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Short and Sweet: Pac13 is a Small, Monomeric Dehydratase that Mediates the Formation of the 3′- Deoxy Nucleoside of Pacidamycins

DOI: 10.1002/anie.201705639 DOI Help

Authors: Freideriki Michailidou (University of St Andrews) , Chun-wa Chung (GSK) , Murray J. B. Brown (GSK) , Andrew F. Bent (University of St Andrews) , James H. Naismith (University of St Andrews) , William J. Leavens (GSK) , Sean M. Lynn (GSK) , Sunil V. Sharma (University of St Andrews) , Rebecca Jane Miriam Goss (University of St Andrews)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: August 2017

Abstract: 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.

Journal Keywords: Nucleoside Dehydratase; Uridyl Peptide Antibiotic

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography