UNDERSTANDING SUBSTRATE SPECIFICITY IN PHOSPHORIBOSYLTRANSFERASES

了解磷酸核糖基转移酶的底物特异性

• 批准号: 6456722
• 负责人: JED PITERA
• 金额: $ 27.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456722
• 关键词: biological products; biomedical resource; enzymes; proteins

Many parasitic organisms are incapable of synthesizing the purine and pyrimidine nucleotides necessary for DNA synthesis. Instead, they scavenge these molecules from the host organism through various biochemical pathways. One such enzyme involved in these pathways is a purine phosphoribosyltransferase, which catalyzes the combination of a nucleotide base and a ribosylphosphate to form a nucleotide. We carried out molecular dynamics calculations to compare a human phosphoribosyltransferase with its analog from the protozoan Tritichomonas foetus. While the human enzyme is highly selective, the parasite enzyme operates with comparable efficiency on a number of different substrates. Our simulations show that this is due to a high degree of flexibility in the parasite substrate-binding pocket, and also allowed us to rationalize the effects of several known mutations. The resources of the Computer Graphics Laboratory are used to visualize the enzyme-substrate complexes from our simulations.

许多寄生生物无法合成嘌呤 DNA合成所需的嘧啶核苷酸和嘧啶核苷酸。 相反，他们 通过各种从宿主有机体清除这些分子 生化途径。 这些途径中涉及的一种这样的酶是 嘌呤磷脂基转移酶，催化A的组合 核苷酸碱和核糖基磷酸盐形成核苷酸。 我们 进行分子动力学计算以比较人类 磷酸贝糖基转移酶的类似物来自原生动物 Tritichomonas胎儿。 虽然人酶具有很高的选择性，但 寄生虫酶在许多方面以可比的效率运行 不同的底物。 我们的模拟表明，这是由于高 寄生虫基质结合口袋的灵活性程度， 还使我们能够合理化几个已知突变的效果。 计算机图形实验室的资源用于 从我们的模拟中可视化酶基底络合物。