Pac13 is a small, monomeric dehydratase that mediates the formation of the 3′-deoxy nucleoside of pacidamycins

Freideriki Michailidou, Chun-wa Chung, Murray J. B. Brown, Andrew F. Bent, James H. Naismith, William J. Leavens, Sean M. Lynn, Sunil V. Sharma, Rebecca J. M. Goss

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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.
Original languageEnglish
Pages (from-to)12492-12497
Number of pages6
JournalAngewandte Chemie International Edition
Volume56
Issue number41
Early online date30 Aug 2017
DOIs
Publication statusPublished - 2 Oct 2017

Keywords

  • Dehydratase
  • Enzymology
  • Nucleoside
  • Structural biology
  • UPA

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