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.

植物已经进化成产生大量复杂的化学结构，以抵御草食动物和病原体的攻击，并保护自己免受往往是恶劣环境的伤害。这些化学结构还为植物提供了人类文明几千年来一直依赖的药用特性。罂粟是世界上最重要的药用植物之一，是制药业使用的天然产品的最大单一来源。罂粟产生吗啡和可待因等鸦片生物碱，这是止痛药的主要类别之一。这些鸦片类生物碱的化学结构非常复杂，工厂仍然是生产它们的最佳工厂。罂粟还产生数百种其他生物碱，这些生物碱已经成为其他几种药物的来源。罂粟的商业种植使用大片土地的耕作方法，作物由机械收获，然后运往工厂提取高价值的化学物质。葛兰素史克(GlaxoSmithKline)和强生(Johnson&Johnson)等制药公司拥有自己的生产系统，可以从罂粟中生产鸦片生物碱。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公司合作开发新的罂粟品种，这种罂粟能产生更多的吗啡和可待因等吗啡生物碱。我们还一直在研究罂粟是如何产生诺斯卡因的，这是一种抗肿瘤的生物碱，可以阻止人类细胞的分裂。几十年来，诺斯汀一直被用作人类的止咳药。它在治疗各种形式的癌症方面的有效性最近得到了证明，美国正在进行早期临床试验。我们特别想知道罂粟是如何制造诺斯卡林的，因为这将有助于我们培育制造更多鸦片的新品种，并深入了解可能也具有有用药用活性的相关分子。我们的工作导致了一项重大突破，最近发表在领先的《科学》杂志上(Winzer等人，Science 2012,336：1704-8)。通过比较产生诺斯汀的罂粟品种和不制造诺斯汀的品种，我们发现合成诺斯汀的途径是由编码五种不同酶类的10个基因组成的复杂簇控制的。这是迄今在植物中发现的最复杂的基因簇，为基因复制和重组驱动簇进化的过程提供了宝贵的见解。这项建议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也制造去甲花碱的相关物种中。这将为基因簇进化中涉及的机制和过程提供新的见解。阐明我们发现的诺斯汀生物合成的生化途径的细节，将使我们能够更好地设计策略，以提高诺斯汀及其相关分子的生产。诺斯汀是由生物碱生物合成途径的另一个分支产生的，而生物合成途径是用于生产吗啡和可待因的途径。是什么调节了分子流入这些不同的分支，目前还不清楚，我们现在有了工具和知识来第一次解决这个重要问题。回答这些问题不仅增加了我们对制药业天然产品原料方面最重要的药用植物的了解，还为我们提供了开发新的罂粟品种的知识平台和工具，这些罂粟品种最适合生产诺斯汀、吗啡和可待因等生物碱。这项提议的最终目标是利用分子育种方法开发新的罂粟品种，使关键的鸦片类生物碱含量达到最佳水平，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