ORIGINATRA : elucidatiOn and engineeRInG of the bIosyNthesis of Alkaloids from moTher natuRe's pharmacopoeiA

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Medicinal plants are used to treat human ailments since prehistoric times and are still the most important source for the majority of today's medicines. Alkaloids constitute a diverse class of specialized metabolites, and due to their potent biological activity, many are commercially exploited. Recently, the alkaloids produced by medicinal plants of the Amaryllidaceae family (e.g. Narcissus and Galanthus) have been attracting increasing interest due to their multiple therapeutic activities. For example, Amaryllidaceae Alkaloids (AAs) such as cherylline possess antiviral activities against RNA viruses like coronaviruses, whereas galanthamine is used to treat the symptoms of Alzheimer's disease. The commercial development of AAs is restricted to limited availability and low amounts in planta. Out of 650 AAs, only galanthamine is produced commercially from plants ($83 000/kg). Although there are obvious interests in engineering AA production, for development of pharmaceuticals, the lack of information on AA regulation and biosynthetic pathways makes this task very challenging, as only few genes have been identified. An improved molecular understanding of AA biosynthesis will contribute to engineered plants with valuable AA profiles and pave the way for biotechnologies such as metabolic engineering to improve production and availability. The elucidatiOn and engineeRInG of the bIosyNthesis of Alkaloids from moTher natuRe's pharmacopoeiA (ORIGINATRA) research program proposes to increase both our knowledge and accessibility to these molecules. To achieve this goal, we will integrate a combination of biochemical, bioinformatics and molecular approaches to elucidate the biosynthetic pathways generating these high value metabolites. Apart from filling important gaps in our understanding of alkaloid metabolism, the project will set the stage for the creation of engineered microalgae for the production of target alkaloids. Since microalgae are microbial plant cells, they represent an ideal platform to support the production of complex plant metabolites without greenhouse gas emissions and residual algal biomass can be recycled for biofuels. This approach offers innovative new solutions to some of the world's most vexing problems, from food security to climate change to medical treatment. This will help improve Canada's repertoire and pave the way for the sustainable production of these precious drugs. The ORIGINATRA program will identify key enzymes in the targeted AA biosynthetic pathways and will apply this knowledge to learn more about extended alkaloid pathways from Amaryllidaceae species. The short objectives include elucidating the biosynthesis of 1) cherylline and 2) assembling its biosynthetic pathway in microalgae for validation of pathway and future sustainable production. Given the ever-increasing need to provide sustainable solutions to produce medicines, ORIGINATRA offers great promise.