Exocyclic C-C Modifications of Aromatic Polyketides

芳香族聚酮化合物的环外C-C修饰

• 批准号: 7177535
• 负责人: Jon Scott Thorson
• 金额: $ 27.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-18 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7177535
• 关键词: Actinobacteria class; Actinomyces; Address; Alkylation; Anabolism; Bacteria; Bacteriophages; Base Sequence; Biological; Biological Assay; Biological Factors; Blast Cell; Carbon; Characteristics; Class; Cloning; Cosmids; DNA Probes; Databases; Daunorubicin; Deoxy Sugars; Disruption; Dynemicin; Electroporation; End Point; Enzyme Gene; Event; Exhibits; Facility Construction Funding Category; Foundations; Genes; Genetic; Genomics; In Vitro; Libraries; Methodology; Methods; Micromonospora; Modification; Numbers; Open Reading Frames; Organism; Peptides; Phase; Polymerase Chain Reaction; Process; Production; Proteins; Protocols documentation; Protoplasts; Research Personnel; Sequence Analysis; Shunt Device; Staging; Streptomyces; Structure; System; Tetracycline; Tetracyclines; Translating; Type I Polyketide Synthase; Walking; antineoplastic antibiotics; combinatorial; design; fascinate; feeding; glycosylation; hedamycin; in vitro Assay; in vivo; mutant; novel; novel therapeutics; plant fungi; plasmid DNA; pluramycin; polyketide synthase; programs; research study; southern hybridization; tool; tumor

DESCRIPTION (provided by applicant): Aromatic polyketides differ from other polyketides by their characteristic polycyclic aromatic structures. These polyketides are widely distributed in bacteria, fungi and plants, and many of them are clinically valuable agents (e.g. tetracyclines, daunorubicin) or exhibit other fascinating biological activities. While the fundamental biosynthetic principles of aromatic polyketides has been extensively explored, little is known regarding the construction of many existing unique exocyclic carbon-carbon (C-C) attachments to these metabolites. The current proposal is designed to expand our understanding of this phenomenon by bringing together the study of two naturally occurring novel aromatic polyketide systems, which promise access to three distinct exocyclic aromatic polyketide C-C modifications. The first, hedamycin from Streptomyces griseoruber, offers one of the only naturally occurring di-C-glycosylation events as well as an additional type I PKS-directed C-alkyl chain substitution of the polycyclic ring system. The second, dynemicin from Micromonospora chersina, offers the only known naturally occurring fusion between an enediyne and aromatic polyketide. The intended studies are expected to lay a foundation to understand the unique mechanisms of these processes and also the potential to utilize these tools for combinatorial biosynthesis toward novel therapeutics. The first phase of this massive project is specifically intended to i) provide the necessary genetic tools and information to form reasonable mechanistic hypotheses for all three events, ii) to initiate in vivo and in vitro experiments explicitly designed to address the C-glycosylation and C-alkylation stages of hedamycin/pluramycin biosynthesis and Hi) attempt to combine aspects of all three aromatic C-C modification systems toward enhancing the diversification of aromatic polyketide structures. A particular focus of the final diversification strategies presented will be focused upon conjugation of these highly reactive antitumor antibiotics with known tumor-directing peptides.

描述（由申请人提供）：芳族聚酮化合物与其他聚酮的特征性多环芳烃结构不同。这些聚酮化合物被广泛分布在细菌，真菌和植物中，其中许多是临床上有价值的剂（例如四环素，daunorubicin）或表现出其他引人入胜的生物学活性。尽管已经广泛探索了芳族聚酮化合物的基本生物合成原理，但对于在这些代谢物上建造许多现有独特的外环碳碳（C-C）附件的构建知之甚少。当前的建议旨在通过将两个天然新颖的芳族聚酮化合物系统的研究汇总在一起，以扩大我们对这一现象的理解，这些系统有望访问三种不同的外循环芳族芳族芳族芳族芳族芳族的C-C-c修饰。首先，来自Griseoruber链霉菌的Hedamycin提供了唯一天然发生的Di-C-糖基化事件之一，以及多环形环系统的额外I型I型PKS指导的C-烷基链取代。第二个来自Micromonospora Chersina的Dynemicin提供了唯一已知的自然融合，在Enediyne和芳族聚酮化合物之间。预期的研究将奠定基础，以了解这些过程的独特机制，并有可能利用这些工具将这些工具用于组合生物合成。该大规模项目的第一阶段是专门针对i）提供必要的遗传工具和信息，以形成所有三个事件的合理机理假设，ii）启动体内和体外实验，明确设计，以解决C-糖基化和C-烷基化阶段，以解决HEDAMYCIN/PLURURAMYCIN BIOSESISS，并尝试使用三）锻炼。增强芳族聚酮化合物结构的多元化。提出的最终多元化策略的特定重点将集中在这些高反应性抗肿瘤抗生素与已知肿瘤导向肽的结合上。