Discovery and reconstitution of securinine alkaloid biosynthesis

叶秋碱生物碱生物合成的发现和重建

• 批准号: BB/Y003586/1
• 负责人: Benjamin Lichman
• 金额: $ 125.61万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY003586%2F1
• 关键词: Discovery; reconstitution; securinine; alkaloid; biosynthesis

Chemicals derived from plant extracts, known as natural products, have been used by humankind for millennia, for applications including dyes, diets and drugs. These chemicals still have great relevance today. In fact, three modern crises can be addressed by the discovery of new plant natural products and discovering the genes the plant uses to make them. These crises are: (i) the demand for new drugs to treat the wide range of contemporary ailments, (ii) the loss of biodiversity caused by human action and (iii) the requirement to achieve net-zero to prevent a climate catastrophe. Natural products have historically be the source of inspiration for drugs, and this could be accelerated with modern genetic and robotic technologies. The loss of biodiversity risks us losing plants with potential cures - the modern genetic approach means we can transfer their talents into a new plant not at risk of extinction. Lastly, discovering the genes for plant natural products will let us make useful chemicals using biology, ending our reliance on petrochemical-derived technologies. It is in this context that we are investigating how a plant called Flueggea suffructicosa, a deciduous shrub native to East Asia, makes a very interesting chemical called securinine. Securinine exhibits anticancer, antifungal, neuromodulatory, cognition enhancing, and neuroprotective activities. Whilst it has not currently in clinical use, there is ongoing interest in the potential of securinine and compounds closely related to securinine, both natural products and chemical modifications.We aim to discover how the F. suffructicosa makes securinine: what genes does it use to make this complex and potent chemical? First, we will obtain genetic information from F. suffructicosa and then put together a list of the genes most likely involved in making securinine by search for those similar to well-understood genes, and then looking at when and where in the plant they are most active. These candidate genes are then to be tested. We do this using a species of tobacco Nicotiana benthamiana and getting that plant to produce the candidate genes. We then analyse the tobacco to see if new chemicals are being made. With this process we can build a pathway step-by-step. When a securinine-related gene is discovered we will analyse them and their enzyme products closely, to understand how securinine is made an atomic scale. The overall aim is to show that we can make securinine in tobacco: this will be proof that we understand the pathway. This work will reveal new enzymes can that be used to make bioactive chemicals. Success will also allow us to make securinine and related chemicals outside the chemistry lab or the native plant. This may help develop new classes of molecules that might be the drugs of the future, benefitting human health.

从植物提取物中提取的化学品，被称为天然产品，数千年来一直被人类用于染料，饮食和药物等应用。这些化学品在今天仍然具有重要意义。事实上，三个现代危机可以通过发现新的植物天然产物和发现植物用来制造它们的基因来解决。这些危机是：（i）对治疗各种当代疾病的新药的需求，（ii）人类行为造成的生物多样性丧失，（iii）实现净零以防止气候灾难的要求。天然产品在历史上一直是药物的灵感来源，现代基因和机器人技术可以加速这一进程。生物多样性的丧失使我们有可能失去具有潜在治愈能力的植物--现代遗传学方法意味着我们可以将它们的才能转移到一种没有灭绝风险的新植物中。最后，发现植物天然产物的基因将使我们能够利用生物学制造有用的化学品，结束我们对石油化工技术的依赖。正是在这种背景下，我们正在研究一种名为Flueggea suffructicosa的植物，一种原产于东亚的落叶灌木，如何制造一种非常有趣的化学物质，称为一叶秋碱。一叶秋碱具有抗癌、抗真菌、神经调节、认知增强和神经保护活性。虽然它目前还没有在临床上使用，有正在进行的兴趣，在潜在的一叶秋碱和化合物密切相关的一叶秋碱，天然产物和化学修饰。Suffructicosa制造一叶秋碱：它使用什么基因来制造这种复杂而有效的化学物质？首先，我们将从F.然后通过寻找那些与已知基因相似的基因，将最有可能参与制造一叶秋碱的基因列在一起，然后观察它们在植物中何时何地最活跃。然后对这些候选基因进行测试。我们用一种烟草本塞姆氏烟草来做这个实验，让这种植物产生候选基因。然后我们分析烟草，看看是否有新的化学物质被制造出来。通过这个过程，我们可以逐步建立一条道路。当一叶秋碱相关基因被发现时，我们将仔细分析它们及其酶产物，以了解一叶秋碱是如何在原子尺度上形成的。总的目标是表明我们可以在烟草中制造一叶秋碱：这将证明我们了解这一途径。这项工作将揭示新的酶可以用来制造生物活性化学品。成功也将使我们能够在化学实验室或本地植物之外制造一叶秋碱和相关化学品。这可能有助于开发新类型的分子，这些分子可能是未来的药物，有益于人类健康。