STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

莽草酸-分支酸途径的研究

• 批准号: 2391893
• 负责人: PAUL A BARTLETT
• 金额: $ 25.73万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-03-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2391893
• 关键词: alkyltransferase; aminoacid biosynthesis; chemical synthesis; cyclic aminoacid; drug design /synthesis /production; enzyme inhibitors; ether hydrolase; isomerase; microorganism metabolism; phosphorus oxygen lyase; shikimate; stereochemistry

DESCRIPTION (adapted from the applicant's abstract): This application proposes to continue the investigation of some of the key enzymes in the shikimate-chorismate pathway. The long term objectives are to elucidate the mechanisms of these enzymes and to develop general strategies for the design of enzyme inhibitors. (1) Dehydroquinase. Substrate analogs capable of aromatization and irreversible covalent linkage to the Type I DHQases are proposed. (2) EPSP Synthase. The intermediate involved in the addition/elimination mechanism of this enzyme, along with its monofluoro analog, will be synthesized to complete a series of tetrahedral analogs. A project in structure-derived inhibitor design, based on the structures of the inhibitor-enzyme complexes, will be initiated. (3) Chorismate Synthase. Some of the remaining mechanistic issues for this enzyme will be resolved by synthesizing and evaluating halo- and cyclopropanated substrate analogs. (4) Chorismate Mutase. New inhibitors of this unique enzyme are proposed, based on the structural information now available on its complex with previous inhibitor; new designs include a ring-expanded analog, potential irreversible inhibitors, and alternative substrates that can differentiate the mechanisms by which the enzymatic and catalytic antibody reactions are accelerated. (5) Shikimate Analogs. A number of analogs of shikimate itself, as well as their 5-enol-pyruvyl-3-phospho-isosteres, will be synthesized and evaluated as alternative substrates for a number of enzymes in the pathway. These analogs include 4-epi-shikimate, 2-halo- shikimates, and 5-membered ring analogs. (6) Isochorismate, Anthranilate, and p-Aminobenzoate Synthases. The project in this area will be concluded through the synthesis of an alternative series of bisubstrate analogs as potential inhibitors of the latter enzyme.

描述（改编自申请人的摘要）：本申请 建议继续研究其中的一些关键酶 莽草酸-分支酸途径。 长期目标是阐明 这些酶的机制并制定一般策略 酶抑制剂的设计。 (1)脱氢喹酶。 底物类似物 能够芳构化和与类型不可逆共价连接 提出了 DHQase。 (2) EPSP 合成酶。 涉及的中间体 在这种酶的添加/消除机制中，以及它的 单氟类似物，将被合成以完成一系列 四面体类似物。 结构衍生抑制剂设计项目， 根据抑制剂-酶复合物的结构，将 发起。 (3)分支酸合酶。 剩下的一些机制 该酶的问题将通过合成和评估来解决 卤代和环丙烷化底物类似物。 (4)分支酸变位酶。 新的 基于结构，提出了这种独特酶的抑制剂 目前可获得有关其与先前抑制剂的复合物的信息；新的 设计包括环扩展模拟，潜在不可逆 抑制剂和替代底物可以区分 酶促和催化抗体反应的机制 加速。 (5)莽草酸类似物。 许多莽草酸类似物 本身，以及它们的 5-烯醇-丙酮酰-3-磷酸-等排体，将是 合成并评估作为许多的替代底物 途径中的酶。 这些类似物包括 4-epi-shikimate、2-halo- 莽草酸酯和五元环类似物。 (6) 异分支酸酯， 邻氨基苯甲酸盐和对氨基苯甲酸盐合成酶。 该地区项目 将通过综合一系列替代方案得出结论 双底物类似物作为后一种酶的潜在抑制剂。