title: Inactivation of a peroxiredoxin by hydrogen peroxide is critical for thioredoxin-mediated repair of oxidized proteins and cell survival.
abstract: Eukaryotic 2-Cys peroxiredoxins (Prx) are abundant antioxidant enzymes whose thioredoxin peroxidase activity plays an important role in protecting against oxidative stress, aging, and cancer. Paradoxically, this thioredoxin peroxidase activity is highly sensitive to inactivation by peroxide-induced Prx hyperoxidation. However, any possible advantage in preventing Prx from removing peroxides under oxidative stress conditions has remained obscure. Here we demonstrate that, in cells treated with hydrogen peroxide, the Prx Tpx1 is a major substrate for thioredoxin in the fission yeast Schizosaccharomyces pombe and, as such, competitively inhibits thioredoxin-mediated reduction of other oxidized proteins. Consequently, we reveal that the hyperoxidation of Tpx1 is critical to allow thioredoxin to act on other substrates ensuring repair of oxidized proteins and cell survival following exposure to toxic levels of hydrogen peroxide. We conclude that the inactivation of the thioredoxin peroxidase activity of Prx is important to maintain thioredoxin activity and cell viability under oxidative stress conditions.
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, Tyne and Wear, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Day
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Brown
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Taylor
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Rand
authors.forename: Brian A
authors.initials: BA
authors.lastname: Morgan
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Veal
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D055786:Gene Knockout Techniques; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology*; D008715:Methionine / Q000031:analogs & derivatives / Q000378:metabolism; D050296:Microbial Viability; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000502:physiology; D029702:Schizosaccharomyces pombe Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004220:Disulfides; C105096:Pap1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C515985:Tpx1 protein, S pombe; C532961:Trx1 protein, S pombe; D013879:Thioredoxins; D008715:Methionine; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins; C013111:methionine sulfoxide