Microbial platforms and tools for benzylisoquinoline alkaloid biosynthesis

该奖项由美国国家科学基金会生物技术、生物化学和生物质工程项目颁发，支持开发天然产物合成的新工程方法。微生物宿主生物合成途径的工程化代表了一种具有令人兴奋潜力的化学合成新途径。虽然设计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，而这与许多天然产物生物合成方案所代表的复杂性不一致，但合成生物学的最新进展正在改变生物系统中可设计的遗传网络的复杂性。本研究的目的是为一类重要的天然产物苯基异喹啉生物碱（BIAs）开发一个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)构建从氨基酸前体生物合成早期BIAs的合成途径；（ii）通过对天然酵母途径的修饰，开发合成BIA途径的保温策略；（iii）制定生物合成专门化和区隔化的细胞器路线策略；（iv）链接优化BIA分支，实现专业BIAs的全合成；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战略。

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.