Administrative Supplement Promote Diversity in Health-Related Research: Caitlin McCadden
行政补充促进健康相关研究的多样性:Caitlin McCadden
基本信息
- 批准号:10828131
- 负责人:
- 金额:$ 6.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:Actinobacteria classAddressAdministrative SupplementAnabolismAntibioticsAntimalarialsBacteriaBiochemistryBioinformaticsBiologicalBiomedical EngineeringBiotechnologyChemicalsClinicalCollaborationsComplexCyclizationCytochrome P450DedicationsDevelopmentEngineeringEnzymatic BiochemistryEnzymesFamilyFutureGene ClusterGenomeGenomicsHealthImmunosuppressive AgentsIn VitroLibrariesMedicineMethodologyMiningNatural Product DrugNatural ProductsNatureOutcomes ResearchPathway interactionsPharmaceutical PreparationsPropertyProteinsResearchSourceStructure-Activity RelationshipSystems DevelopmentTerpenesTerpenoid Biosynthesis PathwayUp-RegulationX-Ray Crystallographyanti-cancercombinatorialdrug developmentdrug discoveryexperiencein vivoinnovationinsightinterdisciplinary approachmetabolomicsnovelnovel therapeuticsprogramssmall moleculesuccesssynthetic biologyterpene synthasetool
项目摘要
PROJECT SUMMARY/ABSTRACT
The long-term objectives of our research program are to (i) discover novel bacterial natural products
(NPs), (ii) elucidate the biosynthetic pathways and regulatory mechanisms of these NPs, and (iii) characterize
and utilize the discovered NPs and their biosynthetic enzymes for biomedical and biotechnological applications.
NPs are highly functionalized and evolutionarily optimized small molecules that possess unrivaled chemical
and structural diversities, resulting in a wide range of biological activities. Terpenoids, the largest and most
structurally diverse family of NPs, are considered rare in bacteria; only ~1.2% of known terpenoids are of
bacterial origin. However, genomics studies revealed that the biosynthetic enzymes responsible for terpenoid
biosynthesis are widely distributed in bacteria, particularly actinobacteria. We hypothesize that (i) bacterial
terpenoids are considerably underestimated among current NP libraries and the discovery and characterization
of novel terpenoids will lead to new drug leads and (ii) understanding the sequence-structure-function
relationships of terpenoid biosynthetic enzymes will lead to new opportunities in genome mining, combinatorial
biosynthesis, and oxidative biocatalysis. Our initial efforts follow two research directions that address
immediate needs and will set the stage for continued success in the field of terpenoid discovery and
biosynthesis. In the first direction, we will use an integrated genomics–metabolomics approach to discovery
novel bacterial terpenoids from bacteria. This will include the development of new and innovative
methodologies for targeted identification of complex bacterial terpenoids and the activation or upregulation of
terpenoid biosynthetic gene clusters. In the second direction, we will elucidate the biosynthetic pathways of
both new and known bacterial terpenoids and functionally, mechanistically, and structurally characterize
terpene synthases and their associated oxidative enzymes, particularly cytochrome P450s. We will use a
rigorous multidisciplinary approach involving genome mining, bioinformatics analysis, in vivo pathway
engineering, (un)natural product isolation and structural determination, in vitro enzymology, and protein X-ray
crystallography. Our experience in terpenoid biosynthesis and enzymology and our significant progress in
both research directions supports the feasibility of the proposed research and that we are well-suited to
establish and sustain a successful independent program in this field. In addition, we have established several
key collaborations with leaders in the fields of synthetic biology, NP drug discovery, and X-ray
crystallography that further strengthen this research program. Expected outcomes of this research program
include the revelation of the bacterial terpenome, understanding the underlying principles of how terpene
synthases dictate terpene cyclization, and the exploitation of naturally evolved oxidative enzymes to create a
toolbox of biocatalysts.
项目概要/摘要
我们研究计划的长期目标是 (i) 发现新型细菌天然产物
(NP),(ii) 阐明这些 NP 的生物合成途径和调节机制,以及 (iii) 表征
并将发现的纳米粒子及其生物合成酶用于生物医学和生物技术应用。
纳米粒子是高度功能化和进化优化的小分子,具有无与伦比的化学性质
且结构的多样性,导致萜类化合物种类繁多、活性最强。
结构多样的 NP 家族,在细菌中被认为是罕见的;已知的萜类化合物中只有约 1.2% 是
然而,基因组学研究表明,负责萜类化合物的生物合成酶。
生物合成广泛分布于细菌中,特别是放线菌中。
目前的 NP 库以及发现和表征中萜类化合物被大大低估
新型萜类化合物的研究将导致新的药物先导化合物的产生,并且(ii)了解序列-结构-功能
萜类生物合成酶之间的关系将为基因组挖掘、组合研究带来新的机遇
我们最初的努力遵循两个研究方向:
迫在眉睫的需求,将为萜类化合物发现领域的持续成功奠定基础
在第一个方向,我们将使用整合的基因组学-代谢组学方法来发现。
来自细菌的新型细菌萜类化合物这将包括开发新的和创新的。
复杂细菌萜类化合物的靶向鉴定和激活或上调的方法
在第二个方向上,我们将阐明萜类生物合成基因簇的生物合成途径。
新的和已知的细菌萜类化合物以及功能、机械和结构特征
我们将使用萜烯合酶及其相关的氧化酶,特别是细胞色素 P450。
严格的多学科方法,涉及基因组挖掘、生物信息学分析、体内途径
工程、(非)天然产物分离和结构测定、体外酶学和蛋白质 X 射线
我们在萜类生物合成和酶学方面的经验以及我们在晶体学方面的重大进展。
两个研究方向都支持拟议研究的可行性,并且我们非常适合
在该领域建立并维持成功的独立计划。
与合成生物学、NP 药物发现和 X 射线领域的领导者进行重要合作
晶体学进一步加强了该研究计划的预期成果。
包括揭示细菌萜烯组,了解萜烯如何产生的基本原理
合酶决定萜烯环化,并利用自然进化的氧化酶来产生
生物催化剂工具箱。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structure-guided product determination of the bacterial type II diterpene synthase Tpn2.
- DOI:10.1038/s42004-022-00765-6
- 发表时间:2022-11-08
- 期刊:
- 影响因子:5.9
- 作者:Stowell, Emma A.;Ehrenberger, Michelle A.;Lin, Ya-Lin;Chang, Chin-Yuan;Rudolf, Jeffrey D.
- 通讯作者:Rudolf, Jeffrey D.
Mutation of the eunicellane synthase Bnd4 alters its product profile and expands its prenylation ability.
- DOI:10.1039/d2ob01931k
- 发表时间:2022-11-23
- 期刊:
- 影响因子:3.2
- 作者:
- 通讯作者:
Biosynthesis, enzymology, and future of eunicellane diterpenoids.
- DOI:10.1093/jimb/kuad027
- 发表时间:2023-02-17
- 期刊:
- 影响因子:3.4
- 作者:
- 通讯作者:
Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis.
- DOI:10.1002/anie.202312490
- 发表时间:2023-09
- 期刊:
- 影响因子:0
- 作者:Zengyuan Wang;Qian Yang;Jingyi He;Haixin Li;Xingming Pan;Zining Li;Hui-Min Xu;Jeffrey D Rudolf;D. Tantillo;Liao-Bin Dong
- 通讯作者:Zengyuan Wang;Qian Yang;Jingyi He;Haixin Li;Xingming Pan;Zining Li;Hui-Min Xu;Jeffrey D Rudolf;D. Tantillo;Liao-Bin Dong
Discovery, Structure, and Mechanism of a Class II Sesquiterpene Cyclase.
- DOI:10.1021/jacs.2c09412
- 发表时间:2022-12-07
- 期刊:
- 影响因子:15
- 作者:Pan, Xingming;Du, Wenyu;Zhang, Xiaowei;Lin, Xiaoxu;Li, Fang-Ru;Yang, Qian;Wang, Hang;Rudolf, Jeffrey D.;Zhang, Bo;Dong, Liao-Bin
- 通讯作者:Dong, Liao-Bin
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Jeffrey Daniel Rudolf其他文献
Jeffrey Daniel Rudolf的其他文献
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{{ truncateString('Jeffrey Daniel Rudolf', 18)}}的其他基金
Discovery and Biosynthesis of Bacterial Terpenoids
细菌萜类化合物的发现和生物合成
- 批准号:
10449400 - 财政年份:2021
- 资助金额:
$ 6.63万 - 项目类别:
Discovery and Biosynthesis of Bacterial Terpenoids
细菌萜类化合物的发现和生物合成
- 批准号:
10667588 - 财政年份:2021
- 资助金额:
$ 6.63万 - 项目类别:
Discovery and Biosynthesis of Bacterial Terpenoids
细菌萜类化合物的发现和生物合成
- 批准号:
10273479 - 财政年份:2021
- 资助金额:
$ 6.63万 - 项目类别:
Cytochrome P450 Enzymes from Streptomyces: Diverse Biocatalysts in Natural Products Biosynthesis
来自链霉菌的细胞色素 P450 酶:天然产物生物合成中的多种生物催化剂
- 批准号:
9889150 - 财政年份:2017
- 资助金额:
$ 6.63万 - 项目类别:
Cytochrome P450 Enzymes from Streptomyces: Diverse Biocatalysts in Natural Products Biosynthesis
来自链霉菌的细胞色素 P450 酶:天然产物生物合成中的多种生物催化剂
- 批准号:
9371636 - 财政年份:2017
- 资助金额:
$ 6.63万 - 项目类别:
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