Microbial platforms and tools for benzylisoquinoline alkaloid biosynthesis

生物技术，生物化学和生物质工程计划的NSF奖项支持开发天然产物合成的新工程方法的工作。微生物宿主中生物合成途径的工程化代表了具有令人兴奋的潜力的化学合成的新方法。虽然工程化细胞生物合成过程的传统方法需要大量的时间和资源投入，但这与许多天然产物生物合成方案中所表现的复杂性不成比例，合成生物学的最新进展正在改变可以在生物系统中工程化的遗传网络的复杂性。本研究的目的是开发一类重要的天然产物苄基异喹啉生物碱（BIA）的微生物生物合成平台。研究人员将利用这个微生物平台广泛推进复杂天然产物的可扩展生物合成策略，并提供对自然界自身生物合成策略的见解。具体而言，研究人员建议：（i）构建用于从氨基酸前体生物合成早期BIA的合成途径;（ii）通过修饰天然酵母途径来开发用于合成BIA途径的绝缘策略;（iii）开发用于生物合成专业化和区室化的细胞器路由的策略;（iv）连接用于专业BIA的全合成的优化BIA分支;（iv）构建用于生物合成的BIA分支。（v）发展新的生物工程课程，强调合成生物学的基本概念和综合系统设计策略。

This NSF award by the Biotechnology, Biochemical and Biomass Engineering program supports work to develop novel engineering approaches for natural product synthesis. The engineering of biosynthetic pathways in microbial hosts represents a newer approach to chemical synthesis with exciting potential. While traditional approaches to engineering cellular biosynthesis processes require a significant investment of time and resources that does not scale with the complexity represented in many natural product biosynthesis schemes, recent advances in synthetic biology are transforming the complexity of genetic networks that can be engineered in biological systems. The goal of this research is to develop a microbial biosynthesis platform for an important class of natural products, the benzylisoquinoline alkaloids (BIAs). The investigators will utilize this microbial platform to broadly advance scalable biosynthesis strategies for complex natural products and provide insights into nature's own biosynthetic strategies. Specifically, the investigators propose to: (i) construct synthetic pathways for the biosynthesis of early BIAs from amino acid precursors; (ii) develop insulation strategies for the synthetic BIA pathway through modification of native yeast pathways; (iii) develop strategies for organelle routing for biosynthesis specialization and compartmentalization; (iv) link optimized BIA branches for the total synthesis of specialty BIAs; (v) develop new biological engineering curriculum that emphasizes foundational concepts in synthetic biology and integrated systems design strategies.