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dc.contributor.author Ruggiero, Melina
dc.contributor.author Curto, Lucrecia María
dc.contributor.author Brunetti, Florencia Lourdes
dc.contributor.author Sauvage, Eric
dc.contributor.author Galleni, Moreno
dc.contributor.author Power, Pablo
dc.contributor.author Gutkind, Gabriel Osvaldo
dc.date.available 2018-06-04T20:31:39Z
dc.date.issued 2017-06
dc.identifier.citation Ruggiero, Melina; Curto, Lucrecia María; Brunetti, Florencia Lourdes; Sauvage, Eric; Galleni, Moreno; et al.; Impact of mutations at Arg220 and Thr237 in PER-2 β-Lactamase on conformation, activity, and susceptibility to inhibitors; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 61; 6; 6-2017; 1-29; e02193
dc.identifier.issn 0066-4804
dc.identifier.uri http://hdl.handle.net/11336/47225
dc.description.abstract PER-2 accounts for up to 10% of oxyimino-cephalosporin resistance in Klebsiella pneumoniae and Escherichia coli in Argentina and hydrolyzes both cefotaxime and ceftazidime with high catalytic efficiencies (kcat/Km). Through crystallographic analyses, we recently proposed the existence of a hydrogen bond network connecting Ser70-Gln69-oxyanion water-Thr237-Arg220 that might be important for the activity and inhibition of the enzyme. Mutations at Arg244 in most class A β -lactamases (such as TEM and SHV) reduce susceptibility to mechanism-based inactivators, and Arg220 in PER β -lactamases is equivalent to Arg244. Alterations in the hydrogen bond network of the active site in PER-2, through modifications in key residues such as Arg220 and (to a much lesser extent) Thr237, dramatically impact the overall susceptibility to inactivation, with up to 300-And 500-fold reductions in the rate constant of inactivation (kinact)/Kivalues for clavulanic acid and tazobactam, respectively. Hydrolysis on cephalosporins and aztreonam was also affected, although to different extents compared to with wild-Type PER-2; for cefepime, only an Arg220Gly mutation resulted in a strong reduction in the catalytic efficiency. Mutations at Arg220 entail modifications in the catalytic activity of PER-2 and probably local perturbations in the protein, but not global conformational changes. Therefore, the apparent structural stability of the mutants suggests that these enzymes could be possibly selected in vivo.
dc.format application/pdf
dc.language.iso eng
dc.publisher American Society for Microbiology
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject ARG220
dc.subject CEFOTAXIMASE
dc.subject CEFTAZIDIMASE
dc.subject ESBL
dc.subject INHIBITOR RESISTANT
dc.subject MECHANISM-BASED INHIBITOR
dc.subject THR237
dc.subject.classification Otras Ciencias Biológicas
dc.subject.classification Ciencias Biológicas
dc.subject.classification CIENCIAS NATURALES Y EXACTAS
dc.title Impact of mutations at Arg220 and Thr237 in PER-2 β-Lactamase on conformation, activity, and susceptibility to inhibitors
dc.type info:eu-repo/semantics/article
dc.type info:ar-repo/semantics/artículo
dc.type info:eu-repo/semantics/publishedVersion
dc.date.updated 2018-06-04T17:02:05Z
dc.journal.volume 61
dc.journal.number 6
dc.journal.pagination 1-29; e02193
dc.journal.pais Estados Unidos
dc.journal.ciudad Washington DC
dc.description.fil Fil: Ruggiero, Melina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil Fil: Curto, Lucrecia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina
dc.description.fil Fil: Brunetti, Florencia Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil Fil: Sauvage, Eric. Université de Liège; Bélgica
dc.description.fil Fil: Galleni, Moreno. Université de Liège; Bélgica
dc.description.fil Fil: Power, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.description.fil Fil: Gutkind, Gabriel Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología; Argentina
dc.journal.title Antimicrobial Agents and Chemotherapy
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1128/AAC.02193-16
dc.relation.alternativeid info:eu-repo/semantics/altIdentifier/url/aac.asm.org/content/61/6/e02193-16
dc.conicet.fuente Elsevier


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    Articulos de INST.DE QUIMICA Y FISICO-QUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"

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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)