Understanding the regulation of alkaloid biosynthesis in opium poppy and breeding new varieties

认识罂粟生物碱生物合成调控及新品种选育

• 批准号: BB/K018809/1
• 负责人: Ian Graham
• 金额: $ 153.71万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK018809%2F1
• 关键词: Understanding; regulation; alkaloid; biosynthesis; opium

Plants have evolved to produce a vast array of complex chemical structures to fight off attacks from herbivores and pathogens and to protect themselves from often hostile environments. These chemical structures also provide plants with medicinal properties that human civilisation has relied on for millennia. Opium poppy is one of the most important medicinal plants in the world and represents the largest single source of natural products used by the pharmaceutical industry. Opium poppies produce opiate alkaloids such as morphine and codeine, which are one of the main classes of painkiller drugs. The chemical structures of these opiate alkaloids are very complex and plants remain the best factory for their production. Opium poppy also produces hundreds of other alkaloids and these have been a source of several other drugs. Opium poppy is commercially grown using broad acre farming methods and the crop is harvested mechanically and shipped to factories for extraction of the high value chemicals. Pharmaceutical companies such as GlaxoSmithKline and Johnson & Johnson have their own production systems for production of opiate alkaloids from opium poppy. Our group in the Centre for Novel Agricultural Products at the University of York have been working with GlaxoSmithKline to develop new varieties of poppy that produce more of the morphinan alkaloids such as morphine and codeine. We have also been investigating how opium poppy produces noscapine, an anti-tumour alkaloid that stops human cells dividing. Noscapine has been used as a human cough suppressant for decades. Its effectiveness in tackling various forms of cancer has been demonstrated more recently, and early stage clinical trials are in progress in the USA. We particularly wanted to discover how noscapine is made in opium poppy as this would help us to breed new varieties that make more of it and also to gain insight into related molecules that may also have useful pharmaceutical activity. Our work led to a major breakthrough that was published recently in the leading journal Science (Winzer et al, Science 2012, 336:1704-8). By comparing opium poppy varieties which make noscapine with those that do not we discovered that the pathway for synthesis of noscapine is controlled by a complex cluster of ten genes encoding five different enzyme classes. This is the most complex gene cluster ever found in plants and provides invaluable insights into the process of gene duplication and re-organisation driving cluster evolution.This proposal builds on our exciting breakthrough and aims to establish if the gene cluster is also present in other related species that also make noscapine. This will provide new insight into the mechanisms and processes involved in gene cluster evolution. Elucidating details of the biochemical pathway we discovered for noscapine biosynthesis will make us better able to design strategies for improved production of noscapine and related molecules. Noscapine is produced by a separate branch of the alkaloid biosynthesis pathway to the one used to produce morphine and codeine. What regulates the flow of molecules into these different branches is not understood and we now have the tools and knowledge to address this important question for the first time. Answering these questions not only adds to our knowledge of the most important medicinal plant in terms of natural product feedstock for the pharmaceutical industry, it also provides us with the knowledge platform and tools to develop new varieties of opium poppy that are optimised for production of alkaloids such as noscapine, morphine and codeine. The final objective of this proposal is to use molecular breeding methods to develop new varieties of opium poppy with optimised levels of key opiate alkaloids for the benefit of the pharmaceutical industry and the UK industrial biotechnology sector.

植物已经进化出大量复杂的化学结构，以抵御食草动物和病原体的攻击，并保护自己免受恶劣环境的影响。这些化学结构还为植物提供了人类文明数千年来所依赖的药用特性。罂粟是世界上最重要的药用植物之一，是制药行业使用的天然产品的最大单一来源。罂粟产生阿片生物碱，如吗啡和可待因，是主要的止痛药之一。这些阿片生物碱的化学结构非常复杂，植物仍然是生产其的最佳工厂。罂粟还产生数百种其他生物碱，这些生物碱是其他几种药物的来源。罂粟采用大面积耕作方法进行商业种植，作物经过机械收割并运往工厂提取高价值化学品。葛兰素史克和强生等制药公司拥有自己的生产系统，用于从罂粟生产阿片生物碱。我们约克大学新型农产品中心的团队一直在与葛兰素史克合作开发罂粟新品种，以生产更多的吗啡喃生物碱，如吗啡和可待因。我们还一直在研究罂粟如何产生诺斯卡品，这是一种阻止人体细胞分裂的抗肿瘤生物碱。诺斯卡品几十年来一直被用作人类止咳药。最近，它在治疗各种癌症方面的有效性已得到证实，并且早期临床试验正在美国进行中。我们特别想了解如何在罂粟中制造诺斯卡品，因为这将有助于我们培育出更多的新品种，并深入了解可能也具有有用药物活性的相关分子。我们的工作带来了一项重大突破，该突破最近发表在领先的《科学》杂志上（Winzer 等人，《科学》2012 年，336：1704-8）。通过比较产生那斯卡品的罂粟品种和不产生那斯卡品的罂粟品种，我们发现，那斯卡品的合成途径是由编码五种不同酶类的十个基因组成的复杂簇控制的。这是迄今为止在植物中发现的最复杂的基因簇，为驱动基因簇进化的基因复制和重组过程提供了宝贵的见解。该提案建立在我们令人兴奋的突破之上，旨在确定该基因簇是否也存在于其他相关基因中。也可产生那可品的物种。这将为基因簇进化所涉及的机制和过程提供新的见解。阐明我们发现的那可品生物合成的生化途径的细节将使我们能够更好地设计提高那可品和相关分子生产的策略。那斯卡品是由生物碱生物合成途径的一个独立分支产生的，该分支用于生产吗啡和可待因。是什么调节分子流入这些不同的分支尚不清楚，我们现在首次拥有了解决这个重要问题的工具和知识。回答这些问题不仅增加了我们对制药行业天然产物原料方面最重要的药用植物的了解，还为我们提供了开发罂粟新品种的知识平台和工具，这些新品种针对生物碱的生产进行了优化例如诺斯卡品、吗啡和可待因。该提案的最终目标是利用分子育种方法开发关键阿片生物碱水平优化的罂粟新品种，以造福制药业和英国工业生物技术部门。

项目成果

Untapped resources for medical research.

未开发的医学研究资源。

• DOI: 10.1126/science.abc8085
• 发表时间: 2020
• 期刊: Science (New York, N.Y.)
• 作者: Pérez-Escobar OA

A functionally conserved STORR gene fusion in Papaver species that diverged 16.8 million years ago.

• DOI: 10.1038/s41467-022-30856-w
• 发表时间: 2022-06-07
• 期刊: Nature communications
• 影响因子: 16.6