Dr. W. David Nes
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Title: |
Paul Whitfield Horn Professor |
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Education: |
Ph.D., University of Maryland, 1979; Postdoctoral Study, NIH Postdoctoral Fellow, University of California, Berkeley; ARS-USDA, Albany, CA |
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Research Area: |
Biochemistry and Natural Products |
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Office: |
Chemistry 413-C |
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Principal Research Interests
- Natural Product Chemistry and Metabolomics
- Functional Analysis and Inhibition of Enzymes in Sterol Biosynthesis Pathways
- Mechanistic Enzymology of Sterol Catalysts
The main focus of Professor Nes' research has been to establish the origin, biosynthesis
and function of sterols in a range of organisms by unearthing the molecular libraries
(genome-metabolome congruence) associated with the phyla-specific reaction sequences
that regulate sterol patterning in nature. Particular emphasis is directed at the
structure and mechanism of sterol catalysts and the characterization of intracellular
metabolite and enzyme specificities involved in sterol production and processing.
We have determined the structure of a panoply of naturally occurring isoprenoids and
other lipids in stereochemical detail using 1H/13C-NMR/X-ray crystallography and tracked
2H and 13C-labeled intermediates to final products using sensitive labeling techniques.
In parallel studies, we have cloned and demonstrated the mechanism and physiological
abundance of crucial sterol catalysts in parasites as well as genetically modified
sterol biosynthesis in crops.Our research program also involves fruitful collaborations
involving several laboratories, including the Waterman/Lepesheva (Nashville, TN),
Nguyen (Columbia, MO), Snell (Dallas, TX) and Kelly (Swansea, Wales) laboratories
to rationally design and prepare substrate-based inhibitors targeted at 24-alkyl sterol
biosynthesis and to examine the factors regulating carbon flux and sterol homeostasis.
These studies have led to chemotherapeutic leads to prevent disease by opportunistic
parasites dependent on an intact ergosterol pathway and afforded success in engineering
transgenic plants with modified sterol seed compositions to benefit human health.
A new graduate student can embark on studies involving natural product isolation and characterization (NMR, GC/MS, HPLC-UV), tracer studies designed to track biosynthesis pathways, prepare and test substrate mimics in vivo against parasites, and learn molecular cloning techniques that involve biochemical applications and molecular biological approaches related to enzyme kinetics, enzyme purification and characterization.
Representative Publications
- "Novel Sterol Metabolic Network of Trypanosoma brucei Procyclic and Bloodstream Forms." Nes, C. R.; Singha, U. K.; Liu, ,J.; Villalta, F.; Waterman, M. R.; Lepesheva, G. I.; Chaudhuri, M. and Nes, W. D. Biochem. J. 2012, 443, 267-276.
- "Evolutionarily Conserved ∆25(27)-Ergosterol Biosynthesis Pathway in the Alga Chlamydomonas reinhardtii is Distinct from the ∆24(28)-Pathway to Fungal Ergosterol." Miller, M. B.; Haubrich, B. A.; Wang, Q.; Snell, W. J. and Nes, W. D. J. Lipid Res. 2012, 53, 1636-1645.
- "Sterol C24-Methyltransferase: Physio- and Stereochemical Features of the Sterol C3-Group Required for Catalytic Competence." Howard, A. L.; Jiu, J.; Elmegeed, G. A.; Collins, E. K.; Gantra, K. S.; Nwogwugwu, C. A. and Nes, W. D. Arch. Biochem. Biophys. 2012, 521, 43-50.
- "Metabolic Engineering of Soybean Affords Improved Phytosterol Seed Traits." Neelakanda, A.; Valliyodan, B.; Chamala, S.; Nes, W. D. and Ngueyn, H. T. Plant Biotech. J. 2012, 10, 12-19.
- "Structural Complex of Sterol 14α-Methyldemethylase (CYP51) with 14α-Methylenecyclopropyl -∆7-24,25-Dihydrolanosterol." Hargrove, T. Y.; Wawrzak, Z.; Liu, J.; Waterman, M.R.; Nes, W. D. and Lepesheva, G. I. J. Lipid Res. 2012, 53, 311-320.
- "Unearthing the Biosynthetic Diversity in the Sterol Metabolome." Nes, W. D. Pharmaceutical Biol. 2012, 50, 633-633.
- "Biosynthesis of Cholesterol and Other Sterols." Nes, W. D. Chem. Rev. 2011, 111, 6423-6451.
- "Mechanism of Binding of Prothioconazole to Mycosphaerella graminicola CYP51 Differs from that of Other Azole Antifungals." Parker, J. E.; Warrilow, A. G. S.; Cools, H. J.; Martel, C. M.; Nes, W. D.; Fraije, A.; Lucas, J. A.; Kelly, D. A. and Kelly. S. L, Appl. Environ. Microbiol. 2011, 77, 1460-1465.
- "Purification, Characterization, and Inhibition of Sterol C24-Methyltransferase from Candida albicans." Ganapathy, K.; Kanagasabai, R.; Nguyen, T. T. M. and Nes, W. D. Arch. Biochem. Biophys. 2011, 505, 194-201.
- "Substrate Preferences and Catalytic Parameters Determined by Structural Characteristics of Sterol 14α-Demethylase CYP51 from Leishmania infantum." Hargrove, T. Y.; Liu, J.; Nes, W. D.; Waterman, M. R. and Lepesheva. G. I. J. Biol. Chem. 2011, 286, 26838-26848.
- "Effect of Substrate Features and Mutagenesis of Active Site Tyrosine Residues on the Reaction Course Catalyzed by Trypanosoma brucei Sterol C24-Methyltransferase." Liu, J.; Ganapathy, K.; Wywial, E.; Bujnicki, J. M.; Nwogwugwu, C. A. and Nes, W. D. Biochem. J. 2011, 439, 413-422.