TOPOLOGICAL ORGANIZATION OF GASTRIC H,K ATPASE

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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.