A variety of roles for versatile zinc in metallo-b-lactamases

Metallo-b-lactamases are important as a major source of resistance of pathogenic bacteria to the widely
used b-lactam antibiotics. They show considerable diversity in terms of sequence and are grouped into
three subclasses, B1, B2 and B3, which share a common overall fold. In each case the active enzyme has
binding sites for two zinc ions in close proximity, although the amino-acid residues which coordinate
the metals vary from one subclass to another. In subclasses B1 and B3, there has been controversy
about whether both zinc ions are required for activity, but the most recent evidence indicates that there
is positive cooperativity in zinc binding and that the catalytically relevant species is the di-zinc enzyme.
Subclass B2 enzymes, on the other hand, are active in the mono-zinc state and are inhibited by the
binding of a second zinc ion. Evidence for the importance of the zinc ions in substrate binding has
come from structures of product complexes which indicate that the b-lactam core binds to subclass B1
and B3 enzymes in a rather consistent fashion, interactions with the zinc ions being centrally important.
The zinc ions play key roles in the catalytic mechanism, including facilitating nucleophilic attack on the
amide carbonyl by the zinc-bound hydroxide ion, stabilising the anionic tetrahedral intermediate and
coordinating the departing amine nitrogen.