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- Title
Kinetic and Molecular-Modelling Studies of Reactions of a Class-A β-Lactamase with Compounds Bearing a Methoxy Group on the β-Lactam Ring.
- Authors
Vilanova, Bartolomé; Donoso, Josefa; Frau, Juan; Muñoz, Francisco
- Abstract
The interactions between Staphylococcus aureus PC1 enzyme and compounds bearing a methoxy group on the α-face of the β-lactam ring (cefmetazole ( 1), moxalactam ( 2) and cefoxitin ( 3)) were studied. With these compounds, a partitioning of the acyl-enzyme between deacylation and a transiently inactivated form of the enzyme were observed. The individual microscopic rate constants were determined, indicating for 1 and 3 that k′3> k3 ( Scheme 1), whereas for 2 k′3≈ k3. This different behavior could be attributed to the presence of the α-carboxy group at the C(7) side chain of 2, which is able to act as a general-base catalyst in the deacylation step. Molecular-modelling studies allowed correlation of KS and k2 with the structures of the Henri-Michaelis complexes that these compounds formed with the S. aureus enzyme. The acylation rate constant ( k2) for these ` β-lactamase-stable' compounds was lower than that observed with substrates lacking the methoxy group. Molecular-modelling studies indicated that the methoxy group increases the displacement of the crystallographically observed water molecule (Wat81), which is involved in the acylation mechanism. On the other hand, an average of the most important interactions in the Henri-Michaelis complexes was related to KS. An increase of 0.2 - 0.5 Å in this average value was found to result in an increase in KS by about one order of magnitude.
- Publication
Helvetica Chimica Acta, 1999, Vol 82, Issue 8, p1274
- ISSN
0018-019X
- Publication type
Article
- DOI
10.1002/(SICI)1522-2675(19990804)82:8<1274::AID-HLCA1274>3.0.CO;2-R