Meropenem and chromacef intermediates observed in IMP-25 metallo-β-lactamase-catalyzed hydrolysis.
Metallo-β-lactamases inactivate most β-lactam antibacterials, and much attention has been paid to their catalytic mechanism. One issue of controversy has been whether β-lactam hydrolysis generally proceeds through an anionic intermediate bound to the active-site Zn(II) ions or not. The formation of an intermediate has not been shown conclusively in imipenemase (IMP) enzymes to date. Here, we provide evidence that intermediates are formed during the hydrolysis of meropenem and chromacef catalyzed by the variant IMP-25 and, to a lesser degree, IMP-1.
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA poelschlaeger@westernu.edu.
Peter
P
Oelschlaeger
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.
Mahesh
M
Aitha
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.
Hao
H
Yang
Department of Biological Sciences, California State Polytechnic University, Pomona, California, USA.
Joon S
JS
Kang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA.
Antonia L
AL
Zhang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, California, USA.
Eleanor M
EM
Liu
Department of Chemistry, Southern Methodist University, Dallas, Texas, USA.
John D
JD
Buynak
Department of Chemistry and Biochemistry, Miami University, Oxford, Ohio, USA.
Michael W
MW
Crowder
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002384:Catalysis; D020134:Catalytic Domain; D002511:Cephalosporins / Q000378:metabolism*; D006868:Hydrolysis; D007700:Kinetics; D000077731:Meropenem; D013845:Thienamycins / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D013845:Thienamycins; C000605808:chromacef; D001618:beta-Lactamases; D000077731:Meropenem; D015032:Zinc