Identification of cysteinyl-tRNA synthetase as the principal supersulfide synthase in vivo

概要

Reactive sulfur species, or persulfides and polysulfides such as cysteine hydropersulfide and glutathione hydropersulfide, are endogenously produced in abundance in both prokaryotes and eukaryotes, including mammals. Various forms of reactive persulfides occur in both low-molecular-weight and protein-bound thiols. The chemical properties and great supply of these molecular species suggest a pivotal role for reactive persulfides/polysulfides in different cellular regulatory processes (e.g., energy metabolism and redox signaling). Akaike et al. (2017) demonstrated that cysteinyl-tRNA synthetase (CARS) is a new cysteine persulfide synthase (CPERS) and is responsible for the in vivo production of most reactive persulfides (polysulfides). Some researchers continue to suggest that 3-mercaptopyruvate sulfurtransferase (3-MST), cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) may also produce hydrogen sulfide and persulfides that may be generated during the transfer of sulfur from 3-mercaptopyruvate to the cysteine residues of 3-MST or direct synthesis from cysteine, respectively. Thus, this study using integrated sulfur metabolome analysis, which was recently developed in Akaike lab, with 3-MST knockout (KO) mice and CBS/CSE/3-MST triple-KO mice, to elucidate the possible contribution of 3-MST, CBS, and CSE to the production of reactive persulfides in vivo. Therefore, sulfide metabolites were quantified in organs derived from both the mutant and wild-type mice via sulfur metabolome analysis, and it has been revealed that there was no significant decrease in reactive persulfide production in the organs of the mutant and wild-type mice. This result indicates that 3-MST, CBS, and CSE are not major sources of endogenous reactive persulfide production; rather, CARS/CPERS is the principal enzyme that is involved in and even primarily responsible for the biosynthesis of reactive persulfides and polysulfides in vivo in mammals.