期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 23, 期 16, 页码 1559-1576出版社
JOHN WILEY & SONS INC
DOI: 10.1002/jcc.10129
关键词
beta-lactamases; penicillin-binding proteins; catalytic mechanism; acylation step
资金
- NIAID NIH HHS [AI-09998] Funding Source: Medline
- NIGMS NIH HHS [GM-29072] Funding Source: Medline
The acylation step of the catalytic mechanism of beta-lactamases and penicillin-binding proteins (PBPs) has been studied with various approaches. The methods applied range from molecular dynamics (MD) simulations to multiple titration calculations using the Poisson-Boltzmann approach to quantum mechanical (QM) methods. The mechanism of class A beta-lactamases was investigated in the greatest detail. Most approaches support the critical role of Glu-166 and hydrolytic water in the acylation step of the enzymatic catalysis in class A beta-lactamases. The details of the catalytic mechanism have been revealed by the QM approach, which clearly pointed out the critical role of Glu-166 acting as a general base in the acylation step with preferred substrates. Lys-73 shuffles a proton abstracted by Glu-166 O-epsilon. to the beta-lactam nitrogen through Ser-130 hydroxyl. This proton is transferred from O-gamma of the catalytic Ser-70 through the bridging hydrolytic water to Glu-166 O-epsilon. Then the hydrogen is simultaneously passed through S(N)2 inversion mechanism at Lys-73 N-zeta to Ser-130 O-gamma which loses its proton to the beta-lactam nitrogen. The protonation of beta-lactam nitrogen proceeds with an immediate ring opening and collapse of the first tetrahedral species into an acyl-enzyme intermediate. However, the studies that considered the effect of solvation lower the barrier for the pathway, which utilizes Lys-73 as a general base, thus creating a possibility of multiple mechanisms for the acylation step in the class A beta-lactamases. These findings help explain the exceptional efficiency of these enzymes. They emphasize an important role of Glu-166, Lys-73, and Ser-130 for enzymatic catalysis and shed light on details of the acylation step of class A beta-lactamase mechanism. The acylation step for class C beta-lactamases and six classes of PBPs were also considered with continuum solvent models and MD simulations. (C) 2002 Wiley Periodicals, Inc.
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