Harnessing light and model endosymbiosis to produce natural products

利用光和模型内共生来生产天然产品

• 批准号: 10797299
• 负责人: Angad Mehta
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797299
• 关键词: Acids; Anacystisnidulans; Antibiotics; Antineoplastic Agents; Area; Artemisinins; Biopolymers; Carbon; Cells; Communication; Complex; Cyanobacterium; Data; Engineering; Escherichia coli; Evolution; FDA approved; Goals; Growth; Human; Life; Light; Mitochondria; Modeling; Natural Products; Organism; Paclitaxel; Pharmaceutical Preparations; Pharmacologic Substance; Photosynthesis; Plants; Saccharomyces cerevisiae; Saccharomycetales; Structure; System; Yeast Model System; Yeasts; chemical synthesis; drug synthesis; endosymbiont; improved; industrial production; metabolic engineering; mutant; novel; taxadiene; technology platform

Project Abstract A large portion of important drugs and pharmaceutical intermediates either originate from plants or are synthesized from petrochemical-based products. Several natural products of significantly high value to human life (e.g., antibiotics, pharmaceuticals like Artemisinin, anticancer agents like Taxol (paclitaxel) among others) have been produced by organisms that are not optimal for industrial production. Although some of these natural products can be chemically synthesized, the complex structures of several of these compounds makes chemical synthesis difficult and commercially infeasible. As a result, there is increasing need to develop sustainable and readily tractable technological platforms to synthesize these drugs and pharmaceutical intermediates. The central objective of this proposal is to develop a sustainable technological platform that harnesses light energy and biocatalysis to synthesize molecules of significant relevance to human life. We envision doing this by establishing cyanobacterial endosymbionts within yeasts cells, such that the endosymbiotic cyanobacteria provide ATP and assimilated carbon (generated from photosynthesis) to the yeast cells, which utilize it to produce biologically important natural products. This platform will allow us to couple the remarkable biosynthetic and biocatalytic potential of yeast to the photosynthetic ability of cyanobacteria to develop a sustainable and simple bioproduction platform to produce natural products of significant value to human life (vide infra). Premise: (i) Saccharomyces cerevisiae has been recently harnessed to produce high titers of biologically important molecules such as amorphadiene and artemisinic acid, (precursors to Artemisinin) and taxadiene (a key precursor to Taxol), (ii) we had previously developed model endosymbiosis between S. cerevisiae /E. coli to study mitochondrial evolution are currently engineering yeast/cyanobacteria endosymbiosis (preliminary data in Specific Aim 1) and (iii) our preliminary data on engineering model yeast/cyanobacteria endosymbiosis. In this proposal, we will focus on three key areas: (i) We have engineered experimental platform to establish endosymbiosis between model cyanobacteria, Synechococcus elongatus, and model budding yeast, S. cerevisiae. We will expand this platform by engineering novel cyanobacterial mutants as putative endosymbionts. We will extensively characterize the engineered yeast/cyanobacteria endosymbiosis to develop strategies to improve their stability, growth rate and homogeneity. (ii) We will create a metabolite-driven synthetic communication system to control endosymbiosis and optimize our platform for metabolic engineering. (iii) We will utilize our photosynthetic endosymbiotic platform to produce key precursors of FDA approved compounds, Artemisinin and Taxol. These studies will be the first step towards our long-term goal of developing a photosynthetic and genetically tractable endosymbiotic platform for the bioproduction of biologically important novel natural products as well as molecules like biopolymers and biofuels.

项目摘要 很大一部分重要的药物和医药中间体要么源自植物，要么来自植物 由石化产品合成。几种对人类具有极高价值的天然产物 生命（例如抗生素、青蒿素等药物、紫杉醇等抗癌药物等） 是由不适合工业生产的生物体产生的。尽管其中一些自然 产品可以化学合成，其中几种化合物的复杂结构使得化学 合成困难且商业上不可行。因此，越来越需要开发可持续和 易于处理的技术平台来合成这些药物和医药中间体。这 该提案的中心目标是开发一个利用光能的可持续技术平台 和生物催化合成与人类生命密切相关的分子。我们设想通过以下方式做到这一点 在酵母细胞内建立蓝藻内共生体，使得内共生蓝藻 向酵母细胞提供 ATP 和同化碳（由光合作用产生），酵母细胞利用它来生产 具有重要生物学意义的天然产物。这个平台将使我们能够将卓越的生物合成和 酵母对蓝藻光合作用能力的生物催化潜力开发可持续且简单的 生物生产平台，生产对人类生命具有重要价值的天然产品（见下文）。前提：（一） 酿酒酵母最近被用来生产具有重要生物学意义的高滴度 分子，如紫穗槐二烯和青蒿酸（青蒿素的前体）和紫杉二烯（一种关键的 紫杉醇的前体），（ii）我们之前开发了酿酒酵母/大肠杆菌之间的内共生模型。大肠杆菌 研究线粒体进化目前正在工程化酵母/蓝藻内共生（初步数据在 具体目标 1) 和 (iii) 我们关于工程模型酵母/蓝细菌内共生的初步数据。 在本提案中，我们将重点关注三个关键领域：（i）我们设计了实验平台 在模型蓝藻、细长聚球藻和模型芽殖酵母之间建立内共生， 酿酒酵母。我们将通过设计新的蓝藻突变体来扩展该平台 内共生体。我们将广泛表征工程酵母/蓝藻内共生，以开发 提高其稳定性、增长率和同质性的策略。 (ii) 我们将创建一种代谢物驱动的合成药物 控制内共生并优化我们的代谢工程平台的通信系统。 （三）我们 将利用我们的光合内共生平台生产 FDA 批准的化合物的关键前体， 青蒿素和紫杉醇。这些研究将是我们朝着开发一个长期目标迈出的第一步。 光合作用和遗传易处理的内共生平台，用于生物生产重要的生物学物质 新型天然产物以及生物聚合物和生物燃料等分子。

项目成果

Engineering artificial photosynthetic life-forms through endosymbiosis.

通过内共生工程设计人工光合生命形式。

• 发表时间: 2022-04-26
• 影响因子: 16.6
• 作者: Cournoyer, Jason E;Altman, Sarah D;Gao, Yang;Wallace, Catherine L;Zhang, Dianwen;Lo, Guo;Haskin, Noah T;Mehta, Angad P
• 通讯作者: Mehta, Angad P