The reactivity of beta-lactams, the mechanism of catalysis and the inhibition of beta-lactamases

Four membered beta-lactam rings do not show unusual reactivity compared wit h their acyclic amide analogues and there is no evidence of concerted mecha nisms for nucleophilic substitution reactions at the carbonyl centre, The i dentity of the general base/acid catalyst in the serine beta-lactamases, wh ich catalyse the hydrolysis of beta-lactams, is unknown. There are no ideal transition state analogue inhibitors for these enzymes which involve sever al intermediates and transition states. The class C serine beta-lactamase e nhances the rate of phosphonylation of its active site serine residue by a similar magnitude to the enzyme rate enhancement factor for the hydrolysis of beta-lactams. Comparisons are made between the stereochemical consequenc es of tetrahedral and trigonal bipyramidal intermediates for hydrolysis and phosphonylation respectively. Class B zinc beta-lactamases are inhibited b y thiol dipeptides with a D configuration at the cysteine centre analogous to the L configuration at C6 in penicillins. The mechanism of hydrolysis ca talysed by the metallo-beta-lactamases probably involves a di-anionic tetra hedral intermediate stabilised by zinc(II).