Enzymes which utilize a nicotinamide adenine dinucleotide (NAD) as a catalyst rather than a cosubstrate constitute a unique subset of NAD- requiring enzymes. Two premier examples of this class of enzyme include 3-dehydroquintate (DHQ) synthase and myo-inositol 1-phosphate (MIP) synthase. Proposed research entails the use of mechanism-based enzymology and chemical synthesis as tools to create potent chemical inhibitors of these NAD-dependent synthases. New strategies to be developed for inhibition of DHQ synthase will serve as paradigms for parallel efforts directed at MIP synthase inhibition. The myo-inositol 1-phosphate generated by MIP synthase in brain tissue is an important source of myo-inositol for the human brain due to the brain's extremely limited access to dietary myo-inositol. Inhibition of brain-localized MIP synthase would thus reduce myo-inositol concentrations in brain tissue and may provide an alternate approach for treating manic disorders. This follows from evidence that control of manic depression with Li+ treatment is the result of reduced concentrations of myo-inositol in brain tissue. While achieving efficient translocation of inhibitors into the brain must remain a long term goal, elaboration of the strategies by which these molecules will inhibit MIP synthase can begin with this research effort.
