Enzymatic Regulation and Biological Functions of Reactive Cysteine Persulfides and Polysulfides

Abstract

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.

Keywords: anti-inflammatory effect; antioxidant; cysteine persulfide; cysteinyl-tRNA synthetase; oxidative stress; sulfur respiration.

Figure 1

Chemical structures of persulfide species that have been identified in biological systems.

Figure 2

Enzymatic production of cysteine persulfides (CysSSHs). CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; CARS, cysteinyl-tRNA synthetase. Cofactors heme and pyridoxal phosphate (PLP) are also indicated.

Figure 3

CARS-mediated incorporation of CysSSH into cysteinyl-tRNA and translation-coupled protein S-sulfhydration. PPi, pyrophosphate.

Figure 4

Domain structure and key amino acid residues involved in the aminoacylation and pyridoxal phosphate (PLP) binding of CARS.

Figure 5

Chemical structures of NAC polysulfides. oxNAC is a control reagent without polysulfide-donating capability.

Figure 6

Schematic representation of LPS-TLR4-mediated inflammatory responses. NAC polysulfides can inhibit signal transduction at the points indicated. LPS, lipopolysaccharide; TLR4, toll-like receptor 4; MKK, MAP kinase kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH₂-terminal kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3 kinase; IKK, IκB kinase; AKT, protein kinase B; IRF3, interferon regulatory factor 3; INFR, interferon receptor; STAT1, signal transducers and activators of transcription 1; iNOS, inducible nitric oxide synthase.