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Kinetic and Molecular‐Modelling Studies of Reactions of a Class‐A β ‐Lactamase with Compounds Bearing a Methoxy Group on the β ‐Lactam Ring
Author(s) -
Vilanova Bartolomé,
Donoso Josefa,
Frau Juan,
Muñoz Francisco
Publication year - 1999
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(19990804)82:8<1274::aid-hlca1274>3.0.co;2-r
Subject(s) - chemistry , acylation , cefoxitin , stereochemistry , enzyme , ring (chemistry) , lactam , cefmetazole , moxalactam , staphylococcus aureus , organic chemistry , catalysis , biochemistry , cephalosporin , bacteria , antibiotics , biology , genetics
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 > k 3 ( Scheme 1 ), whereas for 2 k ′ 3 ≈ k 3 . 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 K S and k 2 with the structures of the Henri‐Michaelis complexes that these compounds formed with the S. aureus enzyme. The acylation rate constant ( k 2 ) 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 K S . An increase of 0.2 – 0.5 Å in this average value was found to result in an increase in K S by about one order of magnitude.