Defining and refining the cysteine redoxome with sulfur chemical biology

Abstract

Posttranslational changes in the redox state of cysteine residues can rapidly and reversibly alter protein function, modulating biological processes and drug pharmacology. Recent innovations in organosulfur chemistry, small-molecule tools, and computational methods for proteomic analysis have dramatically improved selectivity, cellular application, and site-specific quantitation of the cysteine redoxome. In this perspective, we start with a brief overview of cysteine sulfur chemistry and factors affecting thiol reactivity, followed by a critical discussion of similarities and differences between reactive and redox-sensitive cysteine residues. Next, we address mechanisms of post-translational cysteine oxidation and methods to quantify redoxome site-stoichiometry to prioritize follow-up study. Finally, we highlight recent chemoproteomic studies of the cysteine redoxome that offer new insights into the regulation of physiological processes and provide a framework for development of novel redox-based targeted therapeutic strategies.