Faculty & Research

personnel profile

Chaitan Khosla

 
Title:Professor; Wells H. Rauser and Harold M. Petiprin Professorship in the School of Engineering
Department(s):Chemical Engineering, Biochemistry by courtesy, Chemical Engineering, Chemistry
Affiliation(s):Chair, Chemical Engineering
Location:Keck 337
Mail Code:5025
Phone:650.723.6538       
Fax:650.725.7294
E-mail: khosla@stanford.edu
URL: http://www.stanford.edu/dept/chemistry/faculty/khosla
Administrator: Carolynn Gier

Research Statement

Research interests in Khosla's laboratory lie at the interface of enzyme 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 inflammatory 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. We have also synthesized and evaluated mechanism-based inhibitors of human transglutaminase 2, the predominant disease associated auto-antigen, and used them to deduce the high-resolution structure of the antigen-bound protein. 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.

Degree Discipline Year School
PhD 1990 California Institute of Technology
Publication TitleAuthor(s)/Speaker(s)Open Document
Structure-based dissociation of a type I polyketide synthase module Chen, A.Y.; Cane, D.E.; Khosla, C.
Human transglutaminase 2 undergoes a large conformational change upon activation Pinkas, D.M.; Strop, P.; Brunger, A.T....
The 2.7 Ã… crystal structure of a 194 kDa homodimeric fragment of the 6-deoxyerythronolide B synthase Tang, Y.; Kim, C.Y.; Mathews, I.I....
Rational design of combination enzyme therapy for celiac sprue Siegel, M.; Bethune, M.T.; Gass, J....
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....
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Membership in National Academies

American Academy of Arts and Sciences, National Academy of Engineering

Academic Honors & Awards

  • Allan P. Colburn Award, American Institute of Chemical Engineers, 1997
  • ACS Eli Lilly Award in Biological Chemistry, 1999
  • Alan T. Waterman Award, National Science Foundation, 1999
  • ACS Award in Pure Chemistry, 2000
  • Fellow, American Association for the Advancement of Science, 2006
  • Member, American Academy of Arts and Sciences, 2007
  • Member, National Academy of Engineering, 2009
  • Wells H. Rauser and Harold M. Petiprin Professor in the School of Engineering

Collaborators

  • David E. Cane, Ph.D. - Department of Chemistry, Brown University
  • Gary M. Gray, M.D. - Stanford School of Medicine Ludvig M. Sollid, M.D., Ph.D. - Immunology, University of Oslo
  • Keith M. Rich, M.D. - Neurosurgery, Washington University

Current Predoctoral—Undergraduate Institution

  • Michael Bethune (Biochemistry)—UC Davis
  • Alice Chen (Chemical Engineering)—UC Berkeley
  • Abhirup Das (Chemistry)—Indian Institute Of Technology
  • Jennifer Ehren (Chemical Engineering)—Notre Dame
  • Jay Fitzgerald (Chemical Engineering)—Notre Dame
  • Colin Harvey (Chemistry)—McGill University
  • Tracy Holmes (Chemical Engineering)—Vanderbilt University
  • Shiven Kapur (Chemistry)—Indian Institute of Technology
  • Ho Young Lee (Chemistry)—Seoul National University
  • Daniel Pinkas (Chemical Engineering)—UC Berkeley
  • Yinyan Tang (Chemistry)—Nanjing University
  • Harmit Vora (Chemical Engineering)—University of California Berkeley
  • Jin Xi (Chemistry)- Fudan University

Postdoctoral—Graduate Institution

  • Xuefeng Lu (Ph.D. Chemistry)—University of New Mexico
  • Belén Morón – University of Seville