B. Vilanova et al., Kinetic and molecular-modelling studies of reactions of a class-A beta-lactamase with compounds bearing a methoxy group on the beta-lactam ring, HELV CHIM A, 82(8), 1999, pp. 1274-1288
The interactions between Staphylococcus aureus PC1 enzyme and compounds bea
ring a methoxy group on the alpha-face of the beta-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 in
activated form of the enzyme were: observed. The individual microscopic rat
e constants were determined, indicating for 1 and 3 that k'(3)>k(3) (Scheme
1),whereas for 2 k'(3) approximate to k(3). This different behavior could
be attributed to the presence of the alpha-carboxy group at the C(7) side c
hain of 2, which is able to act as a general-base catalyst in the deacylati
on step. Molecular-modelling studies allowed correlation of K-s and k(2) wi
th the structures of the Henri-Michaelis complexes that these compounds for
med with the S. aureus enzyme. The acylation rate constant(k(2)) for these
'beta-lactamase-stable' compounds was lower than that observed with substra
tes lacking the methoxy group. Molecular-modelling studies indicated that t
he methoxy group increases the: displacement of the crystallo-graphically o
bserved water molecule (Wat81),which is involved in the acylation mechanism
; On the other hand, an average of the most important interactions in the H
enri-Michaelis complexes was related to K-s. An increase of 0.2-0.5 Angstro
m in this average value was found to result in an increase in K-s by about
one order of magnitude.