Collaborative Research: A Systems Approach Toward Understanding the Diversification of Tropane and Granatane Alkaloid Biosynthesis

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The goal of this project is to use comparative approaches to investigate the synthesis pathways of two organic, nitrogen containing compounds in three different plant families to discover new genes and test the hypothesis that these two pathways developed independently of one another in each family. These alkaloids defend plants against insects and other pests and pathogens, and are used by humans as flavourings, fragrances, pesticides and medicines. This research will provide multiple opportunities for interdisciplinary training in genomics, structural biology, biochemistry, and analytical chemistry to graduate and undergraduate students. Furthermore, graduate student training will be enhanced through implementation of exchanges between partner labs to facilitate the development of interdisciplinary skills. Formal undergraduate exchanges will be accomplished by the recruitment of female and underrepresented minority students from Texas Tech or Iowa State University into a Research Experience for Undergraduates (REU) Program at Michigan State University. The project also will work directly with a local Community College in Iowa to provide Community College students with exposure to structural biology.Tropane and granatane alkaloids contain a core bicyclic ring structure and appear scattered across unrelated plant families. The research project will utilize a top down approach of combined transcriptomics and metabolomics coupled with comparative functional, biochemical and structural biology based approaches to elucidate the pathways and mechanisms that underlie the biosynthesis of the pharmaceutically important tropane and granatane alkaloids. Gene discovery will occur in three distinct and important crop families: Brassicaceae, Lythraceae and Erythroxylaceae and the resulting data will be compared to an established tropane pathway in the Solanaceae. This comparative approach will be used to test the hypothesis that novel biocatalytic activities within the tropane biosynthetic pathways of distinct species are the source of the independent emergence of the tropane alkaloid system within the plant lineage. Additionally, the research explores the possibility that the different components of tropane alkaloid metabolism were independently co-opted to build new metabolic systems (e.g. granatane alkaloids). Overall, this approach will lead to enhanced understanding of tropane and granatane alkaloid biosynthesis. Moreover, knowledge of the biosynthetic steps leading to tropane and granatane alkaloids is crucial for quantitative modeling and metabolic engineering of these pharmacologically active chemicals.