Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation.
S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis.
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SNO SNOs SNOs H2O2 thiol nitric oxide NO SNO NO Cys S-Nitrosothiols S NO SNO S-nitrosocysteine S-nitrosoglutathione S hydrogen peroxide disulfide cysteines Cys H2O2 Cys cys Prx1 peroxidase peroxidase Prx Trx Trx oxidized Prx1 Prx1 NO Trx Trx reductase Prx Trx reductase mammalian peroxiredoxin-1 Prx1 2-Cys Prxs thioredoxin Trx peroxidases SNO Prx1 2-cys peroxiredoxin S-nitrosocysteine oxygen S-nitrosocysteine S-nitrosocysteine NO