Research interests in this laboratory lie at the interface of protein 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 the biosynthesis of new, pharmaceutically relevant natural products. Examples of natural products that have been studied in our laboratory include anthraquinones such as R1128 (a selective estrogen receptor antagonist) and macrolides such as erythromycin, rifamycin (both antibacterials), and epothilone (anti-tumor agent). Most of our current efforts focus on obtaining atomic insights into polyketide synthase structure and mechanism, and on translating these insights into next generation tools for combinatorial biosynthesis. At the same time, we are also developing directed evolution approaches for engineering new antibiotics. In particular we are interested in dissecting and manipulating two features of polyketide synthases - the relative influence of protein-substrate interactions and protein-protein interactions on the specificity of each step in the overall catalytic cycle, and the highly controlled incorporation of building blocks in each round of chain extension.
More recently, we have undertaken projects aimed at understanding and modulating the chemistry and biology of Celiac Sprue, an HLA-DQ2 associated immune disease of the small intestine. Celiac Sprue is an increasingly diagnosed enteropathy that is induced by dietary exposure to gluten from common food grains such as wheat, rye and barley. Notwithstanding the seriousness of the disorder, little is known about its mechanistic underpinnings. No therapeutic agents are available to counter the toxic effects of the culprit cereals, and the only treatment for Celiac Sprue involves strict lifelong gluten exclusion. Our goals are to understand the biochemical basis of Celiac Sprue, and to translate these insights into pharmacological agents that could allow patients to safely re-incorporate these otherwise nutritious and extremely common food grains into their diet. Specifically we are exploring three therapeutic approaches: (i) protease therapy for rapid detoxification of ingested gluten; (ii) small molecule inhibitors of tissue transglutaminase, the predominant disease associated auto-antigen that regioselectively unmasks the immunogenicity of gluten peptides; and (iii) peptides that selectively inhibit HLA-DQ2 mediated gluten epitope presentation to inflammatory T cells.The newest project in our lab aims to develop fatty alcohols (C10-C16) and their derivatives as a new family of biofuels. Two types of biofuels are on the verge of commercial utility at the present time- alkyl esters of fatty acids (biodiesel) from plants and ethanol from microbial fermentations. The rising price of oil coupled with improvements in technology for the production of these biofuels is making both options increasingly attractive. However, neither biodiesel nor ethanol has emerged as a clear frontrunner. Our goal is to engineer an enzymatic pathway in E. coli that effectively channels endogenous fatty acyl intermediates into biofuels. Building on our expertise in polyketide biosynthesis, this is being achieved through a combination of protein engineering and metabolic engineering approaches. Our approach should allow for rapid development of new types of biofuels in response to changes in automotive technology and the marketplace.
