The Roles of Peroxiredoxin and Thioredoxin in Hydrogen Peroxide Sensing and in Signal Transduction

A challenge in the redox field is the elucidation of the molecular mechanisms, by which H(2)O(2) mediates signal transduction in cells. This is relevant since redox pathways are disturbed in some pathologies. The transcription factor OxyR is the H(2)O(2) 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 H(2)O(2) signaling that are not mutually exclusive. In the simplest pathway, H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) concentrations, making the direct oxidation feasible. Alternatively, high H(2)O(2) levels can hyperoxidize peroxiredoxins leading to local building up of H(2)O(2) that then could oxidize a signaling protein (floodgate hypothesis). In a second model, H(2)O(2) 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.