Biosynthesis of unusual bio-orthogonal functionalities in natural products

天然产物中不寻常的生物正交功能的生物合成

• 批准号: 10600347
• 负责人: Wenjun Zhang
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600347
• 关键词: Alkynes; Anabolism; Biochemical; Biological; Biology; Biotechnology; C-terminal; Carboxy-Lyases; Chemicals; Enzymatic Biochemistry; Enzymes; Generations; Goals; Health; Human; Interdisciplinary Study; Iron; Logic; Membrane; Methionine-tRNA Ligase; N Domain; N-terminal; Natural Products; Oxidases; Parents; Pathway interactions; Personal Satisfaction; Public Health; Research; System; alpha ketoglutarate; bioactive natural products; chemical property; desaturase; design; enzyme pathway; flexibility; functional group; heme a; human disease; innovation; metalloenzyme; novel; pharmacophore; physical property; public health relevance; small molecule; tool

SUMMARY Natural products are important small molecules for studying, treating, and even causing human diseases, and they typically have unique functional groups that are critical for their biological activities. By exploiting the biosynthetic machinery by which these functionalities are synthesized, it is possible to enhance, vary or diminish the biological activities of parent compounds and apply the biosynthetic machinery to new systems for functional group installation. Toward this goal, the chemical logic and enzymatic machinery underlying natural product biosynthesis need to be fully characterized and understood. This project will focus on functional characterization and mechanistical interrogation of enzymes responsible for biosynthesis of unusual pharmacophores of natural products, including terminal alkyne, isonitrile and N-hydroxytriazene. Unique metalloenzymes have been identified important for their biosynthesis, including the membrane-bound di-iron dependent bifunctional desaturase/acetylenase for alkyne generation, the non-heme iron and α-ketoglutarate dependent oxidase/decarboxylase for isonitrile synthesis, and a didomain enzyme consisting of a C-terminal methionyl- tRNA synthetase-like domain and an N-terminal cupin domain for N-hydroxytriazene formation. The biochemical and mechanistic understanding of these newly discovered enzymes remain poor, warranting an in-depth study in this project. In addition to serving as the warheads of bioactive natural products, these functionalities have distinct chemical and physical properties and are utilized in bio-orthogonal chemical transformations for various chemical biology applications. We will thus further explore the application of their biosynthetic machinery to install these “clickable” functionalities on various biomolecules on demand. The research strategy is innovative in terms of the choice of novel functionalities and their unique but poorly understood biosynthetic machinery, the multidisciplinary research tools, and the goal-oriented approaches to directly target health-related applications. In particular, we go beyond the enzyme and pathway characterization in the approach design, pursuing applications of these unique enzymes in terms of flexibility to have a positive impact on human well-being. The proposed research is thus significant due to both implications for the field of natural product enzymology and utilities in biomedical and biotechnological research at the basic and translational levels.

概括 天然产物是研究，治疗甚至引起人类疾病的重要小分子 他们通常会通过利用您的生物学活动至关重要 这些功能合成的生物合成机制，可以增强，变化或减少 母体成分化合物的生物学活性和新系统的生物合成机制 小组安装。 生物合成需要充分表征和理解。 以及负责自然药理生物合成的酶的机械质量 产品，含量藻类，异硝基和N-羟基苯二氮卓。 确定对生物合成很重要，包括膜结合的Di-riond依赖双功能 碱产生的去饱和酶/乙酰烯酶，非血红素铁和酮谷酸酯依赖性 氧化酶/脱羧酶用于异硝基酯合成，以及由C末端甲基二酰基 - tRNA合成酶样结构域和N末端的Cupin结构域，用于N-羟基苯 对新近发现的酶的机械理解仍然很差 在这个项目中，除了作为生物活性自然产品的弹头外， 独特的化学和物理特性，用于各种生物正交化学转化 化学生物学应用。 这些关于各种生物分子的“可点击”功能在需求上是创新的。 选择新功能和。 多学科研究工具以及直接针对健康相关应用的目标的方法。 特别是，我们超越了Apploach设计中的酶和途径，追求 这些Unzymes的应用在灵活性方面对人类的福祉产生积极影响 因此，由于对天然产物酶学和 基本和翻译水平的生物医学和生物技术研究中的公用事业。