Glutathione in Defense and Signaling

Abstract

The mechanisms of thiol metabolism and chemistry have particular relevance to both cellular defenses against toxicant exposure and to redox signaling. Here, we will focus on glutathione (GSH), the major endogenous low- molecular-weight nonprotein thiol synthesized de novo in mammalian cells. The major pathways for GSH metabolism in defense of the cell are reduction of hydroperoxides by glutathione peroxidases (GSHPx) and some peroxiredoxins, which yield glutathione disulfide (GSSG), and conjugation reactions catalyzed by glutathione-S-transferases. GSSG can be reduced to GSH by glutathione reductase, but glutathione conjugates are excreted from cells. The exoenzyme gamma-glutamyltranspeptidase (GGT) removes the glutamate from extracellular GSH, producing cysteinyl-glycine from which a dipeptidase then generates cysteine, an amino acid often limiting for de novo GSH synthesis. Synthesis of GSH from the constituent amino acids occurs in two regulated, enzymatically catalyzed steps. The signaling pathways leading to activation of the transcription factors that regulate these genes are a current area of intense investigation. The elucidation of the signaling for GSH biosynthesis in human bronchial epithelial cells in response to 4-hydroxynonenal (4HNE), an end product of lipid peroxidation, will be used as an example. GSH also participates in redox signaling through the removal of H(2)O(2), which has the properties of a second messenger, and by reversing the formation of sulfenic acid, a moiety formed by reaction of critical cysteine residues in signaling proteins with H(2)O(2). Disruption of GSH metabolism will therefore have major a impact upon function of cells in terms of both defense and normal physiology.

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

“…Glutathione opposes this effect, first, by functioning as a reducing substrate for glutathione peroxidase, which converts hydrogen peroxide to water (Arthur 2000). Second, via direct reactions with sulfenic acid, or via the catalytic impact of glutaredoxin, which likewise employs glutathione as a reducing substrate, glutathione can restore sulfenic acids to their native sulfhydryl form (Dickinson and Forman 2002;Shelton et al 2005;Parsons and Gates 2013). These protective mechanisms are evidently compromised when cellular levels of glutathione decline during the aging process.…”

Oxidative stress in spinal cord injury and antioxidant-based intervention

“…It has a critical role in maintaining the intracellular oxidation-reduction (redox) balance and regulating oxidative stress-induced signaling pathways as well as detoxifying ROS and other reactive aldehydes including acrolein. 32 It is well known that the central nervous system including the spinal cord has relatively low glutathione levels compared with the other organs, such as the liver, which makes the neurons of the spinal cord especially vulnerable to oxidative stress. 1, [33][34][35] In the central nervous system, glutathione is present at high concentrations in the astrocytes, which also provide the substrate for glutathione synthesis such as cysteine and dipeptide cysteinyl-glycine to the neighboring neurons.…”

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

“…27 GCLC, GCLM, and GSS are enzymes essential for synthesis of Effect of Nrf2 knockout on ALS mice Y Guo et al GSH, which is the major endogenous thiol antioxidant, counteracting oxidative injury within cells. 23 Upregulation of HO-1, NQO1, GCLC, and GCLM in the lumbar spinal cord of SOD1-G93A mice implicates that the affected tissues are experiencing chronic oxidative stress. Although the expression of Nrf2-mediated antioxidant genes confers cytoprotection, longer-term induction of some enzymes such as HO-1 may exacerbate oxidative injury to the mitochondria and the microtubular network.…”