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

• 批准号: 10828131
• 负责人: Jeffrey Daniel Rudolf
• 金额: $ 6.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10828131
• 关键词: Actinobacteria class; Address; Administrative Supplement; Anabolism; Antibiotics; Antimalarials; Bacteria; Biochemistry; Bioinformatics; Biological; Biomedical Engineering; Biotechnology; Chemicals; Clinical; Collaborations; Complex; Cyclization; Cytochrome P450; Dedications; Development; Engineering; Enzymatic Biochemistry; Enzymes; Family; Future; Gene Cluster; Genome; Genomics; Health; Immunosuppressive Agents; In Vitro; Libraries; Medicine; Methodology; Mining; Natural Product Drug; Natural Products; Nature; Outcomes Research; Pathway interactions; Pharmaceutical Preparations; Property; Proteins; Research; Source; Structure-Activity Relationship; Systems Development; Terpenes; Terpenoid Biosynthesis Pathway; Up-Regulation; X-Ray Crystallography; anti-cancer; combinatorial; drug development; drug discovery; experience; in vivo; innovation; insight; interdisciplinary approach; metabolomics; novel; novel therapeutics; programs; small molecule; success; synthetic biology; terpene synthase; tool

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.

项目总结/文摘

项目成果

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: COMMUNICATIONS CHEMISTRY
• 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: Organic & biomolecular chemistry
• 影响因子: 3.2

Biosynthesis, enzymology, and future of eunicellane diterpenoids.

• DOI: 10.1093/jimb/kuad027
• 发表时间: 2023-02-17
• 期刊: Journal of industrial microbiology & biotechnology
• 影响因子: 3.4

Discovery, Structure, and Mechanism of a Class II Sesquiterpene Cyclase.

• DOI: 10.1021/jacs.2c09412
• 发表时间: 2022-12-07
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 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

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis.

• DOI: 10.1002/anie.202312490
• 发表时间: 2023-09
• 期刊: Angewandte Chemie
• 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