title: Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily.
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.
authors.affiliation: Center for Protein Engineering/Biological Macromolecules, University of Liège, Allée du 6 Août B6, Sart-Tilman 4000 Liège, Belgium. carine.bebrone@ulg.ac.be
authors.forename: Carine
authors.initials: C
authors.lastname: Bebrone
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D015032:Zinc / Q000737:chemistry*; D001618:beta-Lactamases / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D001618:beta-Lactamases; D015032:Zinc