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EnglishMetallo-beta-lactamases (M beta Ls) 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 M beta Ls, 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 M beta Ls.
Common mechanistic features among metallo-beta-lactamases: a computational study of Aeromonas hydrophila CphA enzyme / Simona, F; Magistrato, Alessandra; DAL PERARO, M; Cavalli, A; Vila, Aj; Carloni, P.. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 294:41(2009), pp. 28164-28171.
| Titolo: | Common mechanistic features among metallo-beta-lactamases: a computational study of Aeromonas hydrophila CphA enzyme | |
| Autori: | Simona, F; Magistrato, Alessandra; DAL PERARO, M; Cavalli, A; Vila, Aj; Carloni, P. | |
| Rivista: | ||
| Data di pubblicazione: | 2009 | |
| Volume: | 294 | |
| Fascicolo: | 41 | |
| Pagina iniziale: | 28164 | |
| Pagina finale: | 28171 | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1074/jbc.M109.049502 | |
| Fulltext via DOI: | http://dx.doi.org/10.1074/jbc.M109.049502 | |
| Appare nelle tipologie: | 1.1 Journal article |
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| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| J. Biol. Chem.-2009-Simona-28164-71.pdf | Versione Editoriale (PDF) | Non specificato | Administrator Richiedi una copia |
