Evolution of Pathways to Pharmaceuticals in the Poppy Family

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DESCRIPTION (provided by applicant): Approximately 25% of current pharmaceuticals are either directly obtained from nature or are structurally based upon natural products that include important anti-cancer drugs and painkillers from plants. The study of selected medicinal compounds from plants requires detailed investigation of exactly that plant species that contains the entire biosynthetic pathway to the drug. Detailed genetic and biochemical information on these highly specialized plants is often missing. It is proposed to fill this knowledge gap and advance research in the field of plant-derived pharmaceuticals discovery and production in the poppy family (Papaveraceae) by identifying genes expressed in plant organs distinct in their alkaloid spectrum in opium poppy Papaver somniferum and the California poppy Eschscholzia californica through comparative transcriptomics using a combination of EST, 454 FLX and Solexa sequencing. Microarrays that represent the transcriptome will be developed for each species so that the temporal and spatial expression patterns during normal development in all three poppy species and in transgenic plants of P. somniferum in which six of the known alkaloid synthesis genes are systematically over- or under-expressed can be determined. BAC libraries will be prepared so that physical maps can be constructed of genomic regions surrounding alkaloid biosynthesis genes in these two members of the poppy family. Molecular evolutionary analysis of sequence data will be carried out within the context of gene family phylogenies, gene expression patterns and alkaloid content in order to identify novel genes that may encode enzymes or transcription factors involved in alkaloid biosynthesis. Functional analyses will be performed with the genes hypothesized to encode enzymes involved in the biosynthesis of medicinal alkaloids. This genetic and biochemical information will be made publicly available in the form of a user-friendly database (PoppyDB) and viewer (PhyloPathway) for metabolic engineering, biomimetic synthesis and directed evolution for the improved production of drugs and for the development of novel drugs. Project Narrative: Approximately 25% of current pharmaceuticals are either directly obtained from nature or are structurally based upon natural products that include important anti-cancer drugs and painkillers from plants. The study of selected medicinal compounds from plants requires detailed investigation of exactly that plant species that contains the synthetic pathway to the drug. Detailed genetic and biochemical information on these highly specialized plants is often missing; it is proposed to fill this knowledge gap and advance research in the field of plant-derived pharmaceuticals discovery and production in the poppy family.