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Biochem Pharmacol. 2007 Dec 15;74(12):1686-701. Epub 2007 Jun 2.

Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily.

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1
Center for Protein Engineering/Biological Macromolecules, University of Liège, Allée du 6 Août B6, Sart-Tilman 4000 Liège, Belgium. carine.bebrone@ulg.ac.be

Abstract

One strategy employed by bacterial strains to resist beta-lactam antibiotics is the expression of metallo-beta-lactamases requiring Zn(2+) for activity. In the last few years, many new zinc beta-lactamases have been described and several pathogens are now known to synthesize members of this class. Metallo-beta-lactamases are especially worrisome due to: (1) their broad activity profiles that encompass most beta-lactam antibiotics, including the carbapenems; (2) potential for horizontal transference; and (3) the absence of clinically useful inhibitors. On the basis of the known sequences, three different lineages, identified as subclasses B1, B2, and B3 have been characterized. The three-dimensional structure of at least one metallo-beta-lactamase of each subclass has been solved. These very similar 3D structures are characterized by the presence of an alphabetabetaalpha-fold. In addition to metallo-beta-lactamases which cleave the amide bond of the beta-lactam ring, the metallo-beta-lactamase superfamily includes enzymes which hydrolyze thiol-ester, phosphodiester and sulfuric ester bonds as well as oxydoreductases. Most of the 6000 members of this superfamily share five conserved motifs, the most characteristic being the His116-X-His118-X-Asp120-His121 signature. They all exhibit an alphabetabetaalpha-fold, similar to that found in the structure of zinc beta-lactamases. Many members of this superfamily are involved in mRNA maturation and DNA reparation. This fact suggests the hypothesis that metallo-beta-lactamases may be the result of divergent evolution starting from an ancestral protein which did not have a beta-lactamase activity.

PMID:
17597585
DOI:
10.1016/j.bcp.2007.05.021
[Indexed for MEDLINE]
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