The research in the Boddy lab is focus on harnessing biosynthetic pathways to produce complex molecules and their analogs. The two key problems we try to address are 1) increasing the chemical diversity accessible through biosynthesis and 2) generating efficient and scalable methods for producing natural products and their analogs. The individual projects currently active in the lab are outlined below.
Characterizing biosynthetic pathways
We use biochemical tools to characterize key steps in polyketide biosynthetic patways. Some of the pathways we are currently working on include the deoxyreythronolide, zearalenone, radicicol, gephyronic acid, and bacillaene pathways.
Combining synthesis and enzymatic chemistry is a powerful method for efficient synthesis. We develop catalysts from polyketide biosynthesis as reagents for rapid chemoenzymatic synthesis of fine and specialty chemicals as well as natural products.
We use chemoenzymatic synthesis to test biosynthetic hypotheses as well as develop new approaches to accessing biosynthetically intractable functional groups. Some of the targets we have work on include the [4.3.0] bicyclic compound spiculoic acid A, as well as the dihydropyran and tetrahydropyran containing compounds laulimalide and neopeltolide.
New biosynthetic pathway discovery
Guided by our microbial ecology program and using next generation sequencing tools, we sequence both whole genomes and environmental DNA to discover new biosynthetic pathways.
We have developed a strong bioinformatics component, which is essential for maximizing our ability to mine sequence data for information on secondary metabolite biosynthesis.
The ability to express secondary metabolite pathways in heterologous hosts is essential for characterizing new biosynthetic pathways as well as discovering the products of silent gene clusters and gene clusters obtained from environmental DNA. We have developed a number of heterologous expression tools in diverse organisms including the workhorse bacteria E. coli and the predatory bacteria Myxococcus xanthus.
To produce substantial quantities of natural products and their analogs, we have developed a core strength in genetic and metabolic engineering to produce E. coli strains that can over produce desired natural products and their analogs. This work has produced strains capable of producing industrial relevant levels of sialic acid, as well as sialic acid analogs, such as N-acyl sialic acids, and pseudamininc acid.
Application of our tools to drug discovery
The lab maintains a strong medicinal chemistry skill set. This enables us to use the chemical diversity that we generate in house to develop small molecules to modulate biological function. We currently have an exciting project developing small molecules that can improve the cell culture-based production of viral vaccines.