Chemical Biology of H 2 S Signalling Through Protein Persulfidation

Abstract

Signaling by H2S is proposed to occur via persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH), and provides a framework for understanding its physiological and pharmacological effects. Due to the inherent instability of persulfides, its chemistry is understudied. We developed a new selective method to label protein persulfides and study their reactivity. Global persulfidome reveals many important metabolic pathways being regulated by this modification. Persulfides are more nucleophilic than corresponding thiols and could serve as a way of protection against oxidative stress. Using improved tag-switch method we find out that the reaction of sulfenic acids with H2S represents major source of persulfides. Furthermore temporal dynamics of persulfidation perfectly matches the sulfenylation, with the latter preceding the former. This process seems to be inherent to all life forms and probably represents the remnant from the past, when early life thrived in H2S rich environment. Persulfidation levels change during the development of C. elegans and start to decay with aging. Pharmacological intervention to increase protein persulfidation levels extends the life span of C. elegans, suggesting that this may be a pharmacological route to treat aging and aging related diseases.