Formation of a tetrahedral intermediate by nucleophilic attack on the
beta-lactam carbonyl carbon of penicillins generates a lone pair on th
e beta-lactam nitrogen which is syn to the incoming nucleophile, in co
ntrast to the normal anti arrangement found in peptides. Ring opening
of the beta-lactam requires protonation of the beta-lactam nitrogen by
a general acid catalyst. The general acid/base catalyst in beta-lacta
mases is probably a glutamate and a tyrosine residue in class A and C
enzymes, respectively. Phosphonamidates inactivate class C beta-lactam
ases by phosphonylation of the active site serine, the rate of which i
s enhanced by a factor of at least 10(6). The enzyme's catalytic machi
nery used for hydrolysis is also used for phosphonylation. The rate en
hancement may be greater than 10(9) if the mechanism occurs by an inhi
bitor assisted reaction involving intramolecular general acid catalysi
s, Class B metallo-beta-lactamases are inhibited by thiol derivatives
with K-i as low as 10 mu M. The mechanism of hydrolysis of the metallo
-beta-lactamase involves a dianionic tetrahedral intermediate stabilis
ed by zinc(II).