Heteroatoms in natural products: Enzymes, pathways, and chemistry

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Introduction: Molecules isolated from living organisms are among the most chemically complex compounds. My program aims to understand how nature constructs natural products, and we use chemistry and structural biology as major tools. We focus on how specific chemical sub-motifs are made, which has applications in the discovery of biocatalysts and targeted isolation of specific types of natural products. In this NSERC Discovery program, we focus on how nature forms nitrogen-nitrogen (N-N) bonds. Program Overview: This program builds on our discovery of the first biosynthetic enzyme to form an N-N bond. We now want to understand the detailed mechanisms of N-N bond formation, elucidate pathways to N-N bonds in plants, and discover new N-N-bond-containing natural products. We are interested in both fundamental aspects of enzymatic N-N bond formation, and applications of our work in biocatalysis, plant engineering, and targeted molecule discovery. Part 1: Enzymes We will determine the crystal structures of N-N-bond-forming enzymes. By combining in vitro studies, structural work, mechanistic studies, and generation of new variants, we expect to unravel the step-by-step mechanisms of N-N bond formation. Part 2: Pathways We will elucidate pathways to N-N-bond-containing molecules. Specifically, we will study the biosynthesis of ß-pyrazol-1-ylalanine in cucumber and linatine in flax. Through in vivo and in vitro studies, we will find new enzymes and study how they generate these unique non-proteinogenic amino acid structures. Part 3: Molecules We will employ a targeted, 15N-NMR-approach to screen fractions from bacteria predicted to produce piperazic acid and N-nitroso-containing molecules to discover new natural products and set the stage for exploration of their biological properties. Impact: Our research program will explore the frontiers of biosynthesis, including structural biology, pathway elucidation, and compound discovery. These studies have application in 1) development of biocatalysts for chemical synthesis, as enzymes are rapidly replacing traditional organic chemistry for fine chemical production; 2) engineering of crop plants to inactivate genes we link to production of unhealthy non-proteinogenic amino acids; 3) targeted discovery of new bioactive natural products. HQP and EDI: My comprehensive training plan will train 5 PhD students, 2 PDFs, and 10 undergraduate students over the next 5 years. I work to build a diverse research team with a recruitment strategy that brings diverse voices. I work toward inclusivity by implementing day-to-day actions to ensure all team members are heard and included. Finally, I champion equal opportunity to ensure personal and professional growth for everyone. My program gives students training in chemistry, molecular biology, and crystallography, and encourages creativity and development of independence, all of which will position students for success in diverse careers e.g. academia, biotechnology.