Cysteine sulfinic acid and sulfinylated peptides

Cysteine sulfinic acid (CSA) is a stable post translational modification in nature. While long considered to be an irreversible by-product of accidental overoxidation of the cysteine sulfur, evidence in the last two decades has accumulated for its role in numerous and tightly regulated mechanisms. Proteomics studies in the last two decades have identified CSA in hundreds of cellular proteins, highlighting its omnipresence at the core of the cysteine redoxome. Elsewhere, structural studies have shed initial light on the molecular mechanisms underlying CSA reduction in vivo by the sulfiredoxin (Srx) enzyme. While peroxiredoxins have for a long time been the only known substrates to be turned over by Srx, recent studies have uncovered a plethora of potential new substrates of Srx, opening new avenues of investigation in fundamental biology, but also possibly opening new opportunities for developing novel medicines targeting the redoxome, especially in cancer and neurodegeneration. This review first summarises important knowledge surrounding the stereo-electronics and biochemical properties of CSA, including how it is reduced by Srx. In a second part, it highlights the chemical methods recently developed for CSA characterisation, with important examples of electrophilic probes for CSA covalent adduct formation. Crucially, in vitro biochemical studies of CSA and its peptides have historically proven difficult, in great part due to the limitations associated with the few existing synthetic methods available. Here, we also provide a summary of synthetic methods currently available for CSA incorporation into peptides, and their current limitations.