NMR metabolic profiling of Aspergillus nidulans to monitor drug and protein activity

被引:29
作者
Forgue, Paxton
Halouska, Steven
Werth, Mark
Xu, Kaimei
Harris, Steve
Powers, Robert
机构
[1] Univ Nebraska, Dept Chem, Lincoln, NE 68588 USA
[2] Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68588 USA
[3] Nebraska Wesleyan Univ, Dept Chem, Lincoln, NE 68504 USA
关键词
drug discovery; NMR; metabolomics; principle component analysis; Aspergillus nidulans; purine degradation pathway; pyrimidine biosynthetic pathway;
D O I
10.1021/pr060114v
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
We describe a general protocol for using comparative NMR metabolomics data to infer in vivo efficacy, specificity and toxicity of chemical leads within a drug discovery program. The methodology is demonstrated using Aspergillus nidulans to monitor the activity of urate oxidase and orotidine-5'-phosphate decarboxylase and the impact of 8-azaxanthine, an inhibitor of urate oxidase. 8-azaxanthine is shown to inhibit A. nidulans hyphal growth by in vivo inactivation of urate oxidase.
引用
收藏
页码:1916 / 1923
页数:8
相关论文
共 83 条
[1]  
Ahlborn H, 2005, CURR OPIN DRUG DISC, V8, P384
[2]  
Ahluwalia GS, 1996, MOL PHARMACOL, V50, P160
[3]  
Berg EL, 2005, CURR OPIN DRUG DISC, V8, P107
[4]  
BERGMANN F, 1964, PSEUDOMONAS AERUGINO, V91, P270
[5]   Prospects for productivity [J].
Booth, B ;
Zemmel, R .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (05) :451-457
[6]   RNA interference: genetic wand and genetic watchdog [J].
Bosher, JM ;
Labouesse, M .
NATURE CELL BIOLOGY, 2000, 2 (02) :E31-E36
[7]   Discrimination of pathogenic clinical isolates and laboratory strains of Bacillus cereus by NMR-based metabolomic profiling [J].
Bundy, JG ;
Willey, TL ;
Castell, RS ;
Ellar, DJ ;
Brindle, KM .
FEMS MICROBIOLOGY LETTERS, 2005, 242 (01) :127-136
[8]  
Caldwell Gary W., 2001, Current Topics in Medicinal Chemistry, V1, P353, DOI 10.2174/1568026013394949
[9]   The art and design of genetic screens: Filamentous fungi [J].
Casselton, L ;
Zolan, M .
NATURE REVIEWS GENETICS, 2002, 3 (09) :683-697
[10]   Crystal Structure of the protein drug urate oxidase-inhibitor complex at 2.05 angstrom resolution [J].
Colloch, N ;
ElHajji, M ;
Bachet, B ;
LHermite, G ;
Schiltz, M ;
Prange, T ;
Castro, B ;
Mornon, JP .
NATURE STRUCTURAL BIOLOGY, 1997, 4 (11) :947-952