The Mechanisms of Catalysis by Metallo β-Lactamases

Michael I. Page, Adriana Badarau

Research output: Contribution to journalReview article

55 Citations (Scopus)

Abstract

Class B β-lactamases or metallo-β-lactamases (MBLs) require zinc ions to catalyse the hydrolysis of β-lactam antibiotics such as penicillins, cephalosporins, carbapenems, and cephamycins. There are no clinically useful inhibitors against MBLs which are responsible for the resistance of some bacteria to antibiotics. There are two metal-ion binding sites that have different zinc ligands but the exact roles of the metal-ion remain controversial, and distinguishing between their relative importance is complex. The metal-ion can act as a Lewis acid by co-ordination to the β-lactam carbonyl oxygen to facilitate nucleophilic attack and stabilise the negative charge developed on this oxygen in the tetrahedral intermediate anion. The metal-ion also lowers the pKa of the directly co-ordinated water molecule so that the metal-bound hydroxide ion is a better nucleophile than water and is used to attack the β-lactam carbonyl carbon. An intrinsic property of binuclear metallo hydrolytic enzymes that depend on a metal-bound water both as the attacking nucleophile and as a ligand for the second metal-ion is that this water molecule, which is consumed during hydrolysis of the substrate, has to be replaced to maintain the catalytic cycle. With MBL this is reflected in some unusual kinetic profiles.

LanguageEnglish
Article number576297
JournalBioinorganic Chemistry and Applications
Volume2008
DOIs
Publication statusPublished - 2008

Fingerprint

beta-Lactamases
Catalysis
Metal ions
Metals
beta-Lactams
Ions
Nucleophiles
Water
Zinc
Hydrolysis
Cephamycins
Oxygen
Anti-Bacterial Agents
Ligands
Lewis Acids
Carbapenems
Molecules
Cephalosporins
Penicillins
Anions

Cite this

Page, Michael I. ; Badarau, Adriana. / The Mechanisms of Catalysis by Metallo β-Lactamases. In: Bioinorganic Chemistry and Applications. 2008 ; Vol. 2008.
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The Mechanisms of Catalysis by Metallo β-Lactamases. / Page, Michael I.; Badarau, Adriana.

In: Bioinorganic Chemistry and Applications, Vol. 2008, 576297, 2008.

Research output: Contribution to journalReview article

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AU - Badarau, Adriana

PY - 2008

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AB - Class B β-lactamases or metallo-β-lactamases (MBLs) require zinc ions to catalyse the hydrolysis of β-lactam antibiotics such as penicillins, cephalosporins, carbapenems, and cephamycins. There are no clinically useful inhibitors against MBLs which are responsible for the resistance of some bacteria to antibiotics. There are two metal-ion binding sites that have different zinc ligands but the exact roles of the metal-ion remain controversial, and distinguishing between their relative importance is complex. The metal-ion can act as a Lewis acid by co-ordination to the β-lactam carbonyl oxygen to facilitate nucleophilic attack and stabilise the negative charge developed on this oxygen in the tetrahedral intermediate anion. The metal-ion also lowers the pKa of the directly co-ordinated water molecule so that the metal-bound hydroxide ion is a better nucleophile than water and is used to attack the β-lactam carbonyl carbon. An intrinsic property of binuclear metallo hydrolytic enzymes that depend on a metal-bound water both as the attacking nucleophile and as a ligand for the second metal-ion is that this water molecule, which is consumed during hydrolysis of the substrate, has to be replaced to maintain the catalytic cycle. With MBL this is reflected in some unusual kinetic profiles.

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