Research interests in this laboratory lie at the interface of chemistry and medicine.
Assembly line enzymes such as polyketide synthases have extraordinary potential for the programmable biosynthesis of complex natural products. Our laboratory seeks to understand the mechanistic logic of assembly line polyketide synthases, and to harness these insights in order to engineer new antibiotics. The prototypical system of interest to us is the 6-deoxyerythronolide B synthase, which synthesizes the macrocyclic core of erythromycin. Other examples of antibiotic biosynthetic pathways under investigation in our laboratory include the novel anti-infective agents A-74528 and guadinomine.
Celiac disease is a T cell driven autoimmune disease of the small intestine that is induced by exposure to gluten from foodgrains such as wheat, rye and barley. Our laboratory seeks to understand the earliest molecular recognition and catalytic events in the pathogenic response of the celiac intestine to dietary gluten. We anticipate that such insights will pave the way for new therapies and biomarkers for this widespread but overlooked disorder. Our present efforts are directed at testing the hypothesis that transglutaminase 2, the principal autoantigen associated with celiac disease, is also a druggable target for therapeutic intervention.
1. Cloning, sequencing, heterologous expression and mechanistic analysis of A-74528 biosynthesis, K. Zaleta-Rivera, L.K. Charkoudian, C.R. Ridley, and C. Khosla, J. Am. Chem. Soc. 132, 9122-9128 (2010)
2. Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase,” S. Kapur, A.Y. Chen, D.E. Cane, and C. Khosla, Proc. Natl. Acad. Sci. USA, 107, 22066-22071 (2010)
3. Probing the interactions of an acyl carrier protein domain from the 6-deoxyerythronolide B synthase,” L.K. Charkoudian, C.W. Liu, S. Capone, C. Kapur, D.E. Cane, A. Togni, D. Seebach, and C. Khosla, Prot. Sci., 20, 1244-1255 (2011)
4. Engineered biosynthesis of the antiparasitic agent frenolicin B and rationally designed analogs in a heterologous host,” J.T. Fitzgerald, C.P. Ridley, and C. Khosla, J. Antibiot., 64, 759-762 (2011)
5. Activation of extracellular transglutaminase 2 by thioredoxin,” X. Jin, J. Stamnaes, C. Klöck, T.R. DiRaimondo, L.M. Sollid, and C. Khosla, J. Biol. Chem, 286, 37866-37873 (2011)
6. In vitro reconstitution and steady-state analysis of the fatty acid synthase from Escherichia coli,” X. Yu, T. Liu, F. Zhu, and C. Khosla, Proc. Natl. Acad. Sci. USA, 108, 18643-18648 (2011)
7. Interferon-γ activates transglutaminase 2 via phosphatidylinositol-3-kinase dependent pathway: Implications for celiac sprue therapy,” T.R. DiRaimondo, C. Klöck, and C. Khosla, J. Pharmacol. Exp. Ther., In press, 2012.
8. Activation and inhibition of transglutaminase 2 in mice,” L. Dafik, M. Albertelli, J. Stamnaes, L.M. Sollid, and C. Khosla, PLoS One 7, e30642 (2012)
9. C. Reprogramming of a module of the 6-deoxyerythronolide B synthase for iterative chain elongation,”, S. Kapur, B. Lowry, S. Yuzawa, S., Kenthirapalan, A.Y. Chen, D.E. Cane, and C. Khosla, Proc. Natl. Acad. Sci. USA, In press, 2012
David E. Cane, Ph.D. - Department of Chemistry, Brown University
Ronald W. Davis, Ph.D. – Stanford Genome Technology Center, Stanford University
Karol Sestak, Ph.D. - Tulane National Primate Research Center, Tulane University
Ludvig M. Sollid, M.D., Ph.D. - Immunology, University of Oslo
Bana Jabri, M.D. - Pathology, University of Chicago
Current Predoctoral Students - Undergraduate Institution
Tommy diRaimondo (Chemical Engineering) University of Michigan, Ann Arbor
Briana Dunn (Chemical Engineering) - Cornell University
Colin Harvey (Chemistry) - McGill University
Tracy Holmes (Chemical Engineering) - Vanderbilt University
Xi Jin (Chemistry) Fudan University, Shanghai
Cornelius Kloeck (Chemistry) Jacobs University Bremen, Germany
Brian Lowery (Chemical Engineering)
Nick Plugis (Chemistry) - Middlebury College
Xirui Xiao (Chemistry) - Nanjing University
Xingye Yu (Chemical Engineering) McGill University
Current Postdoctoral - Doctoral Institution
Andrea Edwards (Ph.D. Biochemistry) - University of Colorado
Aaron May (Ph.D. Chemistry) - University of Minnestota
Robert O'Brien (Ph.D. Chemistry) - Boston College
Katharine Watts (Ph.D. Chemistry) - University of California, Santa Cruz