BIO-ORGANIC CHEMISTRY OF OXIDATIVE PHENOLIC COUPLING

氧化酚偶联的生物有机化学

• 批准号: 6177690
• 负责人: CHARLES J SIH
• 金额: $ 19.22万
• 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/6177690
• 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：氧化酚偶联，通过均裂或 异裂机制在天然产物中具有重要意义 化学.许多杂环产物，包括生物碱、环状 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 目的是更好地了解作用机制 完成这些转化的酶， 用于合成应用。虽然生物合成的机制 甲状腺激素已经研究了大约50年， 中间体和两者偶联的分子机制 碘代酪氨酰残基形成甲状腺素是未知的。两个人的结合 甲状腺球蛋白中的二碘酪氨酰残基形成甲状腺素（T4）是唯一的 不同于苯氧基的通常二聚反应特征， 根的我们的具体目标是：1）定义中间体和 生物合成过程中形成的“丢失侧链”，并推断其机制 这一重要而迷人的分子内氧化偶联， 重排反应2)为了表征假定的反应性 分子间耦合机制中的中间体，易于反应 与甲状腺球蛋白的3，5-二碘酪氨酸残基形成T4。3)到 确定这种反应性中间体在整体中的确切作用 T4生物合成的机理方案，4）开发一种简洁的一锅法 甲状腺激素、三碘甲状腺原氨酸和甲状腺素的化学合成。作为 多种多样的生物活性环肽是通过后- 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偶联的酶促机理 残基（酪氨酸、羟苯甘氨酸和色氨酸） 特别提及环肽的生物合成， 万古霉素、氯肽素1、补体抑制素和巴斯塔定。