Grant: Discovery Grants Program - Individual

My internationally recognized research program asks the fundamental chemistry question: How can we increase the chemical diversity accessible through enzymatic chemistry? Natural product biosynthesis provides the perfect arena to address this question. Using an interdisciplinary set of tools including organic synthesis, enzyme kinetics, structural biology, protein engineering, natural product isolation and characterization, metabolomics, and genomics, we are expanding the chemical diversity accessible via biosynthetic enzymes. Our long-term goal is to introduce biocatalysts capable of significantly expanding molecular complexity by catalyzing unique chemistry on complex substrates. Natural product biosynthesis provides the source for tolerant enzymes that accommodate complex structure and generate a wide diversity of chemistry. To meet this long-term goal, we propose three short-term objectives. 1) The development of macrocyclizing thioesterases (TEs) as biocatalysts. Macrocyclization is demanding chemistry due to enthalpic and entropic barriers. We have characterized TEs from biosynthesis that generate this key functional group. We will further develop our mechanistic models for TE macrocyclization, engineer TEs to optimize macrocylization, and evaluate the scope of known TEs for macrocyclization of de novo substrates. This objective increases our understanding of the biochemistry of enzymatic macrocyclization and provides the biocatalysis community with new enzymes from macrolactonization. 2) Discovery of new biocatalysts. In this objective we will biochemical characterize new biosynthetic enzymes, which can feed into our biocatalyst development work. We will focus on characterization of new enzymes that add significant structural complexity to their substrates, providing new insight into natural product biosynthesis and new enzyme for biocatalyst development. 3) The discovery of new natural products. In this objective we will use metabolomics and genomics to discover new natural products and their biosynthetic gene clusters from cultivatable bacteria and fungi. Using spectroscopy and synthetic methods we will elucidate their structures and using genetic tools confirm their biosynthetic gene clusters. This objective will increase our knowledge of microbial chemical and genetic diversity and provide new biosynthetic enzymes biocatalyst discovery. This research will impact chemical manufacturing and biotechnology industries in Canada and around the world by expanding their capacity to generate new products and providing them with the next generation of leaders.