Abstract
A well-regulated redox state is essential for normal physiological function and cellular metabolism. In most eukaryotic cells, protein cysteine thiols are most sensitive to fluctuations in the cellular redox state. Under normal physiological conditions, the cytosol has a highly reducing environment, which is due to high levels of reduced glutathione and complex system of redox enzymes that maintain glutathione in the reduced state. The reducing environment of the cytosol maintains most protein thiols in the reduced state; although some non-exposed cysteine could be present as disulfides. Upon physiological increase in cellular oxidants, such as due to growth factors, cytokines and thiol-disulfide exchange reactions, specific proteins could act as redox switches that regulate the conformation and activity of different proteins. This reversible post translational modification enables redox-sensitive dynamic changes in cell signaling and function. Physiological oxidative stress could lead to the formation of sulfenic acids, which are usually intermediate states of thiol oxidation that are converted to higher order oxidation states, intramolecular disulfides or mixed disulfides with glutathione. Such glutathiolation reactions have been found to regulate the function of several proteins involved in intracellular metabolism, signal transduction and cell structure. Excessive oxidative stress results in indiscriminate and irreversible oxidation of protein thiols, depletion of glutathione and cell death. Further elucidation of the relationship between changes in cell redox and thiol reactivity could provide a better understanding of how redox changes regulate cell function and how disruption of these relationships lead to tissue injury and dysfunction and the development of chronic diseases such as cancer and cardiovascular disease.