Structural highlights
Publication Abstract from PubMed
Aspergillus fumigatus is the causative agent of 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 N-acetylphosphoglucosamine mutase (AfAGM1), a key enzyme in the biosynthesis of UDP-GlcNAc, 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 to 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 microM range. Together, these data provide a platform for the future development of AfAGM1 inhibitors with antifungal activity.
Genetic and structural validation of Aspergillus fumigatus N-acetylphosphoglucosamine mutase as an antifungal target.,Fang W, Du T, Raimi OG, Hurtado Guerrero R, Marino K, Ibrahim AF, Albarbarawi O, Ferguson MA, Jin C, van Aalten DM Biosci Rep. 2013 Jul 11. PMID:23844980[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Fang W, Du T, Raimi OG, Hurtado Guerrero R, Marino K, Ibrahim AF, Albarbarawi O, Ferguson MA, Jin C, van Aalten DM. Genetic and structural validation of Aspergillus fumigatus N-acetylphosphoglucosamine mutase as an antifungal target. Biosci Rep. 2013 Jul 11. PMID:23844980 doi:10.1042/BSR20130053
