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Chemistry Faculty :
Faculty Research Interests Chaitan Khosla
Principal Research Interests
Research interests in this laboratory lie at the interface of chemistry and medicine. For the past several years, we have investigated the catalytic mechanisms of modular megasynthases such as polyketide synthases, with the concomitant goal of harnessing their programmable chemistry for preparing pharmaceutically relevant natural products. Recent accomplishments include methods for heterologous production of polyketides; genetically reprogrammed biosynthesis of anthraquinones and polypropionates; and chemo-biosynthesis of new polyketides not readily affordable by synthetic or biological methods alone. These methodologies are already finding practical use. At the same time, we have placed a major emphasis on the biochemistry and structural biology of these giant protein assemblies. Fundamental insights into assembly line biosynthetic mechanisms have emerged, including the finding that protein-protein interactions play a central role in intermodular communications. In turn, these insights are highlighting opportunities for enhancing the efficiency of biosynthetic engineering. Over the next decade we envision that the predictive power of polyketide biosynthetic engineering will mature analogous to current protein engineering capabilities. More recently, we have investigated the pathogenesis of Celiac Sprue, an HLA-DQ2 associated autoimmune disease of the small intestine that is induced by exposure to gluten from foodgrains such as wheat, rye and barley. Within the past few years, we have explored three potential therapeutic strategies for this widespread but overlooked disease. By dissecting the unique chemical features of gluten, we discovered an intimate link between proteolytic stability and immunotoxicity of gluten, and translated this knowledge into the design of an oral enzyme therapy for the disease. At the same time, we have synthesized and evaluated mechanism-based inhibitors of human transglutaminase 2, the predominant disease associated auto-antigen. Finally, our structural and mechanistic dissection of HLA-DQ2 has been used to design, synthesize and evaluate gluten peptide analogues that selectively inhibit disease associated T cells. We remain committed to the vision that, within the next decade, safe and effective drugs will start having measurable impact on the health of Celiac Sprue patients. Representative Publications
Polyketide biosynthesis: 2) "The 2.7 Šcrystal structure of a 194 kDa homodimeric fragment of the 6-deoxyerythronolide B synthase," Y. Tang, C.Y. Kim, I.I. Mathews, D.E. Cane, C. Khosla, Proc. Natl. Acad. Sci. USA, 103, 11124-11129 (2006). 3) "Structure-based dissociation of a type I polyketide synthase module," A.Y. Chen, D.E. Cane, C. Khosla, J. Am. Chem. Soc., 128, 3067-3074 (2006).
2) "Inhibition of HLA-DQ2 mediated antigen presentation by analogues of a high affinity 33-residue peptide from a 2-gliadin," Xia, J., Siegel, M., Bergseng, E., L.M. Sollid, L.M., and C. Khosla, J. Am. Chem. Soc. 128, 1859-1867 (2006). 3) "Human transglutaminase 2 undergoes a large conformational change upon activation," D.M. Pinkas, P. Strop, A.T. Brunger, C. Khosla, PLoS Biol. , 5, e327 (2007). Collaborators
David E. Cane, Ph.D. - Department of Chemistry, Brown University Current Trainees
Current Predoctoral Students - Undergraduate Institution Current Postdoctoral - Doctoral Institution |
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