Dr. W. David Nes
Title: Paul Whitfield Horn Professor
Director, Center for Chemical Biology
Education: Ph.D., University of Maryland, 1979; Postdoctoral Study, NIH Postdoctoral Fellow, University of California, Berkeley; ARS-USDA, Albany, CA
Research Area: Biochemistry and Natural Products
Office: Chemistry 413-C
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.
- Opitz, S., Nes, W. D. and Gershenzon, G. Both Methylerthritol Phosphate and Mevalonate Pathways Contribute to Biosynthesis of Each of the Major Isoprenoid Classes in Young Cotton Seedlings. Phytochemistry98, 110-119 (2014).
- Warrilow, A. G. S., Hull, C. M., Rolley, N. J., Parker, J. E. Nes, W. D., Smith, S. N., Kelly, D. K. and Kelly, S. L. Clotrimazole as a Potential Agent for Treating the Oomycete Fish Pathogen Saprolegnia parasitica through Inhibition of sterol 14alpha-Demethylase (CYP51). Appl. Environ, Microbiol. 80, 6154-6166 (2014).
- Shameer, S., Logan-Klumpler, F. J., Vinson, F., Cottret, L., Merlet, B., Achcar, F., Boshart, M., Berriman, M., Breitling, R., Bringaud, F., Butifofer, P., Cattanach, A. M., Bannerman-Chukualim, B., Creek, D. J., Crouch, K., de Koning, H. P., Denise, H., Ebikeme, C., Fairlamb, A. H., Ferguson, M. A. J., Ginger, M. L., Hertz-Fowler, C., Kerkhoven, E. J., Maser, P., Michels, P. A. M., Nayak, A., Nes, W. D., Nolan, D. P., Olsen, C., Silva-Franco, F., Smith, T. K., Taylor, M. C., Tielens, A. G. M., Urbaniak, M. D., van Hellemond, J. J., Vincent, I. M., Wilkinson, S. R., Wyllie, S., Opperdoes, F. R., Barrett, M. P., & Jourdan, F. TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei. Nuc. Acids Res. (2014) doi: 10.1093/narlgku944.
- Haubrich, B. A., Collins, E. K., Howard, A. L., Wang, Q., Snell, W. J., Miller, M. B., Thomas, C. D., Pleasant, S. K. and Nes, W. D. Characterization, Mutagenesis and Mechanistic Analysis of an Ancient Algal Sterol C24-Methyltransferase: Implications for Understanding Sterol Evolution in the Green Lineage. Phytochemistry113, 64-72 (2015).
- Haubrich, B. A., Singha, U.K., Miller, M.B., Nes, W. R., Anyatonwu, H., Lecordier, L., Patkar, P., Leaver, D. J., Villalta, F., Vanhollebeke, B., Chaudhuri, M. and Nes, W. D. Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth. J. Lipid Res, 56, 331-341 (2015).
- Santori, F. R., Huang, P., van dr Pavert, S. A., Douglass, E. F., Leaver, D. J., Haubrich, B. A., Keber, R., Lorbek, G., Konjin, T., Rosales, B. N., Rozman, D., Horvat, S., Rahier, A., Mebius, R. E., Ratinejad, F., Nes, W. D. and . Littman, D. R. Natural RORλ Ligands that Regulate the Development of Lymphoid Cells. (2015) Cell Metabolism21, 286- 297 (2015).
- Price, C. L., Warrilow, A. G., Parker, J. E., Mullins, J. G., Nes, W. D., Kelly, D. E., & Kelly, S. L. Novel Substrate Specificity and Temperature-Sensitive Activity of Mycosphaerella graminicola CYP51 Supported by the Native NADPH Cytochrome P450 Reductase. Applied and environmental microbiology,81, 3379-3386 (2015).
- Moreau, R. A., Bach, T. J., Nes, W. D., Parish, E. J., Moser, J. K., & Nyström, L. 2014 GJ Schroepfer Jr. Memorial AOCS Sterol Symposium: Recent Advances in Sterol Research. Lipids, 50, 719-720 (2015).
- Lepesheva, G. I., Hargrove, T. Y., Rachakonda, G., Wawrzak, Z., Pomel, S., Cojean, S., Nde, P. N., Nes, W. D., Locuson, C. W., Calcutt, M. W., Waterman, M. R., Daniels, J. S., Loiseau, P. M., & Villalta, F. VFV as a new effective CYP51 structure-derived drug candidate for Chagas disease and visceral leishmaniasis. J. Inf. Dis. In press (2015). doi: 10/1093/infdis/jiv228.
- Lamb, D. C., Warrilow, A. G., Rolley, N. J., Parker, J. E., Nes, W. D., Smith, S. N., Kelly, D. E., & Kelly, S. L. Azole antifungal agents to treat the human pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through inhibition of sterol 14α-demethylase (CYP51). Antimicrob. Agents Chem. In press (2015) doi: 10.1128/AAC.00476-15.
- Leaver, D. J., Patkar, P., Singha, U. K., Miller, M.B., Haubrich, B. A., Chaudhuri, M. & Nes, W. D. Fluroinated sterols are Suicide Inhibitors of Ergosterol Biosynthesis in Trypanosoma brucei. Chem. & Biol. in press (2015).
- 105th American Oil Chemists' Society annual meeting & expo, San Antonio, TX (invited speaker and co-organizer of the sterol symposium), May 2014. At this meeting WDN received an award—Inducted into Society as a Fellow. Talk entitled "Novel sterol biosynthesis inhibitors as anti-trypanosomal agents".
- Department of Pharmacy, Texas Tech University, Amarillo, TX, January 2015. Talk entitled "Ergosterol biosynthesis inhibitors for treating opportunistic pathogens and protozoan diseases".