Metallo-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. [10.1074/jbc.M109.049502]
|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.|
|Data di pubblicazione:||2009|
|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|