Modulation of gamma-glutamyl transpeptidase activity by bile acids.
The free bile acids (cholate, chenodeoxycholate, and deoxycholate) stimulate the hydrolysis and transpeptidation reactions catalyzed by gamma-glutamyl transpeptidase, while their glycine and taurine conjugates inhibit both reactions. Kinetic studies using D-gamma-glutamyl-p-nitroanilide as gamma-glutamyl donor indicate that the free bile acids decrease the Km for hydrolysis and increase the Vmax; transpeptidation is similarly activated. The conjugated bile acids increase the Km and Vmax of hydrolysis and decrease both of these for transpeptidation. This mixed type of modulation has also been shown to occur with hippurate and maleate (Thompson, G.A., and Meister, A. (1980) J. Biol. Chem. 255, 2109-2113). Glycine conjugates are substantially stronger inhibitors than the taurine conjugates. The results with free cholate indicate the presence of an activator binding domain on the enzyme with minimal overlap on the substrate binding sites. In contrast, the conjugated bile acids, like maleate and hippurate, may overlap on the substrate binding sites. The results suggest a potential feedback role for bile ductule gamma-glutamyl transpeptidase, in which free bile acids activate the enzyme to catabolize biliary glutathione and thus increase the pool of amino acid precursors required for conjugation (glycine directly and taurine through cysteine oxidation). Conjugated bile acids would have the reverse effect by inhibiting ductule gamma-glutamyl transpeptidase.
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002793:Cholic Acids / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005971:Glutamates / Q000378:metabolism; D005973:Glutamine / Q000031:analogs & derivatives; D006000:Glycocholic Acid / Q000494:pharmacology; D006868:Hydrolysis; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D010189:Pancreatic Juice / Q000201:enzymology; D051381:Rats; D013656:Taurocholic Acid / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001647:Bile Acids and Salts; D002793:Cholic Acids; D005971:Glutamates; D005973:Glutamine; D013656:Taurocholic Acid; C001300:gamma-glutamine-4-nitroanilide; D005723:gamma-Glutamyltransferase; D006000:Glycocholic Acid