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

Elena Kalinina,Maria Novichkova

doi:10.3390/molecules26020435

Elena Kalinina, Maria Novichkova

Open Access

https://doi.org/10.3390/molecules26020435

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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.

Highlights

Redox-dependent processes largely determine cell viability, participating in the regulation of division, bioenergetics, and programmed death
At the beginning, a trans-nitrosylation reaction occurs with the formation of denitrosylated protein (Pr-SH) and S-nitrosylated Trx-nitric oxide (NO), followed by the release of the nitrosyl group and the formation of an intramolecular disulfide bond in thioredoxin, which is reduced by Trx reductase (TrxR) with the participation of NADPH [93,119]
The reduced dithiol Grxs catalyze the denitrosylation reaction in the absence of GSH, whereas monothiol Grx only does so in the presence of GSH [103]. Another member of the Trx family, protein disulfide isomerase (PDI), which is localized on the cytoplasmic membrane, promotes NO transfer from extracellular Pr-SNO to intracellular thiols, suggesting that PDI is involved in NO transfer from the extracellular environment to the cytoplasm [128]

Summary

Introduction

Redox-dependent processes largely determine cell viability, participating in the regulation of division, bioenergetics, and programmed death. The cellular redox status is characterized by low-molecular-weight indicators (GSH, NADH) The change in their oxidized/reduced form ratio occurs as a reaction to changes in reactive oxygen and nitrogen species (RONS) levels and, so, they can play the role of a trigger in the redox-dependent regulation of cellular processes. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), GSH/GSSG—which characterizes the cellular redox status—is 100/1 in the cytoplasm, 10/1 in mitochondria, and 3/1 to 1 in the endoplasmic reticulum [4] This ratio varies depending on the physiological state of cells, such as proliferation, differentiation, or apoptosis, and the consequences of its disturbance are significant changes in cellular signaling reactions. We analyze data concerning the roles of GSH and GSH/GSSG in the redox modulation of S-glutathionylation and S-nitrosylation and their relationship for the maintenance of cell viability

Glutathione and Protein S-Glutathionylation

Protein S-Nitrosylation and Denitrosylation

Nitrosoglutathione

Conclusions