KINAETIC ISOTOPE EFFECT STUDIES ON REACTIONS OF CD38

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CD38 is an important membrane antigen associated with lymphocyte development and implicated in signal transduction. This proposal is designed to evaluate CD38 transition states by measurement of kinetic isotope effects (KIEs) for formation of cyclic ADP ribose (cADPR) from NAD+, formation of ADP-ribose (ADPR) from NAD+, and formation of ADPR from CADPR. All of these reactions are catalyzed by the 30kdal enzyme. Transition site analysis of this enzyme promises to lead to a complete understanding of this enzyme and to provide the opportunity to better probe its biological function by design of transition state analog inhibitors. KIEs to be obtained for a series of NAD+ analogs varying group pK/as will provide a systematic test for the best algorithms available for transition state structure determination to determine if they predict transition states according to established chemical theory.