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    Rights statement: © 2013 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target

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Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target. / Fang, Wenxia; Du, Ting; Raimi, Olawale G. et al.
In: Molecular Microbiology, Vol. 89, No. 3, 08.2013, p. 479-493.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Fang, W, Du, T, Raimi, OG, Hurtado-Guerrero, R, Urbaniak, M, Ibrahim, AFM, Ferguson, MAJ & van Aalten, DMF 2013, 'Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target', Molecular Microbiology, vol. 89, no. 3, pp. 479-493. https://doi.org/10.1111/mmi.12290

APA

Fang, W., Du, T., Raimi, O. G., Hurtado-Guerrero, R., Urbaniak, M., Ibrahim, A. F. M., Ferguson, M. A. J., & van Aalten, D. M. F. (2013). Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target. Molecular Microbiology, 89(3), 479-493. https://doi.org/10.1111/mmi.12290

Vancouver

Fang W, Du T, Raimi OG, Hurtado-Guerrero R, Urbaniak M, Ibrahim AFM et al. Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target. Molecular Microbiology. 2013 Aug;89(3):479-493. Epub 2013 Jul 5. doi: 10.1111/mmi.12290

Author

Fang, Wenxia ; Du, Ting ; Raimi, Olawale G. et al. / Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target. In: Molecular Microbiology. 2013 ; Vol. 89, No. 3. pp. 479-493.

Bibtex

@article{9bfa96eb4f9c4955bb87c5ca6d7d81c4,
title = "Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target",
abstract = "The sugar nucleotide UDP-N-acetylglucosamine (UDP-GlcNAc) is an essential metabolite in both prokaryotes and eukaryotes. In fungi, it is the precursor for the synthesis of chitin, an essential component of the fungal cell wall. UDP-N-acetylglucosamine pyrophosphorylase (UAP) is the final enzyme in eukaryotic UDP-GlcNAc biosynthesis, converting UTP andN-acetylglucosamine-1-phosphate (GlcNAc-1P) to UDP-GlcNAc. As such, this enzyme may provide an attractive target against pathogenic fungi. Here, we demonstrate that the fungal pathogen Aspergillus fumigatus possesses an active UAP (AfUAP1) that shows selectivity for GlcNAc-1P as the phosphosugar substrate. A conditional mutant, constructed byreplacing the native promoter of the A. fumigatus uap1 gene with the Aspergillus nidulans alcA promoter, revealed that uap1 is essential for cell survival andimportant for cell wall synthesis and morphogenesis.The crystal structure of AfUAP1 was determined and revealed exploitable differences in the active site compared with the human enzyme. Thus AfUAP1 could represent a novel antifungal target and this work will assist the future discovery of small molecule inhibitors against this enzyme.",
author = "Wenxia Fang and Ting Du and Raimi, {Olawale G.} and Ramon Hurtado-Guerrero and Mick Urbaniak and Ibrahim, {Adel F. M.} and Ferguson, {Michael A. J.} and {van Aalten}, {Daan M. F.}",
note = "{\textcopyright} 2013 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",
year = "2013",
month = aug,
doi = "10.1111/mmi.12290",
language = "English",
volume = "89",
pages = "479--493",
journal = "Molecular Microbiology",
issn = "0950-382X",
publisher = "Wiley-Blackwell",
number = "3",

}

RIS

TY - JOUR

T1 - Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as a potential antifungal target

AU - Fang, Wenxia

AU - Du, Ting

AU - Raimi, Olawale G.

AU - Hurtado-Guerrero, Ramon

AU - Urbaniak, Mick

AU - Ibrahim, Adel F. M.

AU - Ferguson, Michael A. J.

AU - van Aalten, Daan M. F.

N1 - © 2013 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2013/8

Y1 - 2013/8

N2 - The sugar nucleotide UDP-N-acetylglucosamine (UDP-GlcNAc) is an essential metabolite in both prokaryotes and eukaryotes. In fungi, it is the precursor for the synthesis of chitin, an essential component of the fungal cell wall. UDP-N-acetylglucosamine pyrophosphorylase (UAP) is the final enzyme in eukaryotic UDP-GlcNAc biosynthesis, converting UTP andN-acetylglucosamine-1-phosphate (GlcNAc-1P) to UDP-GlcNAc. As such, this enzyme may provide an attractive target against pathogenic fungi. Here, we demonstrate that the fungal pathogen Aspergillus fumigatus possesses an active UAP (AfUAP1) that shows selectivity for GlcNAc-1P as the phosphosugar substrate. A conditional mutant, constructed byreplacing the native promoter of the A. fumigatus uap1 gene with the Aspergillus nidulans alcA promoter, revealed that uap1 is essential for cell survival andimportant for cell wall synthesis and morphogenesis.The crystal structure of AfUAP1 was determined and revealed exploitable differences in the active site compared with the human enzyme. Thus AfUAP1 could represent a novel antifungal target and this work will assist the future discovery of small molecule inhibitors against this enzyme.

AB - The sugar nucleotide UDP-N-acetylglucosamine (UDP-GlcNAc) is an essential metabolite in both prokaryotes and eukaryotes. In fungi, it is the precursor for the synthesis of chitin, an essential component of the fungal cell wall. UDP-N-acetylglucosamine pyrophosphorylase (UAP) is the final enzyme in eukaryotic UDP-GlcNAc biosynthesis, converting UTP andN-acetylglucosamine-1-phosphate (GlcNAc-1P) to UDP-GlcNAc. As such, this enzyme may provide an attractive target against pathogenic fungi. Here, we demonstrate that the fungal pathogen Aspergillus fumigatus possesses an active UAP (AfUAP1) that shows selectivity for GlcNAc-1P as the phosphosugar substrate. A conditional mutant, constructed byreplacing the native promoter of the A. fumigatus uap1 gene with the Aspergillus nidulans alcA promoter, revealed that uap1 is essential for cell survival andimportant for cell wall synthesis and morphogenesis.The crystal structure of AfUAP1 was determined and revealed exploitable differences in the active site compared with the human enzyme. Thus AfUAP1 could represent a novel antifungal target and this work will assist the future discovery of small molecule inhibitors against this enzyme.

U2 - 10.1111/mmi.12290

DO - 10.1111/mmi.12290

M3 - Journal article

VL - 89

SP - 479

EP - 493

JO - Molecular Microbiology

JF - Molecular Microbiology

SN - 0950-382X

IS - 3

ER -