The mechanism of catalysis and the inhibition of β-lactamases

Michael I. Page, Andrew P. Laws

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Formation of a tetrahedral intermediate by nucleophilic attack on the β-lactam carbonyl carbon of penicillins generates a lone pair on the β-lactam nitrogen which is syn to the incoming nucleophile, in contrast to the normal anti arrangement found in peptides. Ring opening of the β-lactam requires protonation of the β-lactam nitrogen by a general acid catalyst. The general acid/base catalyst in β-lactamases is probably a glutamate and a tyrosine residue in class A and C enzymes, respectively. Phosphonamidates inactivate class C β-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-β-lactamases are inhibited by thiol derivatives with K(i) as low as 10 μM. The mechanism of hydrolysis of the metallo-β-lactamase involves a dianionic tetrahedral intermediate stabilised by zinc(II).

LanguageEnglish
Pages1609-1617
Number of pages9
JournalChemical Communications
Issue number16
DOIs
Publication statusPublished - 21 Aug 1998

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beta-Lactams
beta-Lactamases
Catalysis
Acids
Hydrolysis
Nitrogen
Enzymes
Nucleophiles
Catalysts
Protonation
Sulfhydryl Compounds
Penicillins
Serine
Peptides
Machinery
Tyrosine
Zinc
Glutamic Acid
Carbon
Derivatives

Cite this

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The mechanism of catalysis and the inhibition of β-lactamases. / Page, Michael I.; Laws, Andrew P.

In: Chemical Communications, No. 16, 21.08.1998, p. 1609-1617.

Research output: Contribution to journalArticle

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