title: The Roles of Peroxiredoxin and Thioredoxin in Hydrogen Peroxide Sensing and in Signal Transduction.
abstract: A challenge in the redox field is the elucidation of the molecular mechanisms, by which H2O2 mediates signal transduction in cells. This is relevant since redox pathways are disturbed in some pathologies. The transcription factor OxyR is the H2O2 sensor in bacteria, whereas Cys-based peroxidases are involved in the perception of this oxidant in eukaryotic cells. Three possible mechanisms may be involved in H2O2 signaling that are not mutually exclusive. In the simplest pathway, H2O2 signals through direct oxidation of the signaling protein, such as a phosphatase or a transcription factor. Although signaling proteins are frequently observed in the oxidized state in biological systems, in most cases their direct oxidation by H2O2 is too slow (10(1) M(-1)s(-1) range) to outcompete Cys-based peroxidases and glutathione. In some particular cellular compartments (such as vicinity of NADPH oxidases), it is possible that a signaling protein faces extremely high H2O2 concentrations, making the direct oxidation feasible. Alternatively, high H2O2 levels can hyperoxidize peroxiredoxins leading to local building up of H2O2 that then could oxidize a signaling protein (floodgate hypothesis). In a second model, H2O2 oxidizes Cys-based peroxidases that then through thiol-disulfide reshuffling would transmit the oxidized equivalents to the signaling protein. The third model of signaling is centered on the reducing substrate of Cys-based peroxidases that in most cases is thioredoxin. Is this model, peroxiredoxins would signal by modulating the thioredoxin redox status. More kinetic data is required to allow the identification of the complex network of thiol switches.
authors.affiliation: Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo - SP, Brazil.
authors.forename: Luis E S
authors.initials: LE
authors.lastname: Netto
authors.affiliation: Departamento de Química e Bioquímica, Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Antunes
mesh_terms: D006861:Hydrogen Peroxide / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D054464:Peroxiredoxins / Q000378:metabolism*; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D013879:Thioredoxins; D006861:Hydrogen Peroxide; D054464:Peroxiredoxins
keywords: H2O2; Peroxiredoxin; signal transduction; thiol; thiol-disulfide exchange; thioredoxin
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