个人简介

Wells H. Rauser and Harold M. Petiprin Professor in the School of Engineering and Professor of Chemistry and, by courtesy, of Biochemistry Postdoc, John Innes Centre, U.K., Genetics (1992) PhD, California Institute of Technology, Chemical Engineering (1990)

研究领域

Bioorganic/Biophysical

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.

近期论文

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Yuzawa S, Kapur S, Cane DE, Khosla C. “Role of a conserved arginine residue in linkers between the ketosynthase and acyltransferase domains of multimodular polyketide synthases.” Biochemistry 2012, 51, 3708-3710. Klöck C, Diraimondo TR, Khosla C. “Role of transglutaminase 2 in celiac disease pathogenesis.” Semin Immunopathol 2012. Wang J, Jin X, Liu J, Khosla C, Xia J. “Resolving multiple protein-peptide binding events: implication for HLA-DQ2 mediated antigen presentation in celiac disease.” Chem Asian J 2012, 7, 992-999. Kapur S, Lowry B, Yuzawa S, Kenthirapalan S, Chen AY, Cane DE, Khosla C. “Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation.” Proc Natl Acad Sci USA 2012, 109, 4110-4115. Wong FT, Khosla C. “Combinatorial biosynthesis of polyketides—a perspective.” Curr Opin Chem Biol 2012, 16, 117-123. Dafik L, Albertelli M, Stamnaes J, Sollid LM, Khosla C. “Activation and inhibition of transglutaminase 2 in mice.” PLoS One 2012, 7, e30642. Diraimondo TR, Klöck C, Khosla C. “Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy.” J Pharmacol Exp Ther 2012, 341, 104-114. Bethune MT, Khosla C. “Oral enzyme therapy for celiac sprue.” Methods Enzymol 2012, 502, 241-271. Yu X, Liu T, Zhu F, Khosla C. “In vitro reconstitution and steady-state analysis of the fatty acid synthase from Escherichia coli.” Proc Natl Acad Sci USA 2011, 108, 18643-18648. Fitzgerald JT, Henrich PP, O'Brien C, Krause M, Ekland EH, Mattheis C, Sá JM, Fidock D, Khosla C. “In vitro and in vivo activity of frenolicin B against Plasmodium falciparum and P berghei.” J Antibiot (Tokyo) 2011, 64, 799-801. Fitzgerald JT, Ridley CP, Khosla C. “Engineered biosynthesis of the antiparasitic agent frenolicin B and rationally designed analogs in a heterologous host.” J Antibiot (Tokyo) 2011, 64, 759-762. Jin X, Stamnaes J, Klöck C, DiRaimondo TR, Sollid LM, Khosla C. “Activation of extracellular transglutaminase 2 by thioredoxin.” J Biol Chem 2011, 286, 37866-37873. Szu PH, Govindarajan S, Meehan MJ, Das A, Nguyen DD, Dorrestein PC, Minshull J, Khosla C. “Analysis of the ketosynthase-chain length factor heterodimer from the fredericamycin polyketide synthase.” Chem Biol 2011, 18, 1021-1031. Javidpour P, Das A, Khosla C, Tsai SC. “Structural and biochemical studies of the hedamycin type II polyketide ketoreductase (HedKR): molecular basis of stereo- and regiospecificities.” Biochemistry 2011, 50, 7426-7439. Wong FT, Jin X, Mathews II, Cane DE, Khosla C. “Structure and mechanism of the trans-acting acyltransferase from the disorazole synthase.” Biochemistry 2011, 50, 6539-6548. Charkoudian LK, Liu CW, Capone S, Kapur S, Cane DE, Togni A, Seebach D, Khosla C. “Probing the interactions of an acyl carrier protein domain from the 6-deoxyerythronolide B synthase.” Protein Sci 2011, 20, 1244-1255. Lee Y, Choi JY, Fu H, Harvey C, Ravindran S, Roush WR, Boothroyd JC, Khosla C. “Chemistry and biology of macrolide antiparasitic agents.” J Med Chem 2011, 54, 2792-2804. Dafik L, Khosla C. “Dihydroisoxazole analogs for labeling and visualization of catalytically active transglutaminase 2.” Chem Biol 2011, 18, 58-66. Klöck C, Jin X, Choi K, Khosla C, Madrid PB, Spencer A, Raimundo BC, Boardman P, Lanza G, Griffin JH. “Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2.” Bioorg Med Chem Lett 2011, 21, 2692-6. Yuan L, Holmes TC, Watts RE, Khosla C, Broekelmann TJ, Mecham R, Zheng H, Izaguirre EW, Rich KM. “Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas.” J Neurooncol 2011, 103, 207-219.