title: Peroxiredoxins as preferential targets in H2O2-induced signaling.
abstract: Evidence has accumulated showing that hydrogen peroxide (H2O2) acts as a signaling molecule via oxidation of critical cysteine residues on target proteins. The reaction of H2O2 with thiols is thermodynamically favored, but its selectivity is imposed by differences in reaction kinetics. Previously proposed signal relaying mechanisms, such as the floodgate hypothesis and widespread protein sulfenylation, appear inconsistent with kinetic and diffusion considerations. Among all cellular thiols, the peroxidatic cysteines of peroxiredoxins (Prxs) represent preferential targets considering their high rate constants and their cellular abundance that place them as the first step in the H2O2-induced signaling pathways. The oxidized Prxs could transfer the signal either via thiol-disulfide redox reactions or through nonredox protein-protein interactions. Recent studies evidence Prxs interactions with protein tyrosine kinases and phosphatases, indicating a potential connection between redox and phosphorylation signaling pathways that does not need the direct reaction of H2O2 with phosphatase or kinase critical cysteines. Posttranslational modifications of Prxs have been observed in vivo (mainly overoxidation of cysteines and phosphorylation of threonines) that affect their peroxidase activity, redox state, and/or oligomeric structure, and likely impact on H2O2 signaling. More focus on kinetic data and redox-sensitive protein-protein interactions are needed to unravel the molecular mechanisms of H2O2 signaling.
authors.affiliation: Laboratorio de Fisicoquímica Biológica, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Lía M
authors.initials: LM
authors.lastname: Randall
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferrer-Sueta
authors.forename: Ana
authors.initials: A
authors.lastname: Denicola
mesh_terms: D000818:Animals; D004058:Diffusion; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007700:Kinetics; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D013434:Sulfenic Acids / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D013434:Sulfenic Acids; D013438:Sulfhydryl Compounds; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins
keywords: Diffusion; Hydrogen peroxide; Kinetics; Peroxiredoxins; Redox signaling