Microbial platforms and tools for benzylisoquinoline alkaloid biosynthesis

这项由生物技术、生化和生物质工程项目颁发的NSF奖项支持为天然产物合成开发新的工程方法的工作。在微生物宿主中设计生物合成途径代表了一种具有令人兴奋的潜力的较新的化学合成方法。虽然传统的细胞生物合成过程工程方法需要大量的时间和资源投资，但与许多天然产品生物合成方案所表现的复杂性不同，合成生物学的最新进展正在改变可以在生物系统中工程的遗传网络的复杂性。本研究的目标是为一类重要的天然产物--苄基异喹啉生物碱(BIAS)开发微生物生物合成平台。研究人员将利用这一微生物平台广泛推进复杂天然产品的可扩展生物合成策略，并提供对自然自身生物合成策略的见解。具体地说，研究人员建议：(I)构建从氨基酸前体生物合成早期BIA的合成途径；(Ii)通过修改本地酵母途径，为合成BIA途径制定绝缘策略；(Iii)制定细胞器路径策略，以实现生物合成的专门化和区隔；(Iv)将BIA的优化分支连接起来，以全面合成专业BIA；(V)开发新的生物工程课程，强调合成生物学的基础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.