Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation

Abstract

S-glutathionylation and S-nitrosylation are reversible post-translational modifications on the cysteine thiol groups of proteins, which occur in cells under physiological conditions and oxidative/nitrosative stress both spontaneously and enzymatically. They are important for the regulation of the functional activity of proteins and intracellular processes. Connecting link and "switch" functions between S-glutathionylation and S-nitrosylation may be performed by GSNO, the generation of which depends on the GSH content, the GSH/GSSG ratio, and the cellular redox state. An important role in the regulation of these processes is played by Trx family enzymes (Trx, Grx, PDI), the activity of which is determined by the cellular redox status and depends on the GSH/GSSG ratio. In this review, we analyze data concerning the role of GSH/GSSG in the modulation of S-glutathionylation and S-nitrosylation and their relationship for the maintenance of cell viability.

Keywords: GSH; S-glutathionylation; S-nitrosylation; nitrosoglutathione; redox-regulation.

Figure 1

Glutaredoxin catalytic mechanism in dependence of GSH/GSSH ratio. Under an increase in GSH/GSSG, Grx can catalyze the deglutathionylation of proteins. The glutathionylated sulfur moiety of the protein–SSG is attacked by the thiolate anion of the enzyme (Grx-S⁻), forming the covalent enzyme intermediate (GRx–SSG) and releasing the reduced protein–SH as the first product (1). The second rate-determining step involves the reduction of Grx–SSG by GSH to produce glutathione disulfide (GSSG) as the second product, recycling the reduced enzyme (Grx–S⁻) (2). Under conditions of decreased GSH/GSSG ratio, Grx can catalyze S-glutathionylation of proteins. The S-glutathionylated Grx (Grx–SSG), formed in reaction with GSSG (3), reacts with a protein to create S-glutathionylated protein (protein–SSG) (4).

Figure 2

Protein denitrosylation by the Trx/TrxR system. Two thioredoxin-dependent mechanisms of protein denitrosylation are proposed: (a) formation of Trx linkage with substrate protein by a disulfide bridge; (b) trans-nitrosylation due to transient S-nitrosylation of Trx.