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.

植物已经发展为生产大量复杂的化学结构，以抵抗食草动物和病原体的攻击，并保护自己免受经常敌对的环境。这些化学结构还为植物提供了人类文明依赖数千年的药物特性。罂粟是世界上最重要的药用植物之一，代表了制药行业使用的最大的天然产品。鸦片罂粟产生鸦片生物碱，例如吗啡和可待因，这是止痛药的主要类别之一。这些阿片类生物碱的化学结构非常复杂，植物仍然是其生产的最佳工厂。罂粟还会产生数百种其他生物碱，这些生物碱已成为其他几种药物的来源。罂粟是使用广泛的耕作方法在商业上生长的，并将作物机械收获，并运送到工厂以提取高价值化学物质。葛兰素史克（Glaxosmithkline）和约翰逊（Johnson）和约翰逊（Johnson）等制药公司拥有自己的生产系统，用于从鸦片罂粟中生产鸦片生物碱。我们在约克大学新型农产品中心的小组一直在与葛兰素史克（Glaxosmithkline）合作开发新的罂粟品种，这些品种产生了更多的吗啡生物碱，例如吗啡和可待因。我们还一直在研究罂粟如何产生诺斯卡汀，诺斯卡宾是一种阻止人类细胞分裂的抗肿瘤生物碱。 Noscapine数十年来一直用作人类咳嗽剂。最近已经证明了它在解决各种形式的癌症方面的有效性，并且在美国正在进行早期临床试验。我们特别想发现如何在罂粟中制造氮sp，这将有助于我们繁殖更多的品种，从而使更多的品种有用，并深入了解可能也具有有用的药物活性的相关分子。我们的工作导致了最近在领先的《科学》杂志上发表的重大突破（Winzer等，Science 2012，336：1704-8）。通过比较将硝基蛋白的鸦片罂粟品种与没有的鸦片品种进行比较，我们发现合成Noscapine的途径是由编码五个不同酶类别的十个基因组成的复杂簇控制的。这是植物中有史以来最复杂的基因簇，并为基因重复和重组驱动群集的进化提供了宝贵的见解。该提案以我们令人兴奋的突破为基础，并旨在确定基因簇是否也存在于其他相关物种中，也使noscapine也是如此。这将为基因簇演化所涉及的机制和过程提供新的见解。阐明我们发现的Noscapine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，以改善Noscapine和相关分子的产生。 Noscapine由生物碱生物合成途径的单独分支产生，用于产生吗啡和可待因。什么是调节分子流入这些不同分支的原因，我们现在拥有第一次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品原料的最重要药用植物的了解，还为我们提供了知识平台和工具，以开发新的鸦片罂粟品种，这些品种可用于生产Noscapine，吗啡，吗啡和Codeine等生物碱。该提案的最终目标是使用分子育种方法来开发新的鸦片罂粟品种，并具有优化水平的鸦片生物碱水平，以使制药业和英国工业生物技术部门受益。

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