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  • Title: Common mechanistic features among metallo-beta-lactamases: a computational study of Aeromonas hydrophila CphA enzyme.
    Author: Simona F, Magistrato A, Dal Peraro M, Cavalli A, Vila AJ, Carloni P.
    Journal: J Biol Chem; 2009 Oct 09; 284(41):28164-28171. PubMed ID: 19671702.
    Abstract:
    Metallo-beta-lactamases (MbetaLs) constitute an increasingly serious clinical threat by giving rise to beta-lactam antibiotic resistance. They accommodate in their catalytic pocket one or two zinc ions, which are responsible for the hydrolysis of beta-lactams. Recent x-ray studies on a member of the mono-zinc B2 MbetaLs, CphA from Aeromonas hydrophila, have paved the way to mechanistic studies of this important subclass, which is selective for carbapenems. Here we have used hybrid quantum mechanical/molecular mechanical methods to investigate the enzymatic hydrolysis by CphA of the antibiotic biapenem. Our calculations describe the entire reaction and point to a new mechanistic description, which is in agreement with the available experimental evidence. Within our proposal, the zinc ion properly orients the antibiotic while directly activating a second catalytic water molecule for the completion of the hydrolytic cycle. This mechanism provides an explanation for a variety of mutagenesis experiments and points to common functional facets across B2 and B1 MbetaLs.
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