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J. Biol. Chem., Vol. 255, Issue 14, 6734-6738, 07, 1980
JY Tso, SG Bower and H Zalkin
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.
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)
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