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dc.contributor.author
Fang, Wengxia
dc.contributor.author
Du, Ting
dc.contributor.author
Raimi, Olawale G
dc.contributor.author
Hurtado Guerrero, Ramon
dc.contributor.author
Mariño, Karina
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dc.contributor.author
Ibrahim, Adel F. M.
dc.contributor.author
Albarbarawi, Osama
dc.contributor.author
Ferguson, Michael A. J.
dc.contributor.author
Jin, Cheng
dc.contributor.author
Van Aalten, Daan M. F.
dc.date.available
2015-10-14T13:56:23Z
dc.date.issued
2013-10-01
dc.identifier.citation
Fang, Wengxia; Du, Ting; Raimi, Olawale G; Hurtado Guerrero, Ramon; Mariño, Karina; et al.; Genetic and structural validation of Aspergillus fumigatus N acetylphosphoglucosamine mutase as an antifungal target; Portland Press; Bioscience Reports; 33; 5; 1-10-2013; 689-699
dc.identifier.issn
0144-8463
dc.identifier.uri
http://hdl.handle.net/11336/2526
dc.description.abstract
Aspergillus fumigatus is the causative agent of IA (invasive aspergillosis) in immunocompromised patients. It possesses a cell wall composed of chitin, glucan and galactomannan, polymeric carbohydrates synthesized by processive glycosyltransferases from intracellular sugar nucleotide donors. Here we demonstrate that A. fumigatus possesses an active AfAGM1 (A. fumigatus N-acetylphosphoglucosamine mutase), a key enzyme in the biosynthesis of UDP (uridine diphosphate)?GlcNAc (N-acetylglucosamine), the nucleotide sugar donor for chitin synthesis. A conditional agm1 mutant revealed the gene to be essential. Reduced expression of agm1 resulted in retarded cell growth and altered cell wall ultrastructure and composition. The crystal structure of AfAGM1 revealed an amino acid change in the active site compared with the human enzyme, which could be exploitable in the design of selective inhibitors. AfAGM1 inhibitors were discovered by high-throughput screening, inhibiting the enzyme with IC50s in the low μM range. Together, these data provide a platform for the future development of AfAGM1 inhibitors with antifungal activity.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Portland Press
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights
Atribución-NoComercial-CompartirIgual 2.5 Argentina (CC BY-NC-SA 2.5 AR)
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Cell Wall
dc.subject
Drug Target
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Enzyme
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Inhibitor
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Nucleotide Sugar
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Protein Structure
dc.subject.classification
Bioquímica y Biología Molecular
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Genetic and structural validation of Aspergillus fumigatus N acetylphosphoglucosamine mutase as an antifungal target
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-03-30 10:35:44.97925-03
dc.identifier.eissn
1573-4935
dc.journal.volume
33
dc.journal.number
5
dc.journal.pagination
689-699
dc.journal.pais
Reino Unido
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dc.journal.ciudad
Londres
dc.description.fil
Fil: Fang, Wengxia. University of Dundee. Division of Molecular Microbiology; Escocia;
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Fil: Du, Ting. Chinese Academy Of Sciences. Institute of Microbiology; República de China;
dc.description.fil
Fil: Raimi, Olawale G. University of Dundee. Division of Molecular Microbiology; Escocia;
dc.description.fil
Fil: Hurtado Guerrero, Ramon. University of Dundee. Division of Molecular Microbiology; Escocia;
dc.description.fil
Fil: Mariño, Karina. University of Dundee. Division of Biological Chemistry and Drug Discovery; Escocia; Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
dc.description.fil
Fil: Ibrahim, Adel F. M.. University of Dundee. College of Life Sciences, Escocia;
dc.description.fil
Fil: Albarbarawi, Osama. University of Dundee. Division of Molecular Microbiology; Escocia;
dc.description.fil
Fil: Ferguson, Michael A. J.. University of Dundee. Division of Biological Chemistry and Drug Discovery; Escocia;
dc.description.fil
Fil: Jin, Cheng. Chinese Academy Of Sciences. Institute of Microbiology; República de China;
dc.description.fil
Fil: Van Aalten, Daan M. F.. University of Dundee. Division of Molecular Microbiology; Escocia;
dc.journal.title
Bioscience Reports
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763426/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.bioscirep.org/content/33/5/e00063
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1042/BSR20130053
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