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:10179430
- 负责人:
- 金额:$ 33.36万
- 依托单位:
- 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:
- 关键词:AcidsAcyl Carrier ProteinAlkynesAnabolismBiochemicalBiologicalBiological ModelsBiologyBiotechnologyC-terminalCarboxy-LyasesChemicalsChemistryEngineeringEnzymatic BiochemistryEnzymesFamilyGene ClusterGenerationsGenomeGoalsHealthHumanInterdisciplinary StudyIronIsotope LabelingKnowledgeLibrariesLogicMembraneMethionine-tRNA LigaseMiningMycobacterium tuberculosisN DomainN-terminalNatural ProductsNatureNitrogenNitrous AcidOrganic SynthesisOxidasesParentsPathway interactionsPersonal SatisfactionPharmacologic SubstancePrevalencePublic HealthReactionResearchStreptomyces aureofaciensStructureSubstrate SpecificitySystemTestingVirulence FactorsWorkalpha ketoglutaratebasebioactive natural productschemical propertydesaturasedesignenzyme pathwayexperimental studyfeedingflexibilityfunctional groupheme ahuman diseaseimprovedin vivoinnovationmetalloenzymenovelpharmacophorephysical propertypolyketide synthasescaffoldsmall moleculesynthetic drugtool
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.
天然产物是研究、治疗甚至引起人类疾病的重要小分子,它们通常具有对其生物活性至关重要的独特官能团。通过利用合成这些官能团的生物合成机制,可以增强、改变或减少母体化合物的生物活性,并将生物合成机制应用于官能团安装的新系统。为了实现这一目标,需要充分表征和理解天然产物生物合成的化学逻辑和酶机制。该项目将侧重于负责天然产物(包括末端炔、异腈和N-羟基三氮烯)的不寻常药效团生物合成的酶的功能表征和机理研究。已鉴定出独特的金属酶对它们的生物合成很重要,包括用于炔生成的膜结合二铁依赖性双功能去饱和酶/乙炔酶、用于异腈合成的非血红素铁和α-酮戊二酸依赖性氧化酶/脱羧酶、以及由C-末端甲硫氨酰-tRNA合成酶样结构域和N-末端cupin结构域组成的用于N-羟基三氮烯形成的双结构域酶。这些新发现的酶的生物化学和机制的理解仍然很差,阻碍了本项目的深入研究。除了作为生物活性天然产物的弹头,这些功能具有独特的化学和物理性质,并用于各种化学生物学应用的生物正交化学转化。因此,我们将进一步探索他们的生物合成机制的应用,以根据需要在各种生物分子上安装这些“可点击”的功能。该研究战略在选择新功能及其独特但知之甚少的生物合成机制、多学科研究工具以及直接针对健康相关应用的目标导向方法方面具有创新性。特别是,我们在方法设计中超越了酶和途径表征,追求这些独特酶在灵活性方面的应用,对人类福祉产生积极影响。因此,拟议的研究是显着的,由于天然产物酶学和公用事业领域的生物医学和生物技术研究的基础和翻译水平的影响。
项目成果
期刊论文数量(0)
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Wenjun Zhang其他文献
Wenjun Zhang的其他文献
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{{ truncateString('Wenjun Zhang', 18)}}的其他基金
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:
10440327 - 财政年份:2020
- 资助金额:
$ 33.36万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 33.36万 - 项目类别:
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:
10728378 - 财政年份:2020
- 资助金额:
$ 33.36万 - 项目类别:
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:
10653015 - 财政年份:2020
- 资助金额:
$ 33.36万 - 项目类别:
In Situ Natural Product Labeling and Applications
原位天然产品标签和应用
- 批准号:
10008209 - 财政年份:2015
- 资助金额:
$ 33.36万 - 项目类别:
In Situ Natural Product Labeling and Applications
原位天然产品标签和应用
- 批准号:
9976696 - 财政年份:2015
- 资助金额:
$ 33.36万 - 项目类别:
In Situ Natural Product Labeling and Applications
原位天然产品标签和应用
- 批准号:
8955368 - 财政年份:2015
- 资助金额:
$ 33.36万 - 项目类别:
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