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 (101 M−1s−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.

Hydroxytyrosol inhibits hydrogen peroxide-induced apoptotic signaling via labile iron chelation

“…Apart from its harmful effects, H 2 O 2 has been recently established as indispensable component of specific signal transduction pathways, collectively called “redox signaling” [36], [37]. Whether iron is also implicated in these processes is less well examined, although our group has recently presented strong supporting evidence for this notion [23], [32].…”

Minimizing an Electron Flow to Molecular Oxygen in Photosynthetic Electron Transfer Chain: An Evolutionary View

“…We believe that this observation may be important for the understanding of H 2 O 2 -mediated signal transduction. The stromal H 2 O 2 , which might be considered as a messenger of NADP + /NADPH status, can oxidize thioredoxins (Hofmann, 2010;Netto and Antunes, 2016). Therefore, a temporary H 2 O 2 accumulation in the stroma can affect the expression of chloroplast genes and/or the translation aimed at the fast adaptation of photosynthetic apparatus.…”

Peroxiredoxin 1 – an antioxidant enzyme in cancer

“…Previous studies have indicated that PRDXs or Trx peroxidases are important endogenous antioxidants, protecting cells from oxidative damage by reducing H 2 O 2 and peroxynitrite and scavenging thiyl radicals 20, 21, 22. PRDX1 cooperates with Trx in suppressing H 2 O 2 ‐induced cell death involving different types of kinases and enzymes, such as apoptosis signal‐regulating kinase 1 (ASK1), p66 Shc and glutathione S ‐transferase pi (GSTpi)/c‐Jun NH2‐terminal kinase (JNK), which play key roles in the regulation of cell death and/or apoptosis depending on cell type and stimuli 23, 24, 25.…”