Benzylisoquinoline alkaloid biosynthesis

苄基异喹啉生物碱生物合成

• 批准号: RGPIN-2016-03675
• 负责人: Facchini, Peter
• 金额: $ 6.63万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=614548
• 关键词: Benzylisoquinoline; alkaloid; biosynthesis

A large and diverse array of natural products, also known as specialized metabolites, are responsible for the many colours, flavors, fragrances, and aromas found in plants. These compounds also serve as natural attractors of pollinating insects, effective pest deterrents, and provide plants with important lines of antimicrobial defense. The potent biological activity of plant specialized metabolites has led to the medicinal use of many compounds, among the longest standing and arguably the most important being the painkilling properties of morphine and codeine obtained from the opium poppy. Remarkably, the farming of opium poppy plants has remained the world’s only commercial source of opiate painkillers for many thousands of years. Morphine was first isolated more than 200 years ago and a slow, methodical scientific process eventually led to an understanding of the >15 chemical steps that convert the simple amino acid tyrosine to the complex molecular morphine in the plant. Recent advances in several powerful biotechnologies have dramatically accelerated the rate of scientific discovery in biology, including the isolation of all predicted genes responsible for the formation of morphine in opium poppy. Over the past 20 years, my laboratory has contributed many of the key genetic, biochemical and cellular discoveries involving the biosynthesis not only of morphine, but also several other related alkaloids produced by opium poppy with different pharmacological properties, such as the cough suppressant and anticancer drug noscapine, the muscle relaxant papaverine, and the antimicrobial sanguinarine. The availability of genetic resources and biochemical knowledge has allowed scientists and engineers to begin the process of transferring the complex cellular machinery from the opium poppy plant to other organisms, including simple baker’s yeast. The production of opiate pharmaceuticals by fermentation in yeast as opposed to the farming of plants has several advantages. Yeast grows faster and fermentation systems can be quickly scaled up if demand increases. Plants are vulnerable to environmental uncertainties, such as climate, pathogens and pests. Yeast is also easier to genetically manipulate, which could lead to the generation of new drugs. The global supply of legal opiates, including the availability of the dugs in Canada, also affected by political, social and economic factors. The proposed research aims to capitalize on several recent breakthrough discoveries made in my laboratory to advance our knowledge of morphine and noscapine biosynthesis. Missing parts and unresolved biological processes represent significant obstacles to the realization of important new technologies required to ensure a safe and stable supply of indispensable painkillers and other important drugs. The overarching objective is to fill key gaps in our knowledge of morphine and noscapine metabolism.

大量多样的天然产物，也被称为专门的代谢物，负责植物中发现的许多颜色、味道、香味和香气。这些化合物还可以作为传粉昆虫的天然吸引物，有效的害虫威慑物，并为植物提供重要的抗菌防御线。植物特化代谢物的强大生物活性导致了许多化合物的药用，其中存在时间最长且可以说是最重要的是从罂粟中提取的吗啡和可待因的止痛特性。值得注意的是，几千年来，罂粟种植一直是世界上鸦片类止痛药的唯一商业来源。200多年前，吗啡首次被分离出来，经过缓慢而有条不紊的科学研究，人们最终了解了将植物中简单的氨基酸酪氨酸转化为复杂分子吗啡的化学步骤。几项强大的生物技术的最新进展大大加快了生物学科学发现的速度，包括分离出所有预测的负责在罂粟中形成吗啡的基因。在过去的20年里，我的实验室贡献了许多关键的遗传、生化和细胞发现，不仅涉及吗啡的生物合成，还涉及罂粟产生的其他几种具有不同药理特性的相关生物碱，如止咳药和抗癌药物诺斯卡平、肌肉松弛剂罂粟碱和抗菌血碱。遗传资源和生物化学知识的可用性使科学家和工程师能够开始将复杂的细胞机制从罂粟植物转移到其他生物体，包括简单的面包酵母。与种植植物相比，在酵母中发酵生产鸦片类药物有几个优点。酵母生长得更快，如果需求增加，发酵系统可以迅速扩大规模。植物容易受到环境不确定性的影响，如气候、病原体和害虫。酵母也更容易在基因上进行操纵，这可能会导致新药的产生。合法鸦片剂的全球供应，包括在加拿大的药物供应，也受到政治、社会和经济因素的影响。拟议的研究旨在利用我的实验室最近取得的几项突破性发现，以推进我们对吗啡和诺斯卡平生物合成的了解。缺少的部分和未解决的生物过程是实现确保安全和稳定供应必不可少的止痛药和其他重要药物所需的重要新技术的重大障碍。总体目标是填补我们在吗啡和诺斯卡平代谢方面的知识空白。