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Glutathione

Glutathione (L-gamma-glutamyl-L-cysteinyl-glycine; GSH) is a known cellular tripeptide, present in virtually all cells. Glutathione is a tripeptide consisting of glutamate, cysteine, and glycine. Its diverse functions are important to many biomedical fields, including enzymology, transport, pharmacology, therapy, toxicology, endocrinology and microbiology, as well as to agriculture. Glutathione plays an essential role in the organic redox and detoxification reactions. Glutathione is an endogenous thiol that detoxifies reactive oxygen species. It is involved in the metabolism and detoxification of xenobiotics, drugs and their metabolites and offers protection from oxidizing ROM via reactions catalyzed by GSH-S-transferase, transpeptidases, transhydrogenases, and peroxidases and reductases. Mitochondrial glutathione is critical to cell viability, and the glutathione redox cycle is a primary antioxidant defense system within the mitochondrial matrix. Additional functions include intracellular binding, transport of lipophilic substances and prostaglandin synthesis. Glutathione is synthesised in the body starting from glutamic acid and cysteine which, in the presence of ATP, form gamma-glutamyl-cysteine, which, again in the presence of ATP, reacts with glycine giving rise to the formation of glutathione. Glutathione is a component of many important enzymes, such as glutathione peroxidase or glutathione reductase. Glutathione peroxidase protects intracellularly, for example, against many of the hydroperoxides formed in different ways. It does so by its ability to reduce these in close cooperation with catalases to water.

GSH plays a crucial role in various metabolic districts, as well as in transport and in cellular protection. It serves the reduction of the disulfide linkages of proteins and other molecules, the synthesis of the deoxyribonucleotide precursors of DNA, and the protection of cells against the dangerous effects of free radicals and of the many reactive oxygen intermediates (e.g., peroxides) that are formed at various stages of metabolism. Glutathione helps to protect cells against oxidative damage that would otherwise be caused by free radicals and reactive oxidative intermediates (ROIs) produced during cell metabolism or as the results of, for example, drug overdose. The ubiquitous tripeptide L-glutathione (GSH) is a well known biological antioxidant, and in fact is believed to be the primary intracellular antioxidant for higher organisms. Glutathione is the major scavenger of reactive oxidative intermediates present in all eukaryotic forms of life and is generally required to protect cells against damage by oxidants. Glutathione reduces intracellular oxidants and is consumed by this reaction. Glutathione is oxidized to the disulfide linked dimer (GSSG), which is actively pumped out of cells and becomes largely unavailable for reconversion to reduced glutathione. Thus, unless glutathione is resynthesized through other pathways, utilization of this compound is associated with a reduction in the amount of glutathione available.

GSH acts primarily in the cytosol and in plasma, but it is also important in maintaining cell membrane vitamin E in its active reduced form. The reduced form GSH, when absorbing oxidants, is converted to the oxidized form GSSG which is either converted back to GSH in the cell or expelled as the oxidized form, thus requiring continual replacement. The GSH-GSSG activity depends on the enzymes, glutathione peroxidase and glutathione reductase. Selenium is a key co-factor in this enzyme activity. Glutathione is decreased in the plasma, lung epithelial-lining fluid, and T-lymphocytes of individuals infected with HIV. This deficiency is thought to potentiate HIV replication and accelerate the progression of the disease, whereas GSH replacement therapy is thought to be effective in extending the latency and delaying the development of opportunistic infections. Glutathione is synthesized in a series of biochemical reactions utilizing ATP, magnesium and the three amino acids glycine, glutamate and cysteine. The rate of synthesis of gamma-glutamylcysteine determines the rate of synthesis of glutathione, and the sulfhydral group of cysteine provides glutathione with its biological potency.

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