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

自史前时代以来，药用植物就被用于治疗人类疾病，并且仍然是当今大多数药物的最重要来源。生物碱是一类特殊的代谢产物，由于其强大的生物活性，许多被商业化利用。近年来，石蒜科药用植物（如水仙属和高良姜属）产生的生物碱因其多种治疗活性而引起人们越来越多的关注。例如，石蒜科生物碱（AA）如cherylline具有抗RNA病毒如冠状病毒的抗病毒活性，而加兰他敏用于治疗阿尔茨海默病的症状。AA的商业开发受限于有限的可用性和植物中的低量。在650种氨基酸中，只有加兰他敏是从植物中商业生产的（83 000美元/公斤）。虽然在工程AA生产中存在明显的兴趣，但对于药物的开发，缺乏关于AA调节和生物合成途径的信息使得这项任务非常具有挑战性，因为只有少数基因被鉴定。对AA生物合成的分子理解的改进将有助于具有有价值的AA概况的工程植物，并为诸如代谢工程的生物技术铺平道路，以提高产量和可用性。从自然界药典中生物合成生物碱的阐明和工程研究计划（ORIGINATRA）旨在增加我们对这些分子的了解和可及性。为了实现这一目标，我们将整合生物化学，生物信息学和分子方法的组合，以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理解的重要空白外，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，它们代表了一个理想的平台，以支持生产复杂的植物代谢产物，而不会排放温室气体，残留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棘手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。这将有助于改进加拿大的所有药物，并为这些珍贵药物的可持续生产铺平道路。ORIGINATRA计划将确定目标AA生物合成途径中的关键酶，并将应用这些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）组装其在微藻中的生物合成途径，以验证途径和未来的可持续生产。鉴于对提供可持续的药物生产解决方案的需求不断增长，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.