INVESTIGADORES
VILA Alejandro Jose
artículos
Título:
Common Mechanistic Features among Metallo-beta-lactamases A COMPUTATIONAL STUDY OF AEROMONAS HYDROPHILA CphA ENZYME
Autor/es:
F.SIMONA; A. MAGISTRATO; M.DAL PERARO; A. CAVALLI; P. CARLONI; A. J. VILA
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Año: 2009 vol. 284 p. 28164 - 28171
ISSN:
0021-9258
Resumen:
Metallo--lactamases (MLs) constitute an increasingly serious
clinical threat by giving rise to -lactam antibiotic resistance.
They accommodate in their catalytic pocket one or two
zinc ions, which are responsible for the hydrolysis of -lactams.
Recent x-ray studies on a member of the mono-zinc B2 MLs,
CphAfrom 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 B1MLs