CAREER: Synthetic Biology to Understand and Harness Plant Enzyme Complexes for Natural Product Synthesis in Yeast

职业：合成生物学，了解和利用植物酶复合物在酵母中合成天然产物

• 批准号: 2338009
• 负责人: Sijin Li
• 金额: $ 74.29万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-01 至 2029-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2338009&HistoricalAwards=false
• 关键词: CAREER; Synthetic; Biology; Understand; Harness

Sourcing bioactive natural products from medicinal plants is important in drug production. However, the agriculture-based supply chain is susceptible to environmental changes as well as global crises, as many medicinal plants can only be grown in climate and conflict vulnerable regions. Microbial biomanufacturing is a powerful alternative approach to produce bioactive plant natural products. Engineered microorganisms can produce bioactive plant natural products in a short period of time by fermentation in closed vessels, thus providing an efficient approach to strengthen the supply chain. This project uses emerging synthetic biology methods to engineer microorganisms. In particular, the project reconstitutes, in yeast, the biosynthetic machinery derived from plants to produce valuable plant natural products. This study develops synergistic educational and research activities for women students, ultimately fostering the next generation of women leaders in the field of synthetic biology. The project targets high school students and undergraduate students majoring in plant biology or engineering, as well as established engineers. The activities include summer programs, interdisciplinary education, and research training, as well as opportunities for connecting engineers with leading synthetic biology startups and world-famous women entrepreneurs.The development of synthetic biology has opened the gate to a powerful alternative approach for production of plant natural products in a microbial host, such as baker’s yeast, by reconstructing the plant-derived heterologous biosynthetic pathways. Many critical regulatory activities and the machinery in plants remain poorly understood, which significantly limits plant natural product biomanufacturing. Plants can regulate their natural product biosynthetic pathways by forming dynamic plant enzyme complexes. These complexes widely exist in plants and are believed to be critical spatial organization machinery that promptly and dynamically regulates plant natural product synthesis. This project addresses this knowledge gap through a synthetic biology-based approach to rebuilding and characterizing plant complexes in yeast to advance plant natural product biosynthesis. The medicinal plant Catharanthus roseus is chosen as the example to study due to the valuable pharmaceutical monoterpene indole alkaloids it produces and the pathways and complexes that have been partially characterized. Synthetic biology tools and methods developed in this project enable the dynamic assembly of plant enzymes in yeast for complex reconstruction and characterization, improve the understanding of the post-translational regulation mechanism in plants, and ultimately advance microbial biomanufacturing of valuable plant natural products.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

从药用植物中采购生物活性天然产品在药物生产中非常重要，然而，基于农业的供应链很容易受到环境变化和全球危机的影响，因为许多药用植物只能在气候和冲突脆弱的地区种植。生产生物活性植物天然产品的强大替代方法。工程微生物可以通过在封闭容器中发酵在短时间内生产生物活性植物天然产品，从而提供一种加强高效供应链的方法。特别是，该项目在酵母中重建了源自植物的生物合成机制，以生产有价值的植物天然产品。这项研究为女学生开展了协同教育和研究活动，最终培养了下一代女性领导者。该项目针对植物生物学或工程学专业的高中生和本科生，以及成熟的工程师。活动包括暑期课程、跨学科教育和研究培训，以及将工程师与领先者联系起来的机会。合成的合成生物学的发展为通过重建植物来源的异源生物合成途径在微生物宿主（例如面包酵母）中生产植物天然产物打开了大门。植物中的关键调控活动和机制仍然知之甚少，这极大地限制了植物天然产物的生物制造。植物可以通过形成动态植物酶复合物来调节其天然产物生物合成途径。这些复合物广泛存在于植物中。被认为是快速动态调节植物天然产物合成的关键空间组织机制，该项目通过基于合成生物学的方法来重建和表征酵母中的植物复合物，以促进植物天然产物的生物合成，从而解决了这一知识空白。之所以选择它作为研究的例子，是因为它产生了有价值的药用单萜吲哚生物碱，并且该项目中开发的合成生物学工具和方法已部分表征，从而实现了这一动态。在酵母中组装植物酶以进行复杂的重建和表征，提高对植物翻译后调节机制的理解，并最终推进有价值的天然产物的微生物生物制造。该奖项反映了植物植物的法定使命，并被认为值得通过以下方式支持：使用基金会的智力价值和更广泛的影响审查标准进行评估。