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I.R.F. / Aging news / General / 05091301

Glutathione and Its Action
Posted on: September 13, 2005

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, γ-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by γ-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetylcysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.

Fig. 1. Glutathione synthesis and utilization in animals. Enzymes that catalyze the indicated reactions are:
1) γ-glutamyl transpeptidase,
2) γ-glutamyl cyclotransferase,
3) 5-oxoprolinase,
4) γ-glutamylcysteine synthetase,
5) glutathione synthetase,
6) dipeptidase,
7) glutathione peroxidase,
8) glutathione reductase,
9) superoxide dismutase,
10) BCAA transaminase (cytosolic and mitochondrial),
11) glutaminase,
12) glutamate dehydrogenase,
13) glutamine:fructose-6- phosphate transaminase (cytosolic),
14) nitric oxide synthase,
15) glutathione S-transferase,
16) NAD(P)H oxidase and mitochondrial respiratory complexes,
17) glycolysis,
18) glutathione-dependent thioldisulfide or thioltransferase or nonenzymatic reaction,
19) transsulfuration pathway,
20) deacylase, and
21) serine hydroxymethyltransferase.
Abbreviations: AA, amino acids; BCKA, branched-chain α-ketoacids; GlcN- 6-P, glucosamine-6-phosphate; GS-NO, glutathione-nitric oxide adduct; KG, α-ketoglutarate; LOO°, lipid peroxyl radical; LOOH, lipid hydroperoxide; NAC, N-acetylcysteine; OTC, L-2-oxothiazolidine-4- carboxylate; R°, radicals; R, nonradicals; R-5-P, ribulose-5-phosphate; X, electrophilic xenobiotics.

Roles of GSH

Glutathione participates in many cellular reactions.
First, GSH effectively scavenges free radicals and other reactive oxygen species (e.g., hydroxyl radical, lipid peroxyl radical, peroxynitrite, and H2O2) directly and indirectly through enzymatic reactions. In such reactions, GSH is oxidized to form GSSG, which is then reduced to GSH by the NADPH-dependent glutathione reductase (Fig. 1). In addition, glutathione peroxidase (a selenium-containing enzyme) catalyzes the GSH-dependent reduction of H2O2 and other peroxides.
Second, GSH reacts with various electrophiles, physiological metabolites (e.g., estrogen, melanins, prostaglandins, and leukotrienes), and xenobiotics (e.g., bromobenzene and acetaminophen) to form mercapturates. These reactions are initiated by glutathione-S-transferase (a family of Phase II detoxification enzymes).
Third, GSH conjugates with NO to form an S-nitrosoglutathione adduct, which is cleaved by the thioredoxin system to release GSH and NO. Recent evidence suggests that the targeting of endogenous NO is mediated by intracellular GSH. In addition, both NO and GSH are necessary for the hepatic action of insulin-sensitizing agents, indicating their critical role in regulating lipid, glucose, and amino acid utilization.
Fourth, GSH serves as a substrate for formaldehyde dehydrogenase, which converts formaldehyde and GSH to S-formyl-glutathione. The removal of formaldehyde (a carcinogen) is of physiological importance, because it is produced from the metabolism of methionine, choline, methanol (alcohol dehydrogenase), sarcosine (sarcosine oxidase), and xenobiotics (via the cytochrome P450-dependent monooxygenase system of the endoplasmic reticulum).

Fifth, GSH is required for the conversion of prostaglandin H2 (a metabolite of arachidonic acid) into prostaglandins D2 and E2 by endoperoxide isomerase.
Sixth, GSH is involved in the glyoxalase system, which converts methylglyoxal to D-lactate, a pathway active in microorganisms.
Finally, glutathionylation of proteins (e.g., thioredoxin, ubiquitin-conjugating enzyme, and cytochrome c oxidase) plays an important role in cell physiology. Thus, GSH serves vital functions in animals (Table 1). Adequate GSH concentrations are necessary for the proliferation of cells, including lymphocytes and intestinal epithelial cells. Glutathione also plays an important role in spermatogenesis and sperm maturation. In addition, GSH is essential for the activation of T-lymphocytes and polymorphonuclear leukocytes as well as for cytokine production, and therefore for mounting successful immune responses when the host is immunologically challenged. Further, both in vitro and in vivo evidence show that GSH inhibits infection by the influenza virus. It is important to note that shifting the GSH/GSSG redox toward the oxidizing state activates several signaling pathways (including protein kinase B, protein phosphatases 1 and 2A, calcineurin, nuclear factor κB, c-Jun N-terminal kinase, apoptosis signal-regulated kinase 1, and mitogen- activated protein kinase), thereby reducing cell proliferation and increasing apoptosis. Thus, oxidative stress (a deleterious imbalance between the production and removal of reactive oxygen/nitrogen species) plays a key role in the pathogenesis of many diseases, including cancer, inflammation, kwashiorkor (predominantly protein deficiency), seizure, Alzheimer's disease, Parkinson's disease, sickle cell anemia, liver disease, cystic fibrosis, HIV, AIDS, infection, heart attack, stroke, and diabetes.

Source: Guoyao Wu, Yun-Zhong Fang, Sheng Yang, Joanne R. Lupton, and Nancy D. Turner; Glutathione Metabolism and Its Implications for Health; J. Nutr. 134: 489-492, 2004.
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