STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

莽草酸-分支酸途径的研究

• 批准号: 3276377
• 负责人: PAUL A BARTLETT
• 金额: $ 19.53万
• 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 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276377
• 关键词: antibiotics; chemical synthesis; cyclic compound; drug design /synthesis /production; shikimate; stereochemistry

A broadly based bioorganic program for the study of some of the key enzymes in the shikimate-chorismate pathway is outlined. The key elements are the following: 1. Chorismate mutase: New transition state analog inhibitors will be synthesized and evaluated; a synthesis of chorismic acid itself will be completed. 2. 3-Dehydroquinate synthase: The stereochemistry of the individual steps in the enzymic transformation will be determined by stereoselective synthesis of a key intermediate; blocked-substrate as well as transition state analog inhibitors will be synthesized and evaluated. 3. Chorismate synthetase: An allylic isomer of the natural substrate will be synthesized and evaluated as an alternative substrate or inhibitor. 4. 5-Enolpyruvylshikimate-3-phosphate synthase: The postulated tetrahedral adduct will be synthesized and its enzymatic conversion to product evaluated; transition state and multisubstrate analog inhibitors will also be synthesized. 5. Prephenate dehydratase: A series of sulfoxide and sulfilimine analogs of prephenate will be synthesized and evaluated as transition state analog or suicide inhibitors. 6. A number of other analogs of intermediates in the shikimate-chorismate pathway are proposed as substrates and inhibitors.

用于研究一些关键酶的基础广泛的生物有机计划 概述了莽草酸-分支酸途径。 关键要素是 下列的： 1.分支酸变位酶：新的过渡态类似物抑制剂将 综合和评估；分支酸本身的合成将是 完全的。 2. 3-脱氢喹酸合酶：各个步骤的立体化学 在酶促转化中将通过立体选择性来确定 关键中间体的合成；封闭底物以及过渡 将合成并评估状态类似物抑制剂。 3. 分支酸合成酶：天然底物的烯丙基异构体将 作为替代底物或抑制剂进行合成和评估。 4. 5-烯醇丙酮莽草酸-3-磷酸合酶：假设的四面体 将合成加合物并将其酶促转化为产物 评估；过渡态和多底物类似物抑制剂也将 被合成。 5. Prephenate脱水酶：一系列亚砜和硫亚胺类似物 预酚盐将被合成并评估为过渡态类似物 或自杀抑制剂。 6. 莽草酸-分支酸中间体的许多其他类似物 途径被提议作为底物和抑制剂。