Metabolism of γ‐Glutamyl Amino Acids and Peptides in Mouse Liver and Kidney in vivo

Abstract

The metabolism in vivo of y-glutamyl amino acids and peptides was studied in the mouse after administration of loading doses of ~-y-glutamyl-2-aminobutyrate and several other y-glutamyl compounds, including glutathione. A great and rapid accumulation of glutamate, glutamine, aspartate and pyrrolidone carboxylate was observed in the kidney. Similarly, after administration of a tracer dose of ~-y-[~~C]glutamyl-~-2-aminobutyrate a rapid incorporation of label into kidney glutamate, glutamine and aspartate was found. These results suggest that both the hydrolytic and ;I-glutamyl transfer reactions catalyzed by y-glutamyl transpeptidase are active in the renal handling of y-glutamyl compounds.Indirect evidence was obtained that ~-y-glutamyl-2-aminobutyrate is partially taken up by the kidney cell in an intact form.In contrast to the kidney, administration of several y-glutamyl derivatives did not cause an increase in liver glutamate, glutamine and pyrrolidone carboxylate. After administration of L-7-glutamyl-2-aminobutyrate only a slight increase in liver aspartate and pyrrolidone carboxylate was observed. Experiments with ~-y-['~C]glutamyl-~-2-aminobutyrate suggest that this derivative is largely first degraded to its component amino acids (probably in the kidney) before entering into the metabolism of the liver cell.7-Glutamyl transpeptidase may function in the metabolism and transport of glutathione and other y-glutamyl compounds in a manner analogous to the function of dipeptidases and disaccharidases in the metabolism and transport of dipeptides and disaccharides respectively. y-Glutamyl amino acids and peptides are derivatives of glutamate in which the y-carboxyl group participates in a peptide bond with an amino acid or peptide. The most commonly occurring representative of this class of compounds is glutathione (L-Yglutamyl-L-cysteinylglycine). Glutathione is present in all mammalian tissues. Low concentrations of this tripeptide are also present in plasma, either free [ l ] or protein-bound as a mixed disulfide with thiol groups of albumins [2,3]. Two analogs of glutathione, namely, ophthalmic acid [4] (~-y-glutamyl-~-2-arninobutyrylglycine) and norophthalmic acid [5] (L-y-glutamyl-L-alanylglycine) have been discovered in calf lens. y-Glutamyl derivatives of a number of amino acids have been also found in brain [6] and human urine [7,8]. ~-Enzjwze.7. y-Glutamyl transpeptidase or (y-g1utamyl)-peptide: amino acid y-glutamyltransferase (EC 2.3.2.2); y-Glutamylcyclotransferase (EC 2.3.2.4); y-Glutamylcysteine synthetase (EC 6.3.2.2); Glutathione synthetase (EC 6.3.2.3); Glutamine synthetase (EC 6.3.1.2). y-Glutamyl amino acids are formed in cico by two separate pathways [9]. In the first glutamate reacts with cysteine or several related amino acids to give the corresponding 7)-glutamyl amino acid. This reaction is catalyzed by y-glutamylcysteine synthetase and is limited by the specificity of this enzyme. It constitutes the first of two steps leading to the synthesis of glutathione or its analogs (Reactions 1 ...

Characterization and Physiological Function of Rat Renal γ-Glutamyltranspeptidase

“…The observation that this peptide was a more effective precursor to 5-oxoproline synthesis than administration of T-2-aminobutyrate sug gested that the kidney can at least in part absorb intact 7-glutamyl peptides. This conclu sion was supported by the observation that injections of trace amounts of L-y-[xa Cj-glutamyl-2-aminobutyrate resulted in production of ophthalmic acid (7-glutamyl-2-aminobutyrylglycine) of identical specific radioactivity as the injected material (62,63). Renal absorption of intact 7-glutamyl amino acids was further sup ported by the finding that injected 7-glutamyl-2-aminobutyrate was a much more efficient precursor of ophthalmic acid than injected L-2-aminobutyrate (63).…”

Design, Synthesis and Initial In Vitro Evaluation of Novel Prodrugs for the Treatment of Cystinosis

“…Furthermore, γ -glutamyl residues are unusual in biological systems and are found associated almost exclusively with the glutathione cycle; hence, this targeting strategy is selective for these cells. Despite the fact that GGT is expressed by many cells, experiments with a range of 13 C-labeled γ -glutamyl-amino acids noted that the greatest uptake of γ -glutamyl-dipeptides was demonstrated by kidney cells in the murine tissues used for these experiments [25]. Thus, the expected selective absorption of γ -glutamylcysteamine and γ -glutamylcystamine by these cells should lead to the intracellular release of cysteamine or cystamine in the kidney cells, resulting in a concomitant reduction of cystine.…”

Importance and Regulation of Hepatic Glutathione

“…However, the major enzymatic degradation normally involves the action of -y-glutamyltranspeptidase [13,14], a brush border enzyme of renal tubular cells [15], and intestinal epithelium [16] for which no significant role has been demonstrated in liver [17]. The principal mechanism of hepatocyte glutathione turnover appears to be efflux [3,18].…”