Studies to understand and exploit 10-membered enediyne biosynthesis

研究了解和利用 10 元烯二炔生物合成

• 批准号: 9333663
• 负责人: GEORGE NEAL PHILLIPS
• 金额: $ 53.21万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333663
• 关键词: Achievement; Alkylation; Amination; Amines; Anabolism; Anthraquinones; Anti-Infective Agents; Antibodies; Antitumor Natural Products; Architecture; Biochemical; Biogenesis; Bioinformatics; Biotin; Chemicals; Chemistry; Clinical; Collaborations; Complement; Complex; Crystallization; Cyclization; Development; Dynemicin; Enzymatic Biochemistry; Enzymes; Family member; Foundations; Genetic; Hybrids; Hydroxylation; Iodination reaction; Ligands; Mixed Function Oxygenases; Modality; Modification; Molecular; Natural Products; Nucleotides; Polyenes; Proteins; Reaction; Reagent; Route; Series; Structural Protein; Structure; Sulfur; Trisaccharides; analog; base; cancer therapy; catalyst; chemical genetics; clinical development; design; enzyme pathway; glycosylation; glycosyltransferase; innovation; insight; non-Native; novel; novel strategies; oxidation; polyketide synthase; prototype; structural biology; structural genomics; sugar; targeted agent; thiosugar; tool; tumor

ABSTRACT The 10-membered enediynes [exemplified by calicheamicin (CLM), esperamicin (ESP) and dynemicins (DYN)] are arguably among the most renowned natural products (NPs) discovered to date by virtue of their unprecedented complex molecular architectures, notable anticancer and anti-infective potencies and, in the case of CLM, demonstrated clinical utility. The current study builds on a longstanding collaborative effort of achievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallel innovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will take advantage of this strong foundation and a powerful combination of genetic, biochemical, chemical and protein structural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts for enediyne non-native modification. Specifically, aims 1 and 2 will focus on extending our understanding of the fundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP, DYN anthraquinone biosynthesis and a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N- alkylation, ESP C6-hydroxylation and O-glycosylation). In parallel, aim 3 will focus on tactical structural studies to augment both aims 1 and 2 and the structural study of ‘unknowns’ to facilitate functional annotation. Additional studies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potential for strategic installation of chemoselective handles to enable novel approaches for facile, mild bioconjugation of CLM to tumor-targeting mAbs (in collaboration with Pfizer).

抽象的 10多元的雇员[由Calicheamicin（CLM），杂草素（ESP）和Dynemicin（Dyn）（Dynemicin（Dyn）示例） 可以说是迄今为止发现的最著名的天然产品（NP） 前所未有的复杂分子体系结构，著名的抗癌和抗感染能力，在这种情况下 CLM，展示了临床实用性。当前的研究以长期的合作努力为基础 成就和发现与10元的Emeinye生物合成的关键方面以及平行 为合成应用选择关键的生物合成催化剂的创新努力。提出的研究将接受 这种强大的基础的优势以及遗传，生化，化学和蛋白质的强大组合 阐明其余不寻常的生物合成转化并利用某些催化剂的结构工具 Enediyne非本地修饰。具体而言，目标1和2将集中于扩展我们对 emediyne核心生物合成的基本步骤，clm/dyn/esp，dyn anthraquinone生物合成 以及一组独特的剪裁反应（CLM/ESP硫代硫硫的安装和氨基糖N-） 烷基化，ESP C6-羟基化和O-糖基化）。同时，AIM 3将专注于战术结构研究 为了增强目标1和2的目标和“未知数”的结构研究，以促进功能注释。额外的 用关键催化剂和相应的非本地底物进行的AIM 2研究旨在评估潜力 为了制定化学选择性手柄的战略安装，以实现新颖的方法，以轻松，轻度的生物缀合 CLM到针对肿瘤的mAb（与辉瑞合作）。