Microbial platforms and tools for benzylisoquinoline alkaloid biosynthesis

用于苄基异喹啉生物碱生物合成的微生物平台和工具

• 批准号: 1066100
• 负责人: Christina Smolke
• 金额: $ 40万
• 依托单位: Stanford University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1066100&HistoricalAwards=false
• 关键词: Microbial; platforms; tools; benzylisoquinoline; alkaloid

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.

这项由生物技术、生物化学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颖的工程方法的工作。微生物宿主生物合成途径的工程代表了一种具有令人兴奋潜力的化学合成新方法。虽然工程细胞生物合成过程的传统方法需要投入大量的时间和资源，而这与许多天然产物生物合成方案所代表的复杂性不相匹配，但合成生物学的最新进展正在改变可在生物系统中工程化的遗传网络的复杂性。这项研究的目标是为一类重要的天然产物——苄基异喹啉生物碱（BIA）开发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。具体来说，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) 通过修改天然酵母途径，制定合成 BIA 途径的隔离策略； (iii) 制定生物合成专业化和区室化的细胞器路由策略； (iv) 链接优化的 BIA 分支以实现专业 BIA 的全合成； (v) 开发新的生物工程课程，强调合成生物学和综合系统设计策略的基本概念。