Polyketide Synthases (PKS)

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. We are interested in elements such as acyltransferase specificity, module/domain engineering, and structure-function relationships. Additionally, we hope to elucidate the structure and biological mode-of-action of orphan polyketide products.

Principal areas of interest:
  • De-Orphanizing the NOCAP (NOCardiosis-Associated Polyketide)

Using recombinant protein to reconstitute the biosynthetic pathway of the NOCAP molecule in vitro and in vivo, and using 2D NMR Spectroscopy to elucidate the structure.

  • Understanding the Catalytic Cycles of the 6-Deoxyerythronolide B Synthase

Using monoclonal Fabs to trap a conformation during specific stages of the catalytic cycle to understand the reactions carried out by 6-deoxyerythronolide B synthase

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  • Evolution of Assembly-Line PKSs and Diversification of Their Natural Products

By studying a newly discovered genetic element present in most assembly-line PKSs, we investigate the mechanism by which multi-modularity in PKSs evolved. We are looking to harness evolutionary strategies to generate chemical diversity in the lab. 

Celiac Disease

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.

Principal areas of interest:
  • Celiac Immunobiochemistry

Using biochemical tools, we investigate how immune cells are regulated chemically through post-translational modifications.

Chemical Tools and Therapeutics

Broad-spectrum antiviral drugs can enable faster and cheaper treatment for rapidly emerging and evolving pathogens. Previously, we identified DHODH as the cellular target of a promising broad-spectrum antiviral agent, GSK983. Currently, we are investigating the safety and efficacy of inhibition of de novo pyrimidine biosynthesis as an antiviral strategy in vitro and in vivo. Additional areas of interest include delineating antiviral activities of common macrolide antibiotics.

Principal areas of interest:
  • Identifying the Cellular Target and Mechanism of Action of GSK983

Designing host-targeting antiviral therapies that target pyrimidine biosynthesis