The binding mechanism of glutathione and the anti-tumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125;NSC-163501) to gamma-glutamyltransferase.
The glutathione-protein binding interactions of rat renal gamma-glutamyltransferase (gamma GT) were studied by examining the effect of phenylglyoxal (PGO), a chemical modifying agent for arginyl residues. PGO inactivation of gamma GT followed pseudo-first order kinetics and the rate was dependent upon the concentration of PGO. Glutathione (GSH) protected the enzyme from inactivation by PGO. The anti-tumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) inactivated purified gamma GT. The inactivation capability of AT-125 was abolished by esterification of the carboxyl moiety and was regained upon incubation of AT-125 methyl ester with a carboxyl esterase. AT-125 and glutathione may bind to gamma GT via the electrostatic interaction of their respective carboxyl group(s) and an arginyl residue at the active site.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D001665:Binding Sites; D005978:Glutathione / Q000378:metabolism*; D007555:Isoxazoles / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D010080:Oxazoles / Q000378:metabolism*; D010658:Phenylglyoxal / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D000970:Antineoplastic Agents; D007555:Isoxazoles; D010080:Oxazoles; D001120:Arginine; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D010658:Phenylglyoxal; C006303:acivicin