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

自史前时代以来，药用植物就被用来治疗人类的疾病，至今仍是当今大多数药物的最重要来源。生物碱构成了不同类别的专门代谢物，由于其强大的生物活性，许多被商业开发。近年来，石蒜科药用植物(如水仙、石南花等)所产生的生物碱因具有多种治疗活性而受到越来越多的关注。例如，石蒜科生物碱(AAs)，如樱桃碱，对冠状病毒等RNA病毒具有抗病毒活性，而加兰他明则用于治疗阿尔茨海默病的症状。AAs的商业开发受到可获得性有限、植物用量低的限制。在650种氨基酸中，只有加兰他明是从植物中商业生产的(83000美元/公斤)。尽管对AA的工程生产有明显的兴趣，但对于药物的开发，缺乏关于AA调控和生物合成途径的信息，这使得这项任务非常具有挑战性，因为只有很少的基因被鉴定出来。提高对AA生物合成的分子理解将有助于获得具有有价值的AA谱的工程植物，并为代谢工程等生物技术提高产量和可用性铺平道路。来自大自然药典(ORIGINATRA)的生物合成生物碱的阐明和工程研究计划建议增加我们的知识和对这些分子的可获得性。为了实现这一目标，我们将结合生化、生物信息学和分子方法来阐明产生这些高价值代谢物的生物合成途径。除了填补我们对生物碱代谢了解的重要空白外，该项目还将为创造用于生产目标生物碱的工程微藻奠定基础。由于微藻是微生物植物细胞，它们是支持生产复杂植物代谢物的理想平台，而不会排放温室气体，剩余的藻类生物质可以回收用于生物燃料。这种方法为世界上一些最令人头疼的问题提供了创新的新解决方案，从粮食安全到气候变化再到医疗。这将有助于改善加拿大的药品储备，并为这些珍贵药物的可持续生产铺平道路。ORIGINATRA计划将识别目标AA生物合成途径中的关键酶，并将应用这一知识来了解更多关于石蒜科物种的扩展生物碱途径。短期目标包括阐明1)樱桃碱的生物合成和2)在微藻中组装其生物合成途径，以验证途径和未来的可持续生产。鉴于越来越需要提供可持续的解决方案来生产药品，ORIGINATRA提供了巨大的希望。

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.