Structural highlights
Publication Abstract from PubMedUridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyses 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 characterisation 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 characterisation 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. A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei.,Urbaniak MD, Collie IT, Fang W, Aristotelous T, Eskilsson S, Raimi OG, Harrison J, Hopkins Navratolova I, Frearson JA, van Aalten DM, Ferguson MA ACS Chem Biol. 2013 Jul 8. PMID:23834437[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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