Texas Tech University

Dr. W. David Nes


Title: Paul W. Horn Distinguished Professor, Emeritus

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

Email: wdavid.Nes@ttu.edu

Featured Articles

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.

Representative Publications (2017-present)

  • Nes, W. D., Chaudhuri, M. and Leaver, D.J. Druggable sterol metabolizing enzymes in infectious diseases: Cell targets to therapeutic leads. Biomolcules, 14, 249 (2024).
  • Madan, B., Wadia, S.R., Patnaik, S., Harmston, N., Tan, E.K.W., Bee, L., Tan, H., Nes, W. D., Petretto, E. and Virshup, D.M. The cholesterol biosynthesis enzyme FAXDC2 couples Wnt/beta-catenin to RTK/MAPK signaling. J. Clin. Invest. in press (2024).
  • Chaudhuri, M, Singha, U.K., Vanderloop, B. H., and Nes, W. D. (2022). Steroidal antimetabolites protect mice against Trypanosoma brucei. Molecules, 27, 4088. (2022) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9268410/.
  • Madan, B., Virshup, D. M., Nes, W. D. and Leaver, D. J. (2022). Unearthing the Janus-face cholesterogenesis pathways in cancer. Biochem. Pharmacology. 196, 114611. (2022) Doi: 10.1061/j.bcp.2021.114611.
  • Zu, P., Koch, H., Schwery, O., Pironon, S., Phillips, C., Ondo, I., Farrell, W., Nes, W. D., Moore, E., Wright, G. A., Farman, D. I., and Stevenson, P. C. Pollen Sterols are associated with phylogeny and environment but not with pollinator guilds. New Phytologist, 230 1169-1184 (2021).
  • Lamb, D. C., Hargrove, T.Y., Zhao, B., Wawzrzak, Z., Goldstone, J. V., Nes, W. D., Kelly, S. L., Watermnan, M. R., Stegeman, J. J. and Lepesheva, G. I. Concerning P450 Evolution: Structural analyses support bacterial origin of sterol 14a-demethylase. Mol. Biol. Evol. 38, 952-967 (2021) (doi: 10.1093/molbev/msaa260).
  • Hargrove, T. Y., Wawrzak, Z., Rachakonda, G., Nes, W. D., Villalta, F. P., Guengerich, F. P. and Lepesheva, G. I. (2021) Relaxed substrate requirements of sterol 14a-demethylase from Naelgeleria fowlerii are accompanied by resistance to inhibition. J. Med. Chem. 64, 17511-17522. (2021).
  • Zhou, W., Fisher, P. M., Vanderloop, B. H., Shen, Y., Shi, H., Maldonado, A. J., Leaver, D. J. and Nes, W. D. (2020) A nematode sterol C4a-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity. J. Lipid Res. 61, 192-204. (2020).
  • Commentary: Darnet, S., Fliesler, S.J., Schaller, H. Worming our way toward multiple evolutionary origins of convergent sterol pathways. J. Lipid Res. 61, 129-132 (2020).
  • Festschrift in 2019 published by Molecules: Chemical Biology of Sterols, Triterpenoids and Other Natural Products: A Themed Issue in Honor of Professor W. David Nes on the Occasion of His 65th Birthday- Special Issue editors: De-an Guo and Wenxu Zhou. (2019).
  • Editorial: Bach, T.J. More than 40 years active in steroid and isoprenoid research- A personal note on W. David Nes' career and his multiple achievements in this field. Molecules 24, 901-902 (2019).
  • Zhou, W., Ramos, E., Zhu, X, Fisher, P. M., Kidane, M. E., Vanderloop, B. H., Thomas, C.D., Yan, Y., Singha, U., Chaudhuri, M., Nagel, M. T. and Nes, W. D. Steroidal Antibiotics are Antimetabolites of Acanthamoeba Steroidogenesis with Phylogenetic Implications. 60, 981-984 (2019).
  • Friggeri, L., Hargrove, T.Y., Rachakonda, G., Blobaum, A. L., Fisher, P., de Oliveira, G.M., da Silva, C. F., Soeiro, M. De Nazare, C. Nes, W. D., Lindsley, C. W., Villalta, F., Guengerich, F. P. and Lepesheva, G.I. Sterol 14a-Demethylase Structure-based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. J. Med. Chem. 61, 10910-10921 (2018). (doi: 10.1021/acs.jmedchem.8b01671).
  • Friggeri, L., Hargrove, T.Y., Wawrzak, Z., Blobaum, A.L., Rachakonda, G., Lindsley, C. W., Villalta, F., Nes, W. D., Botta, M., Guengerich, F. P. and Lepesheva, G.I. Sterol 14a-Demethylase Structure-based design of VNI ((R)-N-(1-2,4-dichlorophenyl)-2-(1H-imadazol-1yl)ethyl-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives to Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis. J. Med. Chem. 61, 10910-10921 (2018). (doi: 10.1021/acs.jmedchem.8b01671).
  • Hargrove, T.Y., Wawrzak, Z., Fisher, P. M., Child, S. A., Nes, W. D., Guengerich, F. P., Waterman, M. R. and Lepesheva, G. I. Binding of a Physiological Substrate causes Large-scale Conformational Reorganization in Cytochrome P450 51. J. Biol. Chem. 293, 19344-19353 (2018). (doi: 10.1074/jbc.RA118.005850).
  • Zhou, W., Warrilow, A.G.S, Thomas, C. D., Ramos, E., Parker, J. E., Price, C.L., Vanderloop, B.H., Fisher, P.M., Loftis, M.D., Kelly, D.E., Kelly, S.L. \and Nes, W. D. Functional Importance for Developmental Regulation of Sterol Biosynthesis in Acanthamoeba castellannii. Biochim. Biophys. Acta- Mole. Cell. Biol. Lipids. 1863, 1164-1178 (2018) (doi.org/10.1016/j.bbalip.2018.07.004).
  • Zhou, W., Debnath, A., Jennings, G., Hahn, H. J., Vanderloop, B. H., Chaudhuri, M., Nes, W. D. and Podust, L.M. Enzymatic Chokepoints and Synergistic Drug Targets in the Sterol Biosynthesis Pathway of Naegleria fowlerii Plos Pathogens, 14, e10007245 (2018) (doi.org/10.1371/journal.ppat.1007245).
  • Kildane, M.E., Vanderloop, B. H., Zhou, W., Thomas, C. D., Ramos, E., Singha, U., Chaudhuri, M. and Nes, W. D. Sterol Methyltransferase a Target for Anti-amoeba Therapy: Towards Transition State Analog and Suicide Substrate Design. J. Lipid Res. 58, 2310-2323 (2017). (doi.org/10.1194/jlr/MO79418;
  • Commentary: Nickels, J.T. (2019) Anti-parasitic drug discovery takes a giant leap forward. J. Lipid Res. 60, 919-921.
  • Featured in 2018 February issue of ASBMB Today magazine)
  • Debnath, A., Calvet, C.M., Jennings, G., Zhou, W., Aksenov, A., Luth, M.R., Abagyan, R., Nes, W.D., Mckerrow, J. H., and Podust, L. M. CYP51 is an Essential Drug Target for the Treatment of Primary Amebic Meningoencephalitis (PAM). Plos. Negl. Trop. Disease11, e0006104 (2017) (doi.org/10.1317/journal.pntd.000104).
  • Warrilow, A. G.S., Parker, J. E., Price, C.L., Garvey, E. P., Hoekstra, W. J., Schotzinger, R. J., Wiederhold, N. P., Nes, W. D., Kelly, D. E. and Kelly, S. L. The Tetrazole VT-1161 is a Potent Inhibitor of Trichophyton rubrum through its inhibition of T. rubrum CYP51. Antimicrob. Agents Chemother. 61: e00333-17 (2017) doi.org: 10.1128/ACC.00333-17.
  • Miller, M. B., Patkar, P., Singha, U.K., Chaudhuri, M. and Nes, W. D. 24-Methylenepropane steroidal inhibitors: A Trojan Horse in Ergosterol Biosynthesis that Prevents Growth of Tyrpanosoma brucei. Biochim. Biophys. Acta- Mole. Cell. Biol. Lipids1862, 305-313 (2017). doi: 10.1016/j.bbalip.2016.12.003.

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