The Mechanisms of Catalysis by Metallo 𝛽-Lactamases
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 bacteri...
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| Format: | Article |
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Wiley
2008-01-01
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| Series: | Bioinorganic Chemistry and Applications |
| Online Access: | http://dx.doi.org/10.1155/2008/576297 |
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| author | Michael I. Page Adriana Badarau |
| author_facet | Michael I. Page Adriana Badarau |
| author_sort | Michael I. Page |
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| description | 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. |
| format | Article |
| id | doaj-art-135326f7d9e6437584b42415ffd00217 |
| institution | Kabale University |
| issn | 1565-3633 1687-479X |
| language | English |
| publishDate | 2008-01-01 |
| publisher | Wiley |
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| series | Bioinorganic Chemistry and Applications |
| spelling | doaj-art-135326f7d9e6437584b42415ffd002172025-02-03T01:13:04ZengWileyBioinorganic Chemistry and Applications1565-36331687-479X2008-01-01200810.1155/2008/576297576297The Mechanisms of Catalysis by Metallo 𝛽-LactamasesMichael I. Page0Adriana Badarau1Department of Chemical and Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, UKDepartment of Chemical and Biological Sciences, University of Huddersfield, Huddersfield HD1 3DH, UKClass 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.http://dx.doi.org/10.1155/2008/576297 |
| spellingShingle | Michael I. Page Adriana Badarau The Mechanisms of Catalysis by Metallo 𝛽-Lactamases Bioinorganic Chemistry and Applications |
| title | The Mechanisms of Catalysis by Metallo 𝛽-Lactamases |
| title_full | The Mechanisms of Catalysis by Metallo 𝛽-Lactamases |
| title_fullStr | The Mechanisms of Catalysis by Metallo 𝛽-Lactamases |
| title_full_unstemmed | The Mechanisms of Catalysis by Metallo 𝛽-Lactamases |
| title_short | The Mechanisms of Catalysis by Metallo 𝛽-Lactamases |
| title_sort | mechanisms of catalysis by metallo 𝛽 lactamases |
| url | http://dx.doi.org/10.1155/2008/576297 |
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