Abstract
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from D 120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters, WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of crucial importance for catalysis.
Original language | English |
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Pages (from-to) | 2136-2143 |
Number of pages | 8 |
Journal | Cellular and Molecular Life Sciences |
Volume | 58 |
Issue number | 14 |
Publication status | Published - 1 Dec 2001 |
Keywords
- Catalytic mechanism
- Metallo-β-lactamase
- Molecular mechanics
- Molecular modelling
- Penicillin binding
- Zinc enzyme