Common Mechanistic Features among Metallo-beta-lactamases A COMPUTATIONAL STUDY OF AEROMONAS HYDROPHILA CphA ENZYME

F.SIMONA, A.MAGISTRATO, M.DAL PERARO, A.CAVALLI, A.J.VILA AND P.CARLONI

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: USA; Año: 2009 vol. 284 p. 28164 - 28171

0021-9258

Common Mechanistic Features among Metallo-
-lactamasesA COMPUTATIONAL STUDY OF AEROMONAS HYDROPHILA CphA ENZYME□SMetallo-beta-lactamases (MbLs) constitute an increasingly seriousclinical threat by giving rise to beta-lactam antibiotic resistance.They accommodate in their catalytic pocket one or twozinc ions, which are responsible for the hydrolysis of beta-lactams.Recent x-ray studies on a member of the mono-zinc B2 MbLs,CphAfrom Aeromonas hydrophila, have paved the way to mechanisticstudies of this important subclass, which is selective forcarbapenems. Here we have used hybrid quantum mechanical/molecular mechanical methods to investigate the enzymatichydrolysis by CphA of the antibiotic biapenem. Our calculationsdescribe the entire reaction and point to a new mechanisticdescription, which is in agreement with the available experimentalevidence. Within our proposal, the zinc ion properly orientsthe antibiotic while directly activating a second catalyticwater molecule for the completion of the hydrolytic cycle. Thismechanism provides an explanation for a variety of mutagenesisexperiments and points to common functional facets across B2and B1MbLs.