MODELS FOR THE ASP-HIS COUPLE IN SERINE PROTEASES

丝氨酸蛋白酶中 ASP-HIS 对的模型

• 批准号: 3289090
• 负责人: RICHARD David GANDOUR
• 金额: $ 5.44万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 1988-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3289090
• 关键词: carboxyl group; carboxylation; chemical models; hydrogen bond; imidazole; peptidases; physical chemical interaction; serine

Can an enzyme's catalytic properties be reproduced by constructing in a smaller molecule the exact topography of an enzyme's active site? Designing, synthesizing, and studying the reaction dynamics of molecules that model the Asp-His hydrogen bond found in serine protease active sites is the aim of this research. Specifically, the goal is to test the hypothesis that the orientation of carboxyl(ate) is an important factor in its hydrogen bonding to an imidazole. Serine proteases form an important family of enzymes whose members are essential to a variety of physiological functions: digestion, blood coagulation, lysis of blood clots, and sperm penetration. These enzymes possess a common structural feature in their active sites known as the "charge-relay chain". Previous chemical models have neglected the orientation of the carboxylate in the Asp-His part of the chain. The carboxylate orientation hypothesis states that hydrogen bonding or complete proton transfer to carboxylate is more favored in a syn arrangement than an anti. For the serine protease enzymes, this applies to the Asp-His hydrogen bond. Crystallographic evidence from the enzymes reveals the carboxylate to be oriented syn in all cases. Surprisingly all the reported chemical models of this interaction have the carboxylate oriented anti. The proposal describes the preparation of the first models in which the carboxylate is oriented syn in a hydrogen bonding interaction with imidazole. The utility of chemical models to biomedicine is well recognized. What is there about this proposal that distinguishes it from other model studies? There are three distinguishing features: the testing of an hypothesis, the design approach and the emphasis on optimizing functional group topography.

可以通过在A中构建酶的催化特性 较小的分子酶的活性位点的确切地形？ 设计，合成和研究分子的反应动力学 该模拟在丝氨酸蛋白酶活性位点发现的ASP-HIS氢键 是这项研究的目的。 具体来说，目标是测试 假设羧基（ATE）的方向是重要因素 它与咪唑的氢键。 丝氨酸蛋白酶形成了重要的酶家族，其成员是 各种生理功能的必不可少的：消化，血液 凝血，血凝块的裂解和精子穿透。 这些酶 在其活性站点中具有共同的结构特征 “电荷 - 列链链”。 以前的化学模型忽略了 在链的ASP-HIS部分中羧酸盐的方向。 羧酸盐方向假设指出，氢键或 完全质子转移到羧酸盐中更受青睐 布置比反。 对于丝氨酸蛋白酶酶，这适用于 ASP-HIS氢键。 酶的晶体学证据 在所有情况下，揭示羧酸盐是定向同步的。 令人惊讶的是 报道的这种相互作用的化学模型具有羧酸盐 定向抗。 该提案描述了第一个模型的准备 其中羧酸盐在氢键相互作用中定向同步 与咪唑。 化学模型对生物医学的实用性已得到充分认可。 是什么 关于该提议将其与其他模型研究区分开来的有关？ 有三个不同的特征：假设的测试， 设计方法和强调优化功能组地形。