Biochemical basis of sulphenomics: how protein sulphenic acids may be stabilized by the protein microenvironment

Abstract

Among protein residues, cysteines are one of the prominent candidates to ROS-mediated and RNS-mediated post-translational modifications, and hydrogen peroxide (H2O2) is the main ROS candidate for inducing cysteine oxidation. The reaction with H2O2 is not common to all cysteine residues, being their reactivity an utmost prerequisite for the sensitivity towards H2O2. Indeed, only deprotonated Cys (i.e. thiolate form, S−) can react with H2O2 leading to sulphenic acid formation (SOH), which is considered as a major/central player of ROS sensing pathways. However, cysteine sulphenic acids are generally unstable because they can be further oxidized to irreversible forms (sulphinic and sulphonic acids, SO2H and SO3H, respectively), or alternatively, they can proceed towards further modifications including disulphide bond formation (SS), S-glutathionylation (SSG) and sulphenamide formation (SN). To understand why and how cysteine residues undergo primary oxidation to sulphenic acid, and to explore the stability of cysteine sulphenic acids, a combination of biochemical, structural and computational studies are required. Here, we will discuss the current knowledge of the structural determinants for cysteine reactivity and sulphenic acid stability within protein microenvironments.