Pac13 is a Small, Monomeric Dehydratase that Mediates the Formation of the 3′‐Deoxy Nucleoside of Pacidamycins

• Published in: Angewandte Chemie 2017-10, Vol.129 (41), p.12666-12671
• Main Authors: Michailidou, Freideriki, Chung, Chun‐wa, Brown, Murray J. B., Bent, Andrew F., Naismith, James H., Leavens, William J., Lynn, Sean M., Sharma, Sunil V., Goss, Rebecca J. M.
• Format: Article
• Language: English
• Subjects: Antibiotics; Chemistry; Dehydratasen; Dehydration; Enzymes; Enzymologie; Mode of action; Nucleoside; Peptide antibiotics; Strukturbiologie; UPA; Uridine
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201705639

The uridyl peptide antibiotics (UPAs), of which pacidamycin is a member, have a clinically unexploited mode of action and an unusual assembly. Perhaps the most striking feature of these molecules is the biosynthetically unique 3′‐deoxyuridine that they share. This moiety is generated by an unusual, small and monomeric dehydratase, Pac13, which catalyses the dehydration of uridine‐5′‐aldehyde. Here we report the structural characterisation of Pac13 with a series of ligands, and gain insight into the enzyme's mechanism demonstrating that H42 is critical to the enzyme's activity and that the reaction is likely to proceed via an E1cB mechanism. The resemblance of the 3′‐deoxy pacidamycin moiety with the synthetic anti‐retrovirals, presents a potential opportunity for the utilisation of Pac13 in the biocatalytic generation of antiviral compounds. Kurz und süß: Pac13, eine kleine, monomere und kofaktorunabhängige Dehydratase, katalysiert die Bildung von biosynthetisch einzigartigem 3′‐Desoxyuridin, einem ähnlichen Strukturmotiv wie in synthetischen Retroviren. Einblicke in Struktur‐ und Mechanismusaspekte werden präsentiert.