Discovery and reconstitution of securinine alkaloid biosynthesis

从植物提取物中提取的化学物质被称为天然产物，几千年来一直被人类用于染料、饮食和药物等领域。这些化学物质今天仍然有很大的意义。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）人类活动造成的生物多样性的丧失，以及（iii）为防止气候灾难而实现净零的要求。从历史上看，天然产物一直是药物的灵感来源，而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疗方法的植物——现代遗传方法意味着我们可以将它们的才能转移到一种没有灭绝危险的新植物上。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，结束我们对石化衍生技术的依赖。正是在这种背景下，我们正在研究一种叫做Flueggea suffructicosa的植物，一种原产于东亚的落叶灌木，是如何产生一种非常有趣的化学物质——securinine的。安全碱具有抗癌、抗真菌、神经调节、认知增强和神经保护作用。虽然目前还没有临床应用，但人们对securinine和与securinine密切相关的化合物（天然产物和化学修饰）的潜力一直很感兴趣。我们的目标是发现F. suffructicosa是如何制造securine的：它使用什么基因来制造这种复杂而有效的化学物质？首先，我们将获得F. suffructiccosa的遗传信息，然后通过搜索那些与已知基因相似的基因，将最有可能参与合成securine的基因列在一起，然后观察它们在植物中最活跃的时间和位置。然后对这些候选基因进行测试。我们使用了一种烟草，即烟叶，并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。有了这个过程，我们可以一步一步地建立一个路径。当发现与安全相关的基因时，我们将密切分析它们和它们的酶产物，以了解安全是如何在原子尺度上产生的。总体目标是表明我们可以在烟草中制造出安全物质：这将证明我们了解这一途径。这项工作将揭示用于制造生物活性化学物质的新酶。成功也将使我们能够在化学实验室或本地植物之外制造安全及相关化学品。这可能有助于开发可能成为未来药物的新型分子，有益于人类健康。

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.