Mechanism of inactivation of glutamine amidotransferases by the antitumor drug L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125).
L-(alphaS, 5S)-alpha-Amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), an antitumor drug isolated from Streptomyces sviceus, is an active site-directed affinity analog of glutamine. It selectively inactivates the glutamine-dependent activities of two bacterial glutamine amidotransferases, anthranilate synthase and glutamate synthase. A reversible noncovalent complex is formed prior to irreversible enzyme modification. Inactivation of anthranilate synthase results from incorporation of approximately 1 eq of AT-125/enzyme protomer. Active site cysteine-83 in Serratia marcescens anthranilate synthase Component II is the residue alkylated by AT-125. Anthranilate synthase is rapidly inactivated by AT-125 IN S. marcescens cells. In vivo inactivation is by the same mechanism as in vitro.
D000878:Anthranilate Synthase / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D005970:Glutamate Synthase / Q000378:metabolism; D005973:Glutamine / Q000037:antagonists & inhibitors; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology*; D007700:Kinetics; D019884:Nitrogenous Group Transferases; D010080:Oxazoles / Q000494:pharmacology*; D012706:Serratia marcescens / Q000201:enzymology; D014166:Transferases / Q000037:antagonists & inhibitors*
D007555:Isoxazoles; D010080:Oxazoles; D005973:Glutamine; D005970:Glutamate Synthase; D014166:Transferases; D019884:Nitrogenous Group Transferases; D000878:Anthranilate Synthase; C020655:anthranilate synthase, glutamine amidotransferase subunit; C006303:acivicin; D005998:Glycine