Synthesis of thio and amino analogs for MEP pathway

ORGN 143

Sergiy Krasutsky, Department of Chemsitry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850 and C. Dale Poulter, poulter@chem.utah.edu, Department of Chemisty, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112.
Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), precursors for the biosynthesis of terpenes, can be formed either by the mevalonate or methyleythritol phosphate pathway. The MEP pathway is not present in humans, therefore the enzymes of the pathway are potential targets for the development of novel antibiotic agents. Five steps, catalyzed by the ispD-H proteins, are required for the enzymatic conversion of MEP to IPP and DMAPP. Analogs for MEP, AMEP, MESP, SMEP were synthesized and their enzymatic activity for conversion to the cyclic intermediates by the consecutive action of three proteins ispD, ispE, and ispF, is examined. The last step of the pathway, catalyzed by the ispH protein, requires elimination of the hydroxyl group from hydroxydimethylallyl diphosphate (HDMAPP), the immediate precursor of IPP and DMAPP. Analogs of HDMAPP, ADMAPP, and SDMAPP were synthesized as substrates or inhibitors for ispH protein. The results of these experiments will be described.