to a highly conserved ubiquitous family of peroxidases. These proteins help a cell maintain redox homeostasis by scavenging peroxides through conserved cysteine residues in typical 2-Cys peroxiredoxins. Evident studies have now established a comprehensive understanding of cysteine functioning in peroxiredoxins but recent studies are primarily focused on signaling and chaperon activity. The existence of multiple isoforms in most organisms has made it relatively easier to apprehend their complexity and seek answers for their crucial role in various diseases. For example, mammalian cells express six isoforms (hPrxI to hPrxVI) of peroxiredoxins that work differently under diverse stress conditions and diseases. The active site of peroxiredoxins confers high affinity for and susceptibility to oxidation by hydrogen peroxide, the function of which is highly regulated by a cascade of antioxidant proteins. This research endeavors to bring forth the often-overlooked role of peroxiredoxins in lipid peroxidation. We recently discovered that cysteine residue Cys52 of hPrxI help overcome nitrosative stress and Cys83 have a crucial role in chaperon activity. Additionally, hPrxI behaves very differently than hPrxII in different levels of H2O2, a non-radical signaling molecule continuously produced during intracellular processes. Based on this foundation, we examined the role of different residues of hPrxI and hPrxII in lipid peroxidation using yeast model system. To achieve this, we used oxidative stress sensitive tsaI/tsaIIand#916; yeast strain expressing hPRXI or hPRXII and analyzed their lipid peroxidation activity. The results suggest an essential role of hPrxI, hPrxII, and C83T in overcoming lipid peroxidation. This study digging into salient features of peroxiredoxins will serve as a conceptual foundation for understanding oxidative mechanisms into various pathologies and their potential treatments. newlineKeywords: lipid peroxidation, human peroxiredoxins, catalytic residues, yeast, ferroptosis. newline