Accessing and expanding microbial chemical diversity by synthetic biology and new enzymology

通过合成生物学和新酶学获取和扩大微生物化学多样性

• 批准号: 10189650
• 负责人: Yousong Ding
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189650
• 关键词: Address; Anabolism; Attention; Bioinformatics; Biological; Cell physiology; Chemicals; Complex; Cost efficiency; Cyanobacterium; Development; Enzymatic Biochemistry; Enzymes; Gene Cluster; Genome; Goals; Industrialization; Lead; Medical; Methods; Microbe; Mining; Mission; Natural Product Drug; Natural Products; Process; Research; Sampling; Source; Structure; Testing; United States National Institutes of Health; Work; analog; base; chemical synthesis; drug development; drug discovery; improved; innovation; microbial; microbial genome; new therapeutic target; nitration; novel; novel therapeutics; programs; synthetic biology

Project Summary/Abstract Natural products form a validated and preeminent source of new drug leads, but the low rate of new discoveries and the limited access of bioactive compounds are challenging current natural products-based drug discovery and development. The overall goal of the PI’s research program is to access and expand chemical diversity of microbes by the use of innovative strategies, thereby advancing natural products research. The central hypothesis of this work is that microbial genomes can be exploited to explore natural products and analogs. Bioinformatics mining of biosynthetic gene clusters from thousands of microbial genomes have distinguished microbes as the prominent source of an immense number of new therapeutically relevant compounds. However, current discovery process is able to access only a small fraction of these compounds, underlining the urgent need of new strategies. Enzymes as biocatalysts are proven alternatives for chemical synthesis in academic and industrial settings. The biosynthesis of microbial natural products is enriched with functionally diverse enzymes. Discovery of new enzymology from microbes can advance the synthesis of structural complex natural products and analogs via chemical methods or biological approaches (e.g., synthetic biology). To achieve the goal and test the hypothesis, research direction 1 of this proposal will focus on producing cyanobacterial natural products using multiple synthetic biology chassis. Cyanobacteria are a prolific source of structurally and functionally diverse natural products, but almost all cyanobacterial compounds are accessed only through the isolation from collected field samples. The research direction 1 can lead to the robust, thorough exploration of cyanobacterial strains directly from the genomes. Research direction 2 of this proposal will discover and characterize synthetically significant enzymes from microbial BCs, aiding the access and expansion of chemical diversity of natural products. The new enzymes discovered in direction 1 will also be characterized in direction 2 and can then be used in direction 1 to produce natural and unnatural compounds, demonstrating the improved cost efficiency. Specific attention in direction 2 will be to discover and characterize novel nitration enzymes. Together, these two directions of the PI’s research program can afford innovative strategies that enable effective exploitation of the seemingly limitless chemical diversity of microbes for discovery and development of new drugs and allow the development of new chemical processes. These studies can also boost the transformation of natural products research from small-scale pursuits to a genome-based high-throughput endeavor, therefore potentially triggering a paradigm shift in natural products and drug research.

项目总结/摘要 天然产物是新药先导的一个有效和卓越的来源，但新发现率低， 生物活性化合物的有限获取对目前基于天然产物的药物发现提出了挑战 发展先行者的要求PI的研究计划的总体目标是访问和扩大化学多样性， 微生物通过使用创新的策略，从而推进天然产品的研究。中央 这项工作的假设是，微生物基因组可以用来探索天然产物和类似物。 生物信息学从成千上万的微生物基因组中挖掘生物合成基因簇， 微生物是大量新的治疗相关化合物的主要来源。然而，在这方面， 目前的发现过程只能获得这些化合物中的一小部分，这突出了迫切需要 需要新的战略。作为生物催化剂的酶在学术和科学领域被证明是化学合成的替代品。 工业环境。微生物天然产物的生物合成富含功能多样的酶。 从微生物中发现新的酶学可以促进结构复杂的天然产物的合成 和类似物通过化学方法或生物方法（例如，合成生物学）。为了实现目标， 为了验证这一假设，本项目的研究方向1将集中在蓝藻天然产物的生产上 使用多个合成生物学底盘。蓝细菌是一个丰富的来源，结构和功能 不同的天然产物，但几乎所有的蓝藻化合物只能通过分离， 采集现场样品。研究方向1可以引导对蓝藻的稳健、深入的探索 直接从基因组中分离出来本提案的研究方向2将发现和表征 从微生物BC合成重要的酶，帮助获得和扩大化学多样性， 天然产品。在方向1中发现的新酶也将在方向2中表征，并且可以 然后在方向1中用于生产天然和非天然化合物，证明了改进的成本 效率方向2的特别关注将是发现和表征新的硝化酶。在一起， PI研究计划的这两个方向可以提供创新战略，使有效的 利用微生物看似无限的化学多样性来发现和开发新药 并允许开发新的化学过程。这些研究还可以促进 天然产物的研究从小规模的追求，以基因组为基础的高通量的奋进，因此， 这可能引发天然产品和药物研究的范式转变。