The Mechanisms of Catalysis by Metallo β-Lactamases. (10th March 2008)

• Record Type: Journal Article
• Authors: Page, Michael I.; Badarau, Adriana
• Other Names: Mugesh Govindasamy Academic Editor.
• Is Part Of: Bioinorganic chemistry and applications. Volume 2008(2008)
• Publication Date: 2008-03-10
• Subjects: Bioinorganic chemistry -- Periodicals; Bioinorganic chemistry; Biochemistry; Inorganic Chemistry; Chemistry, Bioinorganic; Periodicals; 572.51
• DOI: 10.1155/2008/576297
• Languages: English
• ISSNs: 1565-3633

Abstract

Abstract : Class Bβ -lactamases or metallo-β -lactamases (MBLs) require zinc ions to catalyse the hydrolysis ofβ -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 theβ -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 theβ -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.