(6r) Understanding and Harnessing Nature's Synthetic Potential to Advance Modern Drug Development

Research Experience:

2^nd Postdoctoral Project (2013-present): Utilizing Synthetic Biology to Understand and Engineer the Biosynthesis of Plant Natural Products in Yeast. Under supervision of Dr. Christina D. Smolke, Bioengineering, Stanford University

1^st Postdoctoral Project (2012-2013): Investigating Microbial Interactions on Microfluidic Devices. Under supervision of Dr. Rustem Ismagilov, Chemistry & Chemical Engineering, California Institute of Technology

PhD Dissertation (2008-2012):  “Engineered Biosynthesis of Aromatic Polyketides”. Under supervision of Dr. Yi Tang, Chemical and Biomolecular Engineering, University of California, Los Angeles

Nature endows organisms including microbes, plants and animals with enormous power to synthesize complex functional molecules from simple building blocks. These complex molecules from natural sources and of diverse bioactivities are so called natural products. Natural products play an indispensable role in modern drug discovery and development. Comprehensive understanding of the biosynthesis of these complex molecules is essential for better harnessing nature’s synthetic potential to address the remaining challenges in the sourcing of many natural products, and to advance natural product based drug discovery and development. My research training has focused on utilizing engineering approaches (such as synthetic biology, metabolic engineering, and protein engineering) to understand the biosynthesis of important natural products (including bacterial and fungal aromatic polyketides, plant benzylisoquinoline alkaloids); and utilizing this enhanced understanding of nature’s synthetic power to advance engineering approaches to biosynthesis. Engineered biosynthesis systems can include engineering native hosts for higher accumulation of key natural products, heterologous reconstitution of valuable natural product biosynthesis pathways in fermentable yeast or E. coli as potential alternative to traditional native host or chemical synthesis for industrial production, and engineering the biosynthesis for novel derivatives as potential lead compounds for drug discovery.

Future Research Interests: 

In recent decades, there has been a decline in natural product-based drug development. This is in part due to a number of challenges associated with decreased frequency of identifying novel NP structures with traditional methods, obtaining sufficient supply of natural product lead compounds through the drug development pipeline, and modifying the highly complex natural product structures for lead optimization. The genomic information obtained through advances in sequencing and bioinformatics suggests that the natural products isolated thus far represent only a small portion of nature’s true synthetic potential, which has been largely underestimated and unused by human society. My future research program will leverage advances in genome sequencing, bioinformatics, and synthetic biology to study and engineer novel natural product and biosynthesis from the less explored sources, so as to expand our understanding of nature’s synthetic potential, and to address these key challenges in natural product discovery and related drug development.

Selected Publications:

Li, Y., Smolke, C., “Elucidating and Engineering Biosynthesis of the Anticancer Alkaloid Noscapine in Yeast”, Nat. Chem. Biol., in revision.

Li, Y., Chooi, Y.-H., Sheng, Y., Valentine, J. S., Tang, Y.*, “Comparative Characterization of Fungal Anthracenone and Naphthacenedione Biosynthetic Pathways Reveals an α-Hydroxylation-Dependent Claisen-Like Cyclization Catalyzed by a Dimanganese Thioesterase.”, J. Am. Chem. Soc. 2011, 133, 15773-15785.

Li, Y., Xu, W., Tang, Y.*, “Classification, Prediction and Verification of the Regioselectivity of    Fungal Polyketide Synthase Product Template Domains.” J. Biol. Chem. 2010, 285, 22762-22771. (Highlighted by Nat. Chem. Biol.)

Zhou, H.†, Li, Y.† (equal contribution), Tang, Y.*, “Cyclization of Aromatic Polyketides from Bacteria and Fungi.”Nat. Prod. Rep. 2010, 27, 839-868.

Zhang, W., Li, Y., Tang, Y.*, “Engineered Biosynthesis of Bacterial Aromatic Polyketides in Escherichia coli.”Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 20683-20685.