Research in this laboratory focuses on problems where deep insights into enzymology and metabolism can be harnessed to improve human health.
For the past two decades, we have studied and engineered enzymatic assembly lines called polyketide synthases that catalyze the biosynthesis of structurally complex and medicinally fascinating antibiotics in bacteria. An example of such an assembly line is found in the erythromycin biosynthetic pathway. Our current focus is on understanding the structure and mechanism of this polyketide synthase. At the same time, we are developing methods to decode the vast and growing number of orphan polyketide assembly lines in the sequence databases.
For more than a decade, we have also investigated the pathogenesis of celiac disease, an autoimmune disorder of the small intestine, with the goal of discovering therapies and related management tools for this widespread but overlooked disease. Ongoing efforts focus on understanding the pivotal role of transglutaminase 2 in triggering the inflammatory response to dietary gluten in the celiac intestine.
Recently, we initiated a collaborative program involving multiple Stanford laboratories (http://med.stanford.edu/virx.html.html) that is aimed at developing a fundamentally new approach to treating viral infections. As part of this initiative, we are developing an antiviral chemotherapy that modulates pyrimidine metabolism in the host, and also a platform to engineer immuno-modulatory glycolipids for the treatment of influenza.
Lowry, B., Li, X., Robbins, T., Cane, D. E., & Khosla, C. (2016). A Turnstile Mechanism for the Controlled Growth of Biosynthetic Intermediates on Assembly Line Polyketide Synthases. ACS Central Science, 2(1), 14–20.
Edwards, A. L., Matsui, T., Weiss, T. M., & Khosla, C. (2014). Architectures of Whole-Module and Bimodular Proteins from the 6-Deoxyerythronolide B Synthase. JOURNAL OF MOLECULAR BIOLOGY, 426(11), 2229–45.
Morón, B., Verma, A. K., Das, P., Taavela, J., Dafik, L., DiRaimondo, T. R., … Makharia, G. K. (2013). CYP3A4-Catalyzed Simvastatin Metabolism as a Non-Invasive Marker of Small Intestinal Health in Celiac Disease. American Journal of Gastroenterology, 108(8), 1344–1351.
Kloeck, C., Herrera, Z., Albertelli, M., & Khosla, C. (2014). Discovery of Potent and Specific Dihydroisoxazole Inhibitors of Human Transglutaminase 2. JOURNAL OF MEDICINAL CHEMISTRY, 57(21), 9042–9064.
Lowry, B., Robbins, T., Weng, C.-H., O'Brien, R. V., Cane, D. E., & Khosla, C. (2013). In vitro reconstitution and analysis of the 6-deoxyerythronolide B synthase. Journal of the American Chemical Society, 135(45), 16809–12.
Deans, R. M., Morgens, D. W., Okesli, A., Pillay, S., Horlbeck, M. A., Kampmann, M., … Bassik, M. C. (2016). Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification. NATURE CHEMICAL BIOLOGY, 12(5), 361-?