STUDIES IN THE SHIKIMATE-CHORISMATE PATHWAY

描述（改编自申请人的摘要）：本申请 建议继续研究一些关键酶， shikimate-分支酸途径 长期目标是阐明 这些酶的机制，并制定一般战略， 酶抑制剂的设计。 (1)脱氢喹酶。 底物类似物 能够芳构化和不可逆共价键连接到类型 提出了一个DHQ方案。 (2)EPSP合酶 所涉及的中间体 在这种酶的添加/消除机制中，沿着其 单氟类似物，将合成完成一系列的 四面体类似物。 结构衍生抑制剂设计项目， 基于生物素-酶复合物的结构， 启动。 (3)分支酸合酶 剩下的一些机械 通过合成和评价，解决了该酶存在的问题 卤代和环丙烷化底物类似物。 (4)分支突变酶 新 这种独特的酶的抑制剂提出，基于结构 现在可获得有关其与以前抑制剂复合物的信息;新的 设计包括环扩展类似物，潜在的不可逆 抑制剂和替代底物，可以区分 酶促和催化抗体反应的机制 加快 (5)Shikimate Analogs. 一些莽草酸类似物 其本身以及它们的5-烯醇-N-乙酰基-3-磷酸-电子等排体将被 合成并评估作为替代底物的一些 酶的途径。 这些类似物包括4-表-莽草酸酯、2-卤代-莽草酸酯、2-甲氧基-异丙基-异 shikimates和5元环类似物。 (6)异分支酸， 邻氨基苯甲酸和对氨基苯甲酸合酶。 该地区的项目 将通过综合一系列备选的 双底物类似物作为后者酶的潜在抑制剂。

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.