Linking metabolic engineering with gene discovery towards biotechnological camptothecin production

点击翻译按钮获取中文摘要

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.