[14] Determining transition states from kinetic isotope effects

BEBOVA-based TS determination has been very successful in elucidating enzyme mechanisms at a level of detail that would be otherwise inaccessible. The resulting TS structures have been used successfully as the basis for designing TS mimics as enzyme inhibitors with dissociation constants to 10(-11) M. The structure interpolation approach has systematized the process of finding a TS, increasing both the speed and the accuracy of TS determination. The combination of information from several TSs into a unified model increases the accuracy of the process significantly and results in an extremely sensitive probe of changes in TS with varying reaction conditions (i.e., enzymatic vs nonenzymatic reactions, different enzymes, or different nucleophiles). The TS determination process is summarized in Fig. 15.