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Issue 7, 2014
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A variety of roles for versatile zinc in metallo-β-lactamases

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Abstract

Metallo-β-lactamases are important as a major source of resistance of pathogenic bacteria to the widely used β-lactam antibiotics. They show considerable diversity in terms of sequence and are grouped into three subclasses, B1, B2 and B3, which share a common overall fold. In each case the active enzyme has binding sites for two zinc ions in close proximity, although the amino-acid residues which coordinate the metals vary from one subclass to another. In subclasses B1 and B3, there has been controversy about whether both zinc ions are required for activity, but the most recent evidence indicates that there is positive cooperativity in zinc binding and that the catalytically relevant species is the di-zinc enzyme. Subclass B2 enzymes, on the other hand, are active in the mono-zinc state and are inhibited by the binding of a second zinc ion. Evidence for the importance of the zinc ions in substrate binding has come from structures of product complexes which indicate that the β-lactam core binds to subclass B1 and B3 enzymes in a rather consistent fashion, interactions with the zinc ions being centrally important. The zinc ions play key roles in the catalytic mechanism, including facilitating nucleophilic attack on the amide carbonyl by the zinc-bound hydroxide ion, stabilising the anionic tetrahedral intermediate and coordinating the departing amine nitrogen.

Graphical abstract: A variety of roles for versatile zinc in metallo-β-lactamases

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Publication details

The article was received on 03 Mar 2014, accepted on 25 Mar 2014 and first published on 26 Mar 2014


Article type: Critical Review
DOI: 10.1039/C4MT00066H
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Citation: Metallomics, 2014,6, 1181-1197

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    A variety of roles for versatile zinc in metallo-β-lactamases

    A. I. Karsisiotis, C. F. Damblon and G. C. K. Roberts, Metallomics, 2014, 6, 1181
    DOI: 10.1039/C4MT00066H

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