Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l, d‐Transpeptidases and Serine β‐Lactamase Cysteine Variants. Issue 7 (21st January 2019)

• Record Type: Journal Article
• Authors: Lohans, Christopher T.; Chan, H. T. Henry; Malla, Tika R.; Kumar, Kiran; Kamps, Jos J. A. G.; McArdle, Darius J. B.; van Groesen, Emma; de Munnik, Mariska; Tooke, Catherine L.; Spencer, James; Paton, Robert S.; Brem, Jürgen; Schofield, Christopher J.
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 7(2019)
• Page Start: 1990
• Page End: 1994
• Publication Date: 2019-01-21
• Subjects: antibiotic resistance -- fragmentation -- hydrolases -- transpeptidases -- β-lactamases; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201809424
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Enzymes often use nucleophilic serine, threonine, and cysteine residues to achieve the same type of reaction; the underlying reasons for this are not understood. While bacteriald, d ‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l, d ‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed byl, d ‐transpeptidases with some β‐lactam antibiotics undergo non‐hydrolytic fragmentation. This is not usually observed for penicillin‐binding proteins, or for the related serine β‐lactamases. Replacement of the nucleophilic serine of serine β‐lactamases with cysteine yields enzymes which fragment β‐lactams via a similar mechanism as thel, d ‐transpeptidases, implying the different reaction outcomes are principally due to the formation of thioester versus ester intermediates. The results highlight fundamental differences in the reactivity of nucleophilic serine and cysteine enzymes, and imply new possibilities for the inhibition of nucleophilic enzymes. Abstract : Weapon of choice : Penicillin‐binding proteins and serine β‐lactamases, which employ nucleophilic serines, hydrolyze β‐lactam antibiotics. However, thel, d ‐transpeptidases, which employ nucleophilic cysteines, also fragment some β‐lactams. Serine β‐lactamases where the nucleophilic serine is substituted with cysteine also catalyze β‐lactam fragmentation, consistent with a mechanism involving the formation of thioester‐enolate intermediates.