Metabolism and function of glutathione: an overview

TL;DR: The hypothesis that the y-glutamyl cycle may function in one of the mechanisms involved in amino acid transport has stimulated research on glutathione and its metabolism; the new findings obtained have led to major revisions in the understanding of glutATHione metabolism.

Abstract: Many functions have been ascribed to glutathione, a tripeptide that has been known for almost a century.* Glutathione is found in virtually all mammalian cells, usually in substantial concentrations (0.510 mM). The concentration of glutathione in extracellular fluids such as blood plasma is in the micromolar range. The intracellular concentration of glutathione exceeds by far that of glutathione disulphide, which is effectively converted into glutathione by the NADPH-utilizing enzyme glutathione reductase. The functions of glutathione are related to its thiol group and its y-glutamyl moiety. The intracellular stability of glutathione is favoured by its y-glutamyl linkage, which is not split by a-peptidases, and which protects the thiol group from rapid oxidation. The C-terminal glycine residue of glutathione protects the tripeptide from the action of y-glutamyl cyclotransferase. There is good evidence that glutathione functions in several different ways. It serves as an intracellular reductant. It functions in the destruction of free radicals and of hydrogen peroxide and other peroxides. Glutathione forms S-substituted derivatives that are involved in detoxification of foreign compounds and also in various phases of endogenous metabolism. Glutathione also plays a role in a variety of other metabolic phenomena and is a coenzyme for certain enzymic reactions. Glutathione functions in one of the systems involved in the transport of amino acids, and glutathione itself is transported out of many cells. The intracellular concentrations of glutathione are much greater than those of cysteine; it appears that glutathione functions as a storage form of cysteine. Glutathione also plays a role in the inter-organ transport of amino acid sulphur. The breakdown of glutathione to its constituent amino acids and the synthesis of glutathione take place by the reactions of the y-glutamyl cycle (Meister & Tate, 1976; Meister, 1981). These include the intracellular synthesis of glutathione from glutamate, cysteine and glycine catalysed by y-glutamylcysteine and glutathione synthetases, the utilization of glutathione by y-glutamyl transpeptidase to form cysteinylglycine and yglutamyl amino acids, enzymic hydrolysis of cysteinylglycine to glycine and cysteine, conversion of y-glutamyl amino acids to 5-oxoproline and the corresponding amino acids catalysed by y-glutamyl cyclotransferase, and the decyclization of 5-0x0proline to glutamate catalysed by 5-oxoprolinase. Various modifications and elaborations of this metabolic pathway have been considered (Meister, 1981). Since the cycle involves the synthesis of glutathione, its functions are intimately associated with the several roles of glutathione. The hypothesis that the cycle may function in one of the mechanisms involved in amino acid transport has stimulated research on glutathione and its metabolism; the new findings obtained have led to major revisions in our understanding of glutathione metabolism. According to the transport hypothesis, membrane-bound y-glutamyl transpeptidase interacts with intracellular glutathione