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

基本信息

批准号：
10728378
负责人：
Wenjun Zhang
金额：
$ 8.61万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
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/10728378
关键词：
Acids Acyl Carrier Protein Alkynes Anabolism Binding Biochemical Biological Biological Models Biology Biotechnology C-terminal Carboxy-Lyases Chemicals Chemistry Engineering Enzymatic Biochemistry Enzymes Family Gene Cluster Generations Genome Goals Health Human Interdisciplinary Study Iron Isotope Labeling Knowledge Libraries Logic Membrane Methionine-tRNA Ligase Mining Mycobacterium tuberculosis N Domain N-terminal Natural Products Nature Nitrogen Nitrous Acid Organic Synthesis Oxidases Parents Pathway interactions Personal Satisfaction Pharmacologic Substance Prevalence Public Health Reaction Research Streptomyces aureofaciens Structure Substrate Specificity System Testing Virulence Factors Work alpha ketoglutarate bioactive natural products chemical property desaturase design experimental study feeding flexibility functional group human disease improved in vivo innovation metalloenzyme novel pharmacophore physical property polyketide synthase polyketides scaffold small molecule synthetic drug tool

项目摘要

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.

天然产物是用于研究的IMALL分子，甚至引起人类疾病PS，这对于生物学活动至关重要。为了实现这一目标，必须完全表征化学逻辑和酶促机械生物合成用于烷基产生的Brane结合的DI-IROR依赖性双功能双饱和度酶/乙酰烯酶，用于异构体合成的非血红素α-酮戊二酸酯依赖性氧化酶/脱羧酶，以及C-末端甲基甲基甲基甲烷类近代蛋白酶型的Didomain酶N-羟基三嗪的末端型结构域作为生物活性天然产物的生物化学和机械理解仍然存在，这些泡沫具有独特的化学和特性，并且在各种化学生物学应用中都具有差异进一步探讨了其生物合成的应用，这些“对各种生物分子的功能都按需进行。研究策略在选择新颖的技术及其独特但知之甚少的生物合成机械，多学科研究工具以及目标方向的方法方面具有创新性尤其是与健康相关的平原，我们超越了在挠性方面的酶，而对人类的福祉产生了积极影响。基本和翻译水平的生物医学和生物技术研究中的天然产品OGY和公用事业。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biosynthesis of Isonitrile Lipopeptide Metallophores from Pathogenic Mycobacteria.

病原分枝杆菌异腈脂肽金属载体的生物合成。

DOI：
10.1021/acs.biochem.2c00611
发表时间：
2023
期刊：
Biochemistry
影响因子：
2.9
作者：
DelRioFlores,Antonio;Narayanamoorthy,Maanasa;Cai,Wenlong;Zhai,Rui;Yang,Siyue;Shen,Yuanbo;Seshadri,Kaushik;DeMatias,Kyle;Xue,Zhaoqiang;Zhang,Wenjun
通讯作者：
Zhang,Wenjun

Tag and Snag: A New Platform for Bioactive Natural Product Screening from Mixtures.