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Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamase
dc.contributor.author | Meliá, Conchín | |
dc.contributor.author | Ferrer Castillo, Silvia | |
dc.contributor.author | Moliner, Vicent | |
dc.contributor.author | Bertrán, Juan | |
dc.date.accessioned | 2016-03-22T10:41:49Z | |
dc.date.available | 2016-03-22T10:41:49Z | |
dc.date.issued | 2015-09-15 | |
dc.identifier.citation | 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. | ca_CA |
dc.identifier.issn | 0003-9861 | |
dc.identifier.uri | http://hdl.handle.net/10234/154805 | |
dc.description.abstract | 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. | ca_CA |
dc.description.sponsorShip | We thank FEDER and the Spanish Ministerio de Economía y Competitividad (project CTQ2012-36253-C03), Universitat Jaume I (project P1 1B2011-23) and Generalitat Valenciana (PROMETEOII/2014/022 and ACOMP/2014/277 projects) | ca_CA |
dc.format.extent | 24 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | Elsevier | ca_CA |
dc.relation.isPartOf | Archives of biochemistry and biophysics, 2015, vol. 582 | ca_CA |
dc.rights | Copyright © 2015 Elsevier Inc. All rights reserved. | ca_CA |
dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | * |
dc.subject | mono zinc metallo-beta-lactamases | ca_CA |
dc.subject | MβLs | ca_CA |
dc.subject | CphA | ca_CA |
dc.subject | imipenen | ca_CA |
dc.subject | cefotaxime | ca_CA |
dc.subject | reaction mechanism | ca_CA |
dc.subject | QM/MM | ca_CA |
dc.subject | carbapenem | ca_CA |
dc.subject | cephalosporine | ca_CA |
dc.subject | free energy profiles | ca_CA |
dc.title | Theoretical studies of the hydrolysis of antibiotics catalyzed by a metallo-B-lactamase | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | http://dx.doi.org/10.1016/j.abb.2015.01.013 | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.relation.publisherVersion | http://www.sciencedirect.com/science/article/pii/S0003986115000363 | ca_CA |
dc.type.version | info:eu-repo/semantics/acceptedVersion | ca_CA |
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