Area of Expertise: Structural biology and biochemistry of natural product biosynthetic enzymes for combinatorial biosynthesis

Natural products are one of our best sources of drugs and drug leads. Natural products from bacteria and fungi have the benefit of being supplied through fermentation, in contrast to sources such as plants and sponges that suffer from slow-growth and ecological concerns such as overharvesting. Natural products exist to benefit their hosts, as such some natural product drugs are not ideal for human use. Synthetic derivatives of these natural products often have superior activity, but cost significantly more to produce. Therefore finding methods to generate natural product derivatives through fermentation is an important goal.

Combinatorial biosynthesis is the process of creating natural products through the genetic engineering of producing organisms to generate natural product derivatives. Currently, the easiest method for producing natural product derivatives is through deletion of genes encoding enzymes that add functionality to a natural product. However, many enzymes are essential to building the core of a natural product, limiting the number of derivatives created through gene deletion. Another approach is to add enzymes to the pathway or to alter the substrate specificity of enzymes within the biosynthetic pathway. The major hurdle to the second approach is a lack in our current understanding of the structure-function relationships of these enzymes.

Our lab is seeking to understand the sequence-structure-function relationships in families of biosynthetic enzymes, so that our knowledge will be of use in engineering multiple biosynthetic pathways. Through reverse engineering the sequence-structure-function relationships of biosynthetic enzyme families we will engineer new substrate specificity into enzymes within pathways, and thus enable true combinatorial biosynthesis.

Using bioinformatics, x-ray crystallography and enzymology together, we will discover how sequence-structure-function is related within families of biosynthetic enzymes. We will have genes synthesized that encode proteins with engineered substrate specificity and probe their activities in vitro. Finally using genetics we will introduce the engineered synthetic genes into natural product producers to isolate natural product derivatives.