Effects of bile acids and their glycine conjugates on gamma-glutamyl transpeptidase.
Glycine and taurine conjugates of bile acids modulate gamma-glutamyl transpeptidase by interacting with the cysteinylglycine binding site (acceptor site) of the enzyme. These compounds stimulate hydrolysis of glutamine and S-methylglutathione and the rate of the inactivation of the enzyme by the gamma-glutamyl site-directed reagent, AT-125 (L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid). Transpeptidation between S-methylglutathione and methionine was inhibited by these compounds. These effects resemble those caused by hippurate; the glycine derivatives of bile acids, however, exhibit a much greater affinity for transpeptidase than hippurate. Cholate, as shown previously for benzoate, also seems to bind to a portion of the acceptor site as indicated by its effects on S-methylglutathione utilization and AT-125-dependent inactivation of the enzyme. The Kd values for cholate and benzoate are, however, at least one order of magnitude larger than those for their respective glycine derivatives. The acceptor site-directed modulators increase the affinity of the enzyme for AT-125 and kinetic and binding studies show that binding of gamma-glutamyl site-directed reagents increases the affinity of the enzyme for cholate. These results thus indicate cooperative interactions between the gamma-glutamyl donor and acceptor binding domains of the transpeptidase active center.
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D019817:Benzoic Acid; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002793:Cholic Acids / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism*; D006000:Glycocholic Acid / Q000494:pharmacology; D006626:Hippurates / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D051381:Rats; D013329:Structure-Activity Relationship; D013656:Taurocholic Acid / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D001565:Benzoates; D001647:Bile Acids and Salts; D002793:Cholic Acids; D006626:Hippurates; D007555:Isoxazoles; D013656:Taurocholic Acid; D019817:Benzoic Acid; D005723:gamma-Glutamyltransferase; D006000:Glycocholic Acid; C006303:acivicin; C030514:hippuric acid; D005998:Glycine