Biochemical Basis of Sulphenomics: How Protein Sulphenic Acids May Be Stabilized by the Protein Microenvironment

Among protein residues, cysteines are one of the prominent candidates to ROS-mediated and RNS-mediated post-translational modifications, and hydrogen peroxide (H O ) is the main ROS candidate for inducing cysteine oxidation. The reaction with H O is not common to all cysteine residues, being their reactivity an utmost prerequisite for the sensitivity towards H O . Indeed, only deprotonated Cys (i.e. thiolate form, S ) can react with H O 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, SO H and SO H, 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.