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.

从药用植物中寻找具有生物活性的天然产物在药物生产中非常重要。然而，以农业为基础的供应链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。微生物生物制取是生产具有生物活性的植物天然产物的有效替代方法。工程微生物可以在短时间内通过密闭容器发酵生产具有生物活性的植物天然产物，从而为加强供应链提供了一种有效的途径。该项目使用新兴的合成生物学方法来设计微生物。特别是，该项目在酵母中重组了从植物中提取的生物合成机械，以生产有价值的植物天然产品。这项研究为女学生开发了协同教育和研究活动，最终培养了合成生物学领域的下一代女性领导者。该项目的目标是植物生物学或工程专业的高中生和本科生，以及知名工程师。这些活动包括暑期项目、跨学科教育和研究培训，以及将工程师与领先的合成生物学初创公司和世界著名的女性企业家联系起来的机会。合成生物学的发展打开了一扇大门，通过重建植物来源的异源生物合成途径，在微生物宿主中生产植物天然产品，如面包酵母。许多关键的调控活动和植物中的机制仍然知之甚少，这大大限制了植物天然产物的生物制造。植物可以通过形成动态的植物酶复合体来调节其天然产物的生物合成途径。这些复合体广泛存在于植物体内，被认为是迅速、动态地调节植物天然产物合成的重要空间组织机制。这个项目通过一种基于合成生物学的方法来解决这一知识差距，以重建和表征酵母中的植物复合体，以促进植物天然产物的生物合成。以药用植物长春花为例进行研究，因为其产生的药用单萜吲哚生物碱以及已被部分表征的途径和络合物。该项目开发的合成生物学工具和方法能够在酵母中动态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控机制的理解，并最终促进有价值的植物天然产品的微生物生物制造。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。