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Review
. 2009 Oct;10(5):401-7.
doi: 10.2174/138920309789351967.

Three decades of the class A beta-lactamase acyl-enzyme

Jed F Fisher  1 , Shahriar Mobashery
Affiliations
Review

Three decades of the class A beta-lactamase acyl-enzyme

Jed F Fisher et al. Curr Protein Pept Sci. 2009 Oct.

Abstract

The discovery that the mechanism of beta-lactam hydrolysis catalyzed by the class A (active site serine-dependent) beta-lactamases proceeds via an acyl-enzyme intermediate was made thirty years ago. Since this discovery, the active site circumstance that enables acylation of the active site serine and further enables hydrolytic deacylation of the acyl-serine intermediate, has received extraordinary scrutiny. The justification for this scrutiny is the direct relevance of the beta-lactamases to the manifestation of bacterial resistance to the beta-lactam antibiotics, and the subsequent (to the discovery of the beta-lactamase acyl-enzyme) recognition of the direct evolutionary relationship between the serine beta-lactamase acyl-enzyme, and the penicillin binding protein acyl-enzyme that is key to beta-lactam antibiotic activity. This short review describes the early events leading to the recognition that serine beta-lactamase catalysis proceeds via an acyl-enzyme intermediate, and summarizes several of the key mechanistic studies--including infrared spectroscopy, cryoenzymology, beta-lactam design, and x-ray crystallography--that have been exploited to understand this pivotal catalytic intermediate.

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Figures

Fig. (1).
Fig. (1).
Comparison of the structures of an N-acyl d-Ala-d-Ala dipeptide (left) and an N-acyl penicillin (right).
Fig. (2).
Fig. (2).
Two-dimensional representation of key active site residues, and the hydrolytic water, in a class A β-lactamase (TEM numbering) arranged around a penicillin substrate.
Fig. (3).
Fig. (3).
Structures of desthio-benzylpenicillin and cefoxitin, a 7α-methoxy-substituted cephalosporin.
Fig. (4).
Fig. (4).
Structures of 6α-hydroxymethylpenam (left) and 6α-[(α-hydroxy-α-methyl)ethyl]penam (right), designed as inhibitors of the serine β-lactamases.
Fig. (5).
Fig. (5).
Ser70 β-lactamase acyl-enzyme formed from the 6a-hydroxymethyl-substituted penam inhibitor.
Fig. (6).
Fig. (6).
Structure of the NMC-A β-lactamase acyl-enzyme derived from 6α-[(α-hydroxy-α-methyl)ethyl]penam (1.9 Å resolution, PDB Code 1BUL). The hydrolytic water is shown as a dotted spherical surface.
See this image and copyright information in PMC

References

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