title: Common mechanistic features among metallo-beta-lactamases: a computational study of Aeromonas hydrophila CphA enzyme.
abstract: Metallo-beta-lactamases (MbetaLs) 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 MbetaLs, 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 MbetaLs.
authors: Laboratory of Computational Chemistry and Biochemistry, Department für Chemie und Biochemie, Universität Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
authors: Fabio
authors: F
authors: Simona
authors: CNR-INFM-Democritos National Simulation Center, via Beirut 4, 34014 Grignano, Trieste, Italy; SISSA, Via Beirut 2-4, 34014 Grignano, Trieste, Italy.
authors: Alessandra
authors: A
authors: Magistrato
authors: Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, EPFL, CH-1015 Lausanne, Switzerland.
authors: Matteo
authors: M
authors: Dal Peraro
authors: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy; Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, I-16163 Genova, Italy.
authors: Andrea
authors: A
authors: Cavalli
authors: Instituto de BiologiaMolecular y Celular de Rosario, Facultad de Bioquímicas y Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
authors: Alejandro J
authors: AJ
authors: Vila
authors: SISSA, Via Beirut 2-4, 34014 Grignano, Trieste, Italy. Electronic address: carloni@sissa.it.
authors: Paolo
authors: P
authors: Carloni
mesh_terms: D016980:Aeromonas hydrophila / Q000201:enzymology* / Q000235:genetics; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D004352:Drug Resistance, Microbial / Q000502:physiology; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011789:Quantum Theory; D013379:Substrate Specificity; D013845:Thienamycins / Q000737:chemistry / Q000378:metabolism; D001618:beta-Lactamases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D013845:Thienamycins; D001618:beta-Lactamases; C082063:cphA protein, Aeromonas hydrophila; C065257:biapenem