Structural Biology of Natural Product Biosynthesis
The most important drug molecules in use today are organic compounds isolated from organisms such as bacteria, plants, and fungi. These molecules, known as natural products, have an incredible diversity of chemical structures and biological activities. Among these compounds are well-known antibiotics such as vancomycin and penicillin, and the newest generation of antibacterial agents such as daptomycin (‘Cubicin’) from Cubist Pharmaceuticals. The most important anti-cancer drugs, including taxol, doxorubicin, and vinblastine are also compounds isolated from living organisms. Other important natural products are antimalarials, analgesics, ACE inhibitors, and cholesterol-lowering drugs.
My research group seeks to understand how natural products are made. Living organisms synthesize complex molecules without any of the ostensible advantages of an organic chemist, such as access to high temperatures and to solvents. These organisms nonetheless are able to construct molecules that are more complex than any that have ever been synthesized in a laboratory. Critical to the assembly of these molecules are enzymes, protein catalysts, that construct these complex natural product molecules from simple and biologically available precursors. Recent technological advances in chemical biology have provided scientists with the tools to ask fundamental questions about how these molecules are made. For instance, which genes encode the necessary enzymes? What are the underlying mechanisms of these enzymes? Can we re-engineer these enzymes to catalyze the production of derivatives of the original natural products?
My research team is working to isolate new biosynthetic pathways from microbes, to engineer enzymes to catalyze new reactions, and to generate natural product derivatives through combinatorial engineering and chemo-enzymatic synthesis. One of our major tools is macromolecular X-ray crystallography. We crystallize biosynthetic enzymes and determine their three-dimensional structures to provide a structural basis for understanding the catalytic mechanisms of these powerful protein machines. Overall, our research leverages a wide range of tools from chemistry and biology: structural biology, protein engineering, microbial genetics, natural product extraction, enzymology, and genomic analysis.
To find out more or to inquire about available positions, please email ksryan at chem.ubc.ca.