期刊
BIOCHEMICAL JOURNAL
卷 415, 期 -, 页码 217-223出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20081000
关键词
Aspergillus fumigatus; inhibitor design; kinetics; mutagenesis; protein structure; UDP-GlcNAc biosynthesis; X-ray crystallography
资金
- Wellcome Trust Senior Research Fellowship
- European Union FP6 STREP Fungwall programme
- Structural Genomics Consortium
- Genome Canada
- Ontario Genomics Institute
- Canadian Institutes for Health Research
- Canada Foundation for Innovation
- Ontario Challenge Fund
- Ontario Innovation Trust
- Wellcome Trust
- GlaxoSmithKline
- Knut and Alice Wallenberg Foundation
- Vinnova and Swedish Foundation for Strategic Research
- Medical Research Council [G0500367] Funding Source: researchfish
- MRC [G0500367] Funding Source: UKRI
Aspergillus fumigatus is the causative agent of aspergillosis, a frequently invasive colonization of the lungs of immuno-compromised patients. GNA1 (D-glucosamine-6-phosphate N-acetyltransferase) catalyses the acetylation of GlcN-6P (glucosamine-6-phosphate) to GlcNAc-6P (N-acetylglucosamine-6-phosphate), a key intermediate in the UDP-GlcNAc biosynthetic pathway. Gene disruption of gnal in yeast and Candida albicans has provided genetic validation of the enzyme as a potential target. An understanding of potential active site differences between the human and A. fumigatus enzymes is required to enable further work aimed at identifying selective inhibitors for the fungal enzyme. In the present study, we describe crystal structures of both human and A. fumigatus GNA1, as well as their kinetic characterization. The structures show significant differences in the sugar-binding site with, in particular, several non-conservative substitutions near the phosphate-binding pocket. Mutagenesis targeting these differences revealed drastic effects on steady-state kinetics, suggesting that the differences could be exploitable with small-molecule inhibitors.
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