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.
Highlights
All β-lactam antibiotics, such as penicillins (1) and cephalosporins (2), contain the four-membered β-lactam ring which occurs relatively rarely in nature, it is not surprising that the biological activity of these compounds should be attributed to the expected enhanced chemical reactivity of the β-lactam ring [1]
Subclass B1 is the largest and contains several well-studied β-lactamases: BCII from Bacillus cereus, CcrA from Bacteroides fragilis, IMP-1, SPM-1 from Pseudomonas aeruginosa, and BlaB from Cryseobacterium meningosepticum. These enzymes efficiently catalyse the hydrolysis of a wide range of substrates such as penicillins, cephalosporins, and carbapenems
Subclass B3 contains the only known tetrameric zinc βlactamase, the L1 enzyme from Stenotrophomonas maltophilia, and the monomeric FEZ-1 from Legionella gormanii. Both enzymes hydrolyze a wide range of β-lactam antibiotics [22, 23] with L1 having higher catalytic rate constants for penicillins compared with FEZ-1, which shows higher kcat values for cephalosporins
Summary
All β-lactam antibiotics, such as penicillins (1) and cephalosporins (2), contain the four-membered β-lactam ring which occurs relatively rarely in nature, it is not surprising that the biological activity of these compounds should be attributed to the expected enhanced chemical reactivity of the β-lactam ring [1]. Contrary to expectations, opening the four-membered ring is not a facile process [3] and, in many of these nucleophilic substitution reactions, the rate limiting step is not the first addition step but a subsequent one which may sometimes even be ring opening itself [1, 2, 4,5,6,7,8] Another interesting difference between nucleophilic substitution in penicillins and peptides/amides is the preferred direction of attack and the geometry of the initially formed tetrahedral intermediate. Nucleophilic attack on the β-lactams of penicillins occurs from the least hindered α-face (exo) so that the β-lactam nitrogen lone pair is syn to the incoming nucleophile in the tetrahedral intermediate (8) [9] This has obvious consequences for the placement of catalytic groups—if catalysis involves coordination to metal-ions [10]. On the basis of their amino acid sequences, the serine βlactamases are subdivided into three classes: A, C, and D, whereas the class B β-lactamases consist of the zinc enzymes [15]
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