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A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei.

Research output: Contribution to journalJournal article

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  • Mick Urbaniak
  • Iain T. Collie
  • Wenxia Fang
  • Tonia Aristotelous
  • Susanne Eskilsson
  • Olwale G. Raimi
  • Justin Harrison
  • Iva Hopkins Navratilova
  • Julie A. Frearson
  • Daan M. F. van Aalten
  • Michael A J Ferguson
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<mark>Journal publication date</mark>20/09/2013
<mark>Journal</mark>ACS Chemical Biology
Issue number9
Volume8
Number of pages7
Pages (from-to)1981-1987
<mark>State</mark>Published
Early online date8/07/13
<mark>Original language</mark>English

Abstract

Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in many
organisms including Trypanosoma brucei, the etiological agent of Human African Trypanosomiasis. High-throughput screening of recombinant T. brucei UAP identified a UTP-competitive inhibitor with selectivity over the human counterpart despite the high level of conservation of active site residues. Biophysical characterization of the UAP enzyme kinetics revealed that the human and trypanosome enzymes both display a strictly ordered bi−bi mechanism, but with
the order of substrate binding reversed. Structural characterization of the T. brucei UAP−inhibitor complex revealed that the inhibitor binds at an allosteric site absent in the human homologue that prevents the conformational rearrangement required to bind UTP.
The identification of a selective inhibitory allosteric binding site in the parasite enzyme has therapeutic potential.

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