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

Authors
Citation
Mi. Page, The reactivity of beta-lactams, the mechanism of catalysis and the inhibition of beta-lactamases, CUR PHARM D, 5(11), 1999, pp. 895-913
Citations number
131
Categorie Soggetti
Pharmacology & Toxicology
Journal title
CURRENT PHARMACEUTICAL DESIGN
ISSN journal
13816128 → ACNP
Volume
5
Issue
11
Year of publication
1999
Pages
895 - 913
Database
ISI
SICI code
1381-6128(199911)5:11<895:TROBTM>2.0.ZU;2-R
Abstract
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).