Page, Michael I. and Laws, Andrew P. (1998) The mechanism of catalysis and the inhibition of β-lactamases. Chemical Communications (16). pp. 1609-1617. ISSN 1359-7345Metadata only available from this repository.
Formation of a tetrahedral intermediate by nucleophilic attack on the -lactam carbonyl carbon of penicillins generates a lone pair on the -lactam nitrogen which is syn to the incoming nucleophile, in contrast to the normal anti arrangement found in peptides. Ring opening of the -lactam requires protonation of the -lactam nitrogen by a general acid catalyst. The general acid/base catalyst in -lactamases is probably a glutamate and a tyrosine residue in class A and C enzymes, respectively. Phosphonamidates inactivate class C -lactamases by phosphonylation of the active site serine, the rate of which is enhanced by a factor of at least 106. The enzyme s catalytic machinery used for hydrolysis is also used for phosphonylation. The rate enhancement may be greater than 109 if the mechanism occurs by an inhibitor assisted reaction involving intramolecular general acid catalysis. Class B metallo- -lactamases are inhibited by thiol derivatives with Ki as low as 10 µM. The mechanism of hydrolysis of the metallo- -lactamase involves a dianionic tetrahedral intermediate stabilised by zinc(II).
|Subjects:||Q Science > Q Science (General)|
Q Science > QD Chemistry
|Schools:||School of Applied Sciences|
|Depositing User:||Sharon Beastall|
|Date Deposited:||04 Nov 2009 13:05|
|Last Modified:||04 Nov 2009 13:05|
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