Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides.

Takaaki Akaike,Hozumi Motohashi,Tomohiro Sawa,Hideshi Ihara

doi:10.3390/biom10091245

Takaaki Akaike, Hozumi Motohashi + Show 2 more

Open Access

https://doi.org/10.3390/biom10091245

Copy DOI

Abstract

Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSSnH, 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.

Highlights

Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSSnH, n > 1) are cysteine derivatives that have sulfane sulfur atoms that are bound to cysteine thiol [1,2,3,4]
In vitro experiments with recombinant enzymes showed that both CBS and cystathione γ-lyase (CSE) catalyzed the formation of CysSSH from cystine, an oxidized form of cysteine, that was used as a substrate (Figure 2) [5]
CARS can catalyze the production of CysSSH from cysteine as a substrate

Summary

Introduction

Cysteine persulfide (CysSSH) and cysteine polysulfides (CysSSnH, n > 1) are cysteine derivatives that have sulfane sulfur atoms that are bound to cysteine thiol [1,2,3,4]. Ichinose and colleagues investigated endogenous levels of persulfide species in the lungs and found that levels of persulfide species, including CysSSH, GSSH, and GSSSH, were reduced in lung-resident cells and in epithelial lining fluid obtained from airways of patients with COPD [8]. Nakazawa and colleagues reported the endogenous occurrence of persulfide species in the aqueous and vitreous humour [7] They measured persulfides and polysulfides by means of LC-MS/MS with HPE-IAM, and found that patients with diabetes mellitus (DM) had elevated levels of CysSSH, cystine, and GSSSG in the aqueous humour compared with healthy subjects. Bacterial persulfides and polysulfides inactivated 8-nitro-cGMP so that it did not modify surface proteins and trigger autophagy [11] Taken together, these observations suggest that persulfides and polysulfides play important roles in the protection against oxidative and electrophilic stresses, which will be discussed in more detail in Section 4 below

Biosynthesis of CysSSH and Related Molecules

Anti-inflammatory Actions of NAC Polysulfides

Findings

Conclusions