BIO-ORGANIC CHEMISTRY OF OXIDATIVE PHENOLIC COUPLING

氧化酚偶联的生物有机化学

• 批准号: 6381192
• 负责人: CHARLES J SIH
• 金额: $ 19.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381192
• 关键词: cyclic peptides; drug design /synthesis /production; enzyme mechanism; hormone biosynthesis; molecular rearrangement; oxidation; phenols; thyroglobulin; thyroid hormones; thyroxine; triiodothyronine

DESCRIPTION: Oxidative phenolic coupling, either by a homolytic of heterolytic mechanism, is of great importance in natural products chemistry. Many heterocyclic products, including alkaloids, cyclic peptides, thyroid hormones, and glycopeptide antibiotics are biosynthesized via enzyme-catalyzed oxidative coupling. Our long-range objectives are to gain a better understanding of the mechanism of action of the enzymes that accomplish these transformation and to utilize them for synthetic applications. Although the mechanism of biosynthesis of thyroid hormones has been investigated from some 50 years, the intermediates and the molecular mechanism of the coupling of the two iodotyrosyl residues to form thyroxine are not known. The coupling of two diiodotyrosyl residues in thyroglobulin to form thyroxine (T4) is uniquely different from the usual dimerization reactions characteristic of phenoxy radicals. Our specific aims are: 1) To define the intermediates and the "lost side chain" formed during biosynthesis and to deduce the mechanism of this important and fascinating intramolecular oxidative coupling and rearrangement reaction. 2) To characterize the putative reactive intermediate in the intermolecular coupling mechanism that reacts readily with 3,5-diiodotyrosine residues of thyroglobulin to form T4. 3) To establish the exact role of this reactive intermediate in the overall mechanistic scheme of T4 biosynthesis, 4) To develop a concise one-pot chemical synthesis of thyroid hormones, triiodothyronine and thyroxine. As a diverse array of biologically active cyclic peptides are formed by post- translational oxidative coupling reactions, we intend to investigate the enzymatic mechanisms of C-0 and C-C coupling of aromatic amino acid residues (tyrosine, hydroxyphenylglycine, and tryptophan) in peptides with special reference to the biosynthesis of the cyclic peptides such as vancomycin, chloropeptin 1, complestatin, and the bastadins.

描述：氧化性酚醛偶联，通过均裂的 异解机理，在天然产物中具有重要意义 化学反应。许多杂环产品，包括生物碱，环状 多肽、甲状腺激素和糖肽抗生素是 通过酶催化氧化偶联生物合成。我们的远程 目的是更好地了解其作用机制 完成这些转化并利用它们的酶 用于合成应用。尽管生物合成的机制 甲状腺激素已经被研究了大约50年， 中间体及其偶联的分子机制 形成甲状腺素的碘酪氨酰残留物尚不清楚。两者之间的耦合 二碘酪氨酸残基在甲状腺球蛋白中形成甲状腺素(T4)是独一无二的 不同于通常的苯氧基二聚反应的特点 激进分子。我们的具体目标是：1)定义中间体和 生物合成过程中形成的“丢失侧链”及其机制 这种重要而迷人的分子内氧化偶联和 重排反应。2)描述假定的反应性 分子间耦合机制中的中间体，很容易发生反应 与甲状腺球蛋白的3，5-二碘酪氨酸残基形成T4。3)至 确定这种反应性中间体在总体上的确切作用 T4生物合成的机械方案，4)研制简明的一锅法 甲状腺激素、三碘甲状腺原氨酸和甲状腺激素的化学合成。AS 一系列不同的生物活性环肽通过后处理形成 翻译氧化偶联反应，我们打算研究 芳香族氨基酸C-0和C-C偶联的酶机制 多肽中的残留物(酪氨酸、羟基苯甘氨酸和色氨酸) 特别提及环肽的生物合成，如 万古霉素、氯普汀1、达维菌素和巴曲菌素。