Glutathione and related gamma-glutamyl compounds, including glutamine, have a number of significant functions in amino acid and protein metabolism. We propose continuation of research on the structure-function relationships and on the mechanisms of catalysis and regulation of a group of closely related enzymes that are involved in the metabolism and function of glutathione. These enzymes include gamma-glutamylcysteine synthetase, glutathione synthetase, gamma-glutamyl transpeptidase, gamma- glutamyl cyclotransferase, 5-oxoprolinase, and glutamine- dependent carbamyl phosphate synthetase. These research activities overlap and integrate in many ways because the metabolic phenomena involved are closely related and also because the experimental approaches used in this work are similar. The proposed research includes studies on the active sites of enzymes and on their chemical, catalytic and regulatory properties. Emphasis is given to the development of potent and selective inhibitors that can be used in vivo to probe metabolism. Analogs of substrates may serve as inhibitors which may be useful in studies of enzyme structure and mechanism, as model compounds in the investigation of metabolism, and also to achieve physiological effects that may be useful in therapy. Previously, enzyme-oriented studies of this type have led to the development of compounds that are active in vivo and of potential value in treatment. These compounds include buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase which is currently planned for clinical trials, L-2-oxothiazolidine-4- carboxylate, an in vivo cysteine precursor, and glutathione mono ethyl ester, a compound useful for increasing glutathione levels of cells. In the further course of this work, additional insights will be sought about the relationships between enzyme-catalyzed reactions and physiological and pathological phenomena. The evidence that has thus far been achieved indicates that further studies on the modulation of glutathione metabolism may be a promising pathway of research.
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