TOPOLOGICAL ORGANIZATION OF GASTRIC H,K ATPASE

胃 H,K ATP酶的拓扑结构

• 批准号: 8363731
• 负责人: JOHN G FORTE
• 金额: $ 0.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363731
• 关键词: Acidity; Chemistry; Drug Kinetics; Drug usage; Funding; Gastric Acid; Grant; H(+)-K(+)-Exchanging ATPase; Lansoprazole; Mass Spectrum Analysis; National Center for Research Resources; Omeprazole; Pharmaceutical Preparations; Principal Investigator; Property; Proteins; Proton Pump; Proton Pump Inhibitors; Reaction; Research; Research Infrastructure; Resources; Source; Stomach; Sulfhydryl Compounds; United States National Institutes of Health; amino group; chemical reaction; cost; in vivo

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our research seeks to define the chemical reactions that operate for gastric proton pump inhibitors (PPIs). PPIs are widely used drugs that are typically prescribed for hypersecretion of gastric acid. There is a currently defined mechanism of action that ultimately involves (i) drug accumulation in acidic spaces, (ii) activation local acidity, and (iii) reaction with a sulfhydryl (SH) group\ of the proton pump. These are the generally accepted paths of action; however, the different commercially prescribed PPIs (omeprazole, pantoprazole, rabeprazole, lanzoprazole) appear to have some different pharmacokinetic properties. In some discovery trials carried out in our lab, it was discovered that the PPIs had protein interactions not quite like the accepted path, but differed according to the proximity of the SH-reactive group with a nearby amino group. This could be the difference that might explain PPI differences in vivo, and/or simply increase our understanding of the chemistry of PPIs.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们的研究旨在定义胃质子泵抑制剂 (PPI) 的化学反应。 PPI 是广泛使用的药物，通常用于治疗胃酸分泌过多。 目前确定的作用机制最终涉及（i）酸性空间中的药物积累，（ii）激活局部酸性，以及（iii）与质子泵的巯基（SH）基团反应。 这些是普遍接受的行动路径；然而，不同的商业处方质子泵抑制剂（奥美拉唑、泮托拉唑、雷贝拉唑、兰佐拉唑）似乎具有一些不同的药代动力学特性。 在我们实验室进行的一些发现试验中，发现 PPI 的蛋白质相互作用与公认的路径不太一样，而是根据 SH 反应基团与附近氨基的接近程度而有所不同。 这可能是解释体内 PPI 差异的差异，和/或只是增加我们对 PPI 化学的理解。