y-Glutamyl transpeptidase, y-glutamyl cyclotransferase, L-pyrrolidone carboxylate hydrolase, y-glutamylcysteine synthetase and glutathione synthetase, the enzymes of the y-glutamyl cycle, were found in mouse brain, liver and kidney. The activity of L-pyrrolidone carboxylate hydrolase was many times lower than the activities of the other enzymes, and thus the conversion of L-pyrrolidone carboxylate to L-glutamate is likely to be the rate-limiting step of the cycle. The specificity of y-glutamyl cyclotransferase from mouse tissues was similar to that from rat tissues. The concentration of pyrrolidone carboxylate and y-glutamyl amino acids, intermediates of the y-glutamyl cycle, was determined by a gas chromatographic procedure coupled with electron capture detection. Administration of ~-2-aminobutyrate, an amino acid that is utilized as substrate in the reaction catalyzed by y-glutamylcysteine synthetase, led to a large accumulation of y-glutamyl-2-aminobutyrate and pyrrolidone carboxylate in mouse tissues. L-Methionine-RS-sulfoximine, an inhibitor of y-glutamylcysteine synthetase, abolished the increase in concentration of pyrrolidone carboxylate. No accumulation of pyrrolidone carboxylate was observed after L-cysteine. The separate administration of several protein amino acids had little effect on the concentration of pyrrolidone carboxylate ; however formation of small amounts of the corresponding y-glutamyl derivatives (e.g. y-glutamylmethionine and y-glutamylphenylalanine) was detected. These intermediates are probably formed by transpeptidation between glutathione and the corresponding amino acid, catalyzed by y-glutamyl transpeptidase. The concentration of pyrrolidone carboxylate increased significantly after administration of a mixture containing all protein amino acids, the highest increase occurring in the kidney.The results suggest that two separate pathways for the formation of y-glutamyl amino acids and pyrrolidone carboxylate exist in vivo. One of these results from the function of y-glutamylcysteine synthetase in glutathione synthesis. The other pathway involves the amino-acid-dependent degradation of glutathione, mediated by y-glutamyl transpeptidase. Only very small amounts of free intermediates are apparently derived from the latter pathway, suggesting that the y-glutamyl amino acids formed in this pathway are either enzyme-bound or are directly hydrolyzed to glutamate and free amino acid. y-glutamyl amino acids with the concomitant release of free amino acid. The enzyme is widely distributed in animal tissues [4] and is part of the y-glutamyl cycle which was proposed as a transport system for amino acids [5]. Further reactions of the cycle include: (a) conversion of L-pyrrolidone carboxylate to L-glutamate in an ATP-requiring reaction [6,7]; (b) the ATPdependent synthesis of glutathione catalyzed in sequence by y-glutamylcysteine synthetase and glutathione synthetase [8]; and (c) transfer of the y-glutamyl moiety of GSH to an amino acid to form the correEur. J. Biochem. 53 (1975)
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