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Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l,d ‐Transpeptidases and Serine β‐Lactamase Cysteine Variants
Author(s) -
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.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201809424
Subject(s) - serine , chemistry , cysteine , nucleophile , penicillin binding proteins , biochemistry , enzyme , stereochemistry , antibiotics , penicillin , catalysis
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 bacterial d,d ‐transpeptidases (penicillin‐binding proteins) employ a nucleophilic serine, l,d ‐transpeptidases use a nucleophilic cysteine. The covalent complexes formed by l,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 the l,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.