Linking metabolic engineering with gene discovery towards biotechnological camptothecin production

将代谢工程与基因发现联系起来，以实现生物技术喜树碱生产

• 批准号: 571673-2021
• 负责人: Dang, ThuThuyT
• 金额: $ 14.19万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761661
• 关键词: Linking; metabolic; engineering; gene; discovery

Some of the most effective chemotherapeutics come from plants. Among these, the Chinese happy tree (Camptotheca acuminata) produces the anticancer compound camptothecin, which can be converted to more potent drugs topotecan (Hycamtin) and irinotecan (Camptosar) for the treatment of lung, cervix, ovary and colon cancers. However, virtually nothing is known about how plants make camptothecin, and we continue to rely on chemical syntheses and/or extraction from plants, all of which use petroleum-based solvents or toxic chemicals for semisynthesis. So far, efforts to understand and ultimately engineer camptothecin biosynthesis have been held back by the lack of key biosynthetic genes and metabolic intermediates. In this project, Canadian and German researchers want to overcome these key challenges by linking metabolic engineering with gene discovery towards camptothecin production biotechnology. We will combine the expertise from the two laboratories to generate a yeast platform for the production of key precursors of camptothecin, and ultimately camptothecin itself. The resulting biosynthetic approach will allow us to explore the untapped medicinal potentials of a whole host of novel camptothecin-related chemicals in addition to topotecan and irinotecan. Furthermore, it will offer an alternative for anticancer drug production to plant sources from outside Canada or from petrochemicals. This project is the opportunity for two groups to build a unique platform that capitalizes their expertise to answer both pharmaceutical needs and fundamental scientific questions. It is a perfect proof-of-concept system in which chemistry, biochemistry, and synthetic biology are intertwined with new breadth and impact in learning from nature's chemical diversity to make currently unobtainable therapeutic molecules available. Lastly, this international collaboration will also help to pivot and strengthen strategic links between the bioeconomy sectors in Canada and Germany.

一些最有效的化疗药物来自植物。其中，中国快乐树（喜树）产生抗癌化合物喜树碱，可以转化为更有效的药物拓扑替康（Hycamtin）和伊立替康（Camptosar），用于治疗肺癌，宫颈癌，卵巢癌和结肠癌。然而，实际上对植物如何产生喜树碱一无所知，我们继续依赖于化学合成和/或从植物中提取，所有这些都使用石油基溶剂或有毒化学品进行半合成。到目前为止，由于缺乏关键的生物合成基因和代谢中间体，理解并最终设计喜树碱生物合成的努力受到阻碍。在这个项目中，加拿大和德国的研究人员希望通过将代谢工程与喜树碱生产生物技术的基因发现联系起来来克服这些关键挑战。我们将联合收割机从两个实验室的专业知识，以产生一个酵母平台的关键前体喜树碱的生产，并最终喜树碱本身。由此产生的生物合成方法将使我们能够探索除了拓扑替康和伊立替康之外的一系列新型喜树碱相关化学物质的未开发的药用潜力。此外，它将为抗癌药物生产提供一种替代方案，以从加拿大以外的植物来源或石油化工产品。该项目是两个团队建立一个独特平台的机会，利用他们的专业知识来回答制药需求和基本科学问题。这是一个完美的概念验证系统，其中化学，生物化学和合成生物学相互交织，在从自然界的化学多样性中学习新的广度和影响，使目前无法获得的治疗分子可用。最后，这种国际合作还将有助于加强加拿大和德国生物经济部门之间的战略联系。