Specificity of Modular Polyketide Synthases

模块化聚酮化合物合成酶的特异性

• 批准号: 7114108
• 负责人: Jeffrey David Kittendorf
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7114108
• 关键词: X ray crystallography; antibiotics; catalyst; chemical kinetics; chemical synthesis; enzyme activity; enzyme structure; enzyme substrate; erythromycin; macrolide antibiotics; polyketide synthase; postdoctoral investigator; protein structure function; structural biology

DESCRIPTION (provided by applicant): Bacterial type I modular polyketide synthases (PKSs) are complex, multifunctional enzymes that synthesize structurally diverse and medicinally relevant natural products. Given their modular organization, the manipulation of type I PKSs holds tremendous promise for the generation of novel macrolide antibiotics that are not easily accessible by standard chemical synthetic approaches. To fully harness this potential, however, a thorough evaluation of a variety of PKS systems is needed. To this end, the experiments described within this proposal seek to interface chemical synthesis with rigorous kinetic analysis and structural biology in an effort to enhance our understanding of specificity and catalysis of the pikromycin PKS system. In addition to providing detailed information regarding the kinetics of individual PKS modules, this work will also begin to uncover substrate specificity differences between the pikromycin and erythromycin (DEBS) PKS systems. Furthermore, a detailed understanding of the specificity of the pikromycin thioesterase domain will be achieved via x-ray co-crystallization studies.

描述（由申请人提供）：细菌 I 型模块化聚酮化合物合酶 (PKS) 是复杂的多功能酶，可合成结构多样且具有药用相关性的天然产物。鉴于其模块化组织，I 型 PKS 的操作为产生新型大环内酯类抗生素带来了巨大的希望，而这些抗生素是通过标准化学合成方法不易获得的。然而，为了充分利用这一潜力，需要对各种 PKS 系统进行彻底评估。为此，本提案中描述的实验寻求将化学合成与严格的动力学分析和结构生物学结合起来，以增强我们对匹克霉素 PKS 系统的特异性和催化作用的理解。除了提供有关各个 PKS 模块动力学的详细信息外，这项工作还将开始揭示匹克霉素和红霉素 (DEBS) PKS 系统之间的底物特异性差异。此外，通过 X 射线共结晶研究将详细了解匹克霉素硫酯酶结构域的特异性。