STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

莽草酸-分支酸途径的研究

• 批准号: 3276372
• 负责人: PAUL A BARTLETT
• 金额: $ 24.39万
• 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 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276372
• 关键词: antibiotics; chemical synthesis; cyclic compound; drug design /synthesis /production; enzyme inhibitors; enzyme mechanism; ether hydrolase; isomerase; phosphorus oxygen lyase; shikimate; stereochemistry

Continuation of a broadly based bioorganic program to study some of the key enzymes in the shikimate-chorismate pathway is proposed. The major elements are the following: 1.5-Enolpyruvylshikimate-3-phosphate Synthase. We propose to continue our work on the synthesis of stabilized analogs of the tetrahedral intermediate and on the synthesis of this species itself; we will also study the mechanism and stereochemistry of the elimination step. 2.Chorismate Synthase. Through the use of isotopically labeled substrate analogs and of 5-deazaflavin, we will study the role of the flavin cofactor and the mechanism of the 1,4-elimination reaction catalyzed by this enzyme. 3.Chorismate Mutase. We expect to complete our study of this enzyme with the synthesis of ammonium and aziridinium inhibitor analogs and an investigation of an electronically perturbed substrate analog. 4.Dehydroquinate Synthase. We propose to resolve the remaining mechanistic issue, namely the extent of enzymatic involvement in the final step of the transformation, and to synthesize some potential suicide inhibitors of the enzyme. 5.Dehydroquinase. We will initiate a program to develop suicide inhibitors for this early enzyme in the pathway. 6.Isochorismate Synthase and Isochorismatase. We will initiate programs to develop inhibitors and reaction intermediate analogs for these enzymes of a branch pathway.

继续一个基础广泛的生物有机计划，研究一些关键的 提出了在志喜酸-分支酸途径中的酶。 主要 主要内容如下： 1.5-烯醇式莽草酸-3-磷酸合酶。 我们建议继续我们的 合成四面体中间体的稳定类似物的工作 以及这个物种本身的合成;我们还将研究 消除步骤的机理和立体化学。 2.分支酸合酶 通过使用同位素标记的底物 类似物和5-脱氮黄素，我们将研究黄素辅因子的作用， 以及该酶催化的1，4-消除反应的机理。 3.分支突变酶 我们希望完成我们对这种酶的研究， 铵和氮丙啶鎓抑制剂类似物的合成 电子扰动衬底模拟物的研究。 4.脱氢奎尼酸合酶。 我们建议解决剩余的机械问题， 问题，即酶参与最后步骤的程度， 转化，并合成一些潜在的自杀抑制剂， 酵素 5.Dehydroquinase. 我们将启动一个项目来开发自杀抑制剂 这种早期的酶在通路中。 6.异分支酸合酶和异分支酸酶。 我们将启动一些项目 开发这些酶的抑制剂和反应中间体类似物 一个分支通路的分支。