Enzymatic regulation and biological functions of reactive cysteine persulfides and polysulfides

Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSS_nH, n > 1) are cysteine derivatives that have sulfane sulfur atoms bound to cysteine thiol. Advances in analytical methods that detect and quantify persulfides and polysulfides have shown that CysSSH and related species such as glutathione persulfide occur physiologically and are prevalent in prokaryotes, eukaryotes, and mammals in vivo. The chemical properties and abundance of these compounds suggest a central role for reactive persulfides in cell-regulatory processes. CysSSH and related species have been suggested to act as powerful antioxidants and cellular protectants and may serve as redox signaling intermediates. It was recently shown that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase. In addition, we discovered that CARS is involved in protein polysulfidation that is coupled with translation. Mitochondrial activity in biogenesis and bioenergetics is supported and upregulated by CysSSH derived from mitochondrial CARS. In this review article, we discuss the mechanisms of the biosynthesis of CysSSH and related persulfide species, with a particular focus on the roles of CARS. We also review the antioxidative and anti-inflammatory actions of persulfides.