STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

描述(改编自申请人的摘要)：本申请 建议继续对生物多样性中的一些关键酶进行研究 莽草酸-分枝酸途径。其长期目标是阐明 这些酶的机制，并制定通用的策略 酶抑制剂的设计。(1)脱氢奎宁酶。底物类似物 能够芳构化和不可逆共价键的类型 提出了I-DHQ的概念。(2)EPSP合酶。涉及的中间体 在该酶的添加/消除机制中，以及它的 一氟类似物，将合成完成一系列 四面体类似物。结构衍生抑制剂设计项目， 基于抑制剂-酶复合体的结构，将 已启动。(3)氯水酸合成酶。剩下的一些机械式的 这种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)氯酸变位酶。新的 根据这种独特的酶的结构，提出了抑制该酶的药物 关于其与以前的抑制剂的复合体的信息现已公布；新的 设计包括扩环模拟，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是 加速了。(5)Shikimate Analog。莽草的一些类似物 本身以及它们的5-烯醇丙酮基-3-磷酸异构体将是 合成并评价作为替代底物的许多 途径中的酶。这些类似物包括4-表-莽草酸、2-卤代- Shikimates和5元环类似物。(6)异枝藻， 邻氨基苯甲酸和对氨基苯甲酸合成酶。这一地区的项目 将通过合成一系列替代的 双底物类似物作为后一种酶的潜在抑制剂。

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.