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

Research output: Contribution to Journal/Magazine › Journal article › peer-review

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A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei. / Urbaniak, Mick; Collie, Iain T.; Fang, Wenxia et al.
In: ACS Chemical Biology, Vol. 8, No. 9, 20.09.2013, p. 1981-1987.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Urbaniak, M, Collie, IT, Fang, W, Aristotelous, T, Eskilsson, S, Raimi, OG, Harrison, J, Hopkins Navratilova, I, Frearson, JA, van Aalten, DMF & Ferguson, MAJ 2013, 'A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei.', ACS Chemical Biology, vol. 8, no. 9, pp. 1981-1987. https://doi.org/10.1021/cb400411x

APA

Urbaniak, M., Collie, I. T., Fang, W., Aristotelous, T., Eskilsson, S., Raimi, O. G., Harrison, J., Hopkins Navratilova, I., Frearson, J. A., van Aalten, D. M. F., & Ferguson, M. A. J. (2013). A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei. ACS Chemical Biology, 8(9), 1981-1987. https://doi.org/10.1021/cb400411x

Vancouver

Urbaniak M, Collie IT, Fang W, Aristotelous T, Eskilsson S, Raimi OG et al. A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei. ACS Chemical Biology. 2013 Sept 20;8(9):1981-1987. Epub 2013 Jul 8. doi: 10.1021/cb400411x

Author

Urbaniak, Mick ; Collie, Iain T. ; Fang, Wenxia et al. / A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei. In: ACS Chemical Biology. 2013 ; Vol. 8, No. 9. pp. 1981-1987.

Bibtex

@article{8f732bf64c27410b964cd39bd22ab9a5,
title = "A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei.",
abstract = "Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in manyorganisms 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 withthe 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.",
author = "Mick Urbaniak and Collie, {Iain T.} and Wenxia Fang and Tonia Aristotelous and Susanne Eskilsson and Raimi, {Olwale G.} and Justin Harrison and {Hopkins Navratilova}, Iva and Frearson, {Julie A.} and {van Aalten}, {Daan M. F.} and Ferguson, {Michael A J}",
note = "ACS Author Choice CCA-BY",
year = "2013",
month = sep,
day = "20",
doi = "10.1021/cb400411x",
language = "English",
volume = "8",
pages = "1981--1987",
journal = "ACS Chemical Biology",
issn = "1554-8929",
publisher = "American Chemical Society",
number = "9",

}

RIS

TY - JOUR

T1 - A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei.

AU - Urbaniak, Mick

AU - Collie, Iain T.

AU - Fang, Wenxia

AU - Aristotelous, Tonia

AU - Eskilsson, Susanne

AU - Raimi, Olwale G.

AU - Harrison, Justin

AU - Hopkins Navratilova, Iva

AU - Frearson, Julie A.

AU - van Aalten, Daan M. F.

AU - Ferguson, Michael A J

N1 - ACS Author Choice CCA-BY

PY - 2013/9/20

Y1 - 2013/9/20

N2 - Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in manyorganisms 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 withthe 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.

AB - Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in manyorganisms 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 withthe 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.

U2 - 10.1021/cb400411x

DO - 10.1021/cb400411x

M3 - Journal article

VL - 8

SP - 1981

EP - 1987

JO - ACS Chemical Biology

JF - ACS Chemical Biology

SN - 1554-8929

IS - 9

ER -