title: Are free radicals involved in thiol-based redox signaling?
abstract: Cells respond to many stimuli by transmitting signals through redox-regulated pathways. It is generally accepted that in many instances signal transduction is via reversible oxidation of thiol proteins, although there is uncertainty about the specific redox transformations involved. The prevailing view is that thiol oxidation occurs by a two electron mechanism, most commonly involving hydrogen peroxide. Free radicals, on the other hand, are considered as damaging species and not generally regarded as important in cell signaling. This paper examines whether it is justified to dismiss radicals or whether they could have a signaling role. Although there is no direct evidence that radicals are involved in transmitting thiol-based redox signals, evidence is presented that they are generated in cells when these signaling pathways are activated. Radicals produce the same thiol oxidation products as two electron oxidants, although by a different mechanism, and at this point radical-mediated pathways should not be dismissed. There are unresolved issues about how radical mechanisms could achieve sufficient selectivity, but this could be possible through colocalization of radical-generating and signal-transducing proteins. Colocalization is also likely to be important for nonradical signaling mechanisms and identification of such associations should be a priority for advancing the field.
authors.affiliation: Centre for Free Radical Research, Department of Pathology, University of Otago, P.O. Box 4345, Christchurch, New Zealand. Electronic address: christine.winterbourn@otago.ac.nz.
authors.forename: Christine C
authors.initials: CC
authors.lastname: Winterbourn
mesh_terms: D000818:Animals; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004583:Electrons; D005609:Free Radicals / Q000737:chemistry* / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000737:chemistry / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D004220:Disulfides; D005609:Free Radicals; D018398:Homeodomain Proteins; C512693:PRRX2 protein, human; D013438:Sulfhydryl Compounds; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D005978:Glutathione
keywords: Cell signalling; Free radicals; Hydrogen peroxide; Superoxide; Thiol protein oxidation