Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamase
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Otros documentos de la autoría: Meliá, Conchín; Ferrer Castillo, Silvia; Moliner, Vicent; Bertrán, Juan
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Título
Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamaseFecha de publicación
2015-09-15Editor
ElsevierISSN
0003-9861Cita bibliográfica
MELIÁ, Conchín, et al. Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-β-lactamase. Archives of biochemistry and biophysics, 2015, vol. 582, p. 116-126.Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://www.sciencedirect.com/science/article/pii/S0003986115000363Versión
info:eu-repo/semantics/acceptedVersionPalabras clave / Materias
Resumen
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been
performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI),
an antibiotic belonging to the subgroup of carbapenems, ... [+]
In this paper, hybrid QM/MM molecular dynamics (MD) simulations have been
performed to explore the mechanisms of hydrolysis of two antibiotics, Imipenen (IMI),
an antibiotic belonging to the subgroup of carbapenems, and the Cefotaxime (CEF), a
third-generation cephalosporin antibiotic, in the active site of a mono-nuclear β-
lactamase, CphA from Aeromonas hydrophila. According to our results, significant
different transition state structures are obtained for the hydrolysis of both antibiotics:
while the TS of the CEF is a ionic species with negative charge on nitrogen, the IMI TS
presents a tetrahedral-like character with negative charge on oxygen atom of the
carbonyl group of the lactam ring. Thus, dramatic conformational changes can take
place in the cavity of CphA to accommodate different substrates, which would be the
origin of its substrate promiscuity. This feature of the β-lactamase would be in turn,
associated to the different mechanisms that the protein employs to hydrolyze the
different antibiotics; i.e. the catalytic promiscuity. Since CphA shows only activity
against carbapenem antibiotic, this study will be used to shed some light into the origin
of the selectivity of the different MbL and, as a consequence, into the discovery of
specific and potent MβL inhibitors against a broad spectrum of bacterial pathogens. [-]
Publicado en
Archives of biochemistry and biophysics, 2015, vol. 582Derechos de acceso
Copyright © 2015 Elsevier Inc. All rights reserved.
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