Non‐Hydrolytic β‐Lactam Antibiotic Fragmentation by l,d‐Transpeptidases and Serine β‐Lactamase Cysteine Variants

• Published in: Angewandte Chemie 2019-02, Vol.131 (7), p.2012-2016
• Main 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.
• Format: Article
• Language: English
• Subjects: Amides; Antibiotics; Antibiotikaresistenz; Binding; Chemistry; Coordination compounds; Cysteine; Enzymes; Fragmentation; Fragmentierung; Hydrolasen; Intermediates; Penicillin; Proteins; Serine; Threonine; Transpeptidasen; β-Lactamasen
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201809424

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. Wahl der Waffen: Penicillinbindende Proteine und Serin‐β‐Lactamasen, die nukleophile Serine verwenden, hydrolysieren β‐Lactam‐Antibiotika. Die l,d‐Transpeptidasen, die nukleophile Cysteine verwenden, fragmentieren jedoch ebenfalls bestimmte β‐Lactame. Serin‐β‐Lactamasen, in denen das nukleophile Serin durch Cystein substituiert ist, katalysieren auch die β‐Lactam‐Fragmentierung, in Einklang mit einem Mechanismus, der die Bildung von Thioesterenolat‐Intermediaten einschließt.