Effect of the 3'-leaving group on turnover of cephem antibiotics by a class C beta-lactamase.
It has been previously demonstrated for class A beta-lactamases and the DD-peptidase of Streptomyces R61 that the presence of a leaving group at the 3'-position of a cephalosporin can lead to the generation of more-inert acyl-enzyme intermediates than from cephalosporins lacking such a leaving group, and thus to beta-lactamase inhibitors and potentially better antibiotics. In the present work we extend this result to a class C beta-lactamase, that of Enterobacter cloacae P99. The effect is not seen with first-generation cephalosporins, since here deacylation generally seems faster than elimination of the leaving group, but it does clearly appear with cephamycins and third-generation cephalosporins. The structural and/or mechanistic features of the active site giving rise to this phenomenon may thus be common to all serine beta-lactamases and transpeptidases.
Mazzella
L J
LJ
Department of Chemistry, Wesleyan University, Middletown.
Pratt
R F
RF
D002506:Cephalexin / Q000031:analogs & derivatives* / Q000378:metabolism; D004754:Enterobacter / Q000201:enzymology; D006868:Hydrolysis; D007700:Kinetics; D001618:beta-Lactamases / Q000378:metabolism*
C028352:cefems; D001618:beta-Lactamases; D002506:Cephalexin