'Omics'-based approaches and synthetic biology platform to investigate valuable plant natural products.

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Plant natural products (PNPs) have been used for treating human ailments since prehistoric times and are still the most important source for the majority of today's medicines. About 90% of the world's population relies on traditional medicinal plants, not only to meet their primary care needs but also for income generation. Although there are a vast number of medicinal plants, few are cultivated on a large scale and the majority of the world's supply is collected from the wild. Consequently, the commercial success of certain medicinal plants may lead to their over-collection, making the cultivation of these plants and production of their valuable PNPs necessary. Recently, PNPs of the alkaloid group produced by medicinal plants of the Amaryllidaceae family (e.g. Amaryllis, Galanthus and Narcissus), have been attracting increasing interest due to their multiple pharmacological activities. The properties of Amaryllidaceae alkaloids (AAs) include analgesic, anticancer and antimicrobial activities, and effects on cardiovascular and respiratory system. For example, narciclasine displays potent antimitotic activity, crinamine is reputed for its psychoactive properties whereas galanthamine, an acetylcholinesterase inhibitor, is used to treat symptoms of Alzheimer's disease. The commercial development of most AAs is restricted by their limited availabilities due to their low concentrations in planta. Only galanthamine is produced commercially. Although there are obvious interests in engineering AA production for crop improvement and development of pharmaceuticals, the lack of information on AA biosynthetic pathways and their regulation make this task very challenging. Recently, systems biology-based approaches have facilitated the discovery of biosynthetic genes involved in PNP metabolic pathways in other plant families through the integration of multiple `omics' (genomic, transcriptomic, proteomic and metabolomic) datasets. To date, no `omics' resources have been developed for the Amaryllidaceae. Consequently, several AA pathways remain hypothetical and enzymes and metabolic intermediates await discovery. The overall goal of the proposed research is to increase knowledge on the metabolism of AAs in plants through the application of innovative and modern genomics and integrated systems biology strategies. Specific aims are (i) the establishment of `omic' databases to facilitate discovery of novel AA biosynthetic genes, (ii) biochemical genomics to characterize novel genes and (iii) the development of a sustainable `green' microalgal synthetic biology platform to functionally validate genes and to produce AAs with promising medicinal value. An improved molecular understanding of AA biosynthesis is a necessary prerequisite to develop novel Amaryllidaceae cultivars with valuable AA profiles, and will pave the way for biotechnologies, such as synthetic biology, to create engineered microalgae strains for the production of high-value AAs relevant to diversifying Canadian agricultural and pharmaceutical industries.