Thiol chemistry and specificity in redox signaling.
Exposure of cells to sublethal oxidative stress results in the modulation of various signaling pathways. Oxidants can activate and inactivate transcription factors, membrane channels, and metabolic enzymes, and regulate calcium-dependent and phosphorylation signaling pathways. Oxidation and reduction of thiol proteins are thought to be the major mechanisms by which reactive oxidants integrate into cellular signal transduction pathways. This review focuses on mechanisms for sensing and transmitting redox signals, from the perspective of their chemical reactivity with specific oxidants. We discuss substrate preferences for different oxidants and how the kinetics of these reactions determines how each oxidant will react in a cell. This kinetic approach helps to identify initial oxidant-sensitive targets and elucidate mechanisms involved in transmission of redox signals. It indicates that only those proteins with very high reactivity, such as peroxiredoxins, are likely to be direct targets for hydrogen peroxide. Other more modestly reactive thiol proteins such as protein tyrosine phosphatases are more likely to become oxidized by an indirect mechanism. The review also examines oxidative changes observed during receptor-mediated signaling, the strengths and limitations of detection methods for reactive oxidant production, and the evidence for hydrogen peroxide acting as the second messenger. We discuss areas where observations in cell systems can be rationalized with the reactivity of specific oxidants and where further work is needed to understand the mechanisms involved.
Free Radical Research Group and the National Research Centre for Growth and Development, Department of Pathology, University of Otago, Christchurch, New Zealand. christine.winterbourn@otago.ac.nz
Christine C
CC
Winterbourn
Mark B
MB
Hampton
D000818:Animals; D006801:Humans; D008954:Models, Biological; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism*
D016877:Oxidants; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds