Linking metabolic engineering with gene discovery towards biotechnological camptothecin production

一些最有效的化疗药物来自植物。其中，喜树(喜树)产生抗癌化合物喜树碱，可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，关于植物如何制造喜树碱几乎一无所知，我们仍然依赖于化学合成和/或从植物中提取，所有这些都使用基于石油的溶剂或有毒化学物质进行半合成。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一直受到阻碍。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基因发现相结合来克服这些关键挑战，从而实现喜树碱生产生物技术。我们将结合两个实验室的专业知识，创建一个酵母平台，用于生产喜树碱的关键前体，并最终生产喜树碱本身。由此产生的生物合成方法将使我们能够探索除拓扑替康和伊立替康之外的一系列与喜树碱相关的新化学物质的未开发的药用潜力。此外，它还将为抗癌药物生产提供一种替代方案，以替代来自加拿大以外或石化产品的植物来源。这个项目是两个团队建立一个独特平台的机会，该平台利用他们的专业知识来回答制药需求和基本的科学问题。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在学习自然的化学多样性方面具有新的广度和影响，以使目前无法获得的治疗分子可用。最后，这一国际合作还将有助于推动和加强加拿大和德国生物经济部门之间的战略联系。

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.