INHIBITION OF NAD DEPENDENT SYNTHASES

利用烟酰胺腺嘌呤二核苷酸（NAD）作为辅酶的酶 催化剂而不是共底物构成NAD的独特子集。 需要酶。 这类酶的两个主要例子包括 3-脱氢奎尼酸（DHQ）合酶和肌醇1-磷酸（MIP） 合成酶 拟议的研究需要使用机制为基础的酶学 和化学合成作为工具来创造有效的化学抑制剂， 这些依赖NAD的酶。 将制定的新战略 DHQ合酶抑制将作为平行努力的范例 针对MIP合酶抑制。 脑组织中MIP合酶产生的肌醇1-磷酸， 由于大脑的功能， 对膳食肌醇的获取极其有限。 抑制 因此，脑定位MIP合酶会降低肌醇浓度 并可能为治疗躁狂症提供另一种方法 紊乱 有证据表明，控制躁狂抑郁症 Li+处理的结果是肌醇浓度降低 在脑组织中。 在实现抑制剂有效转移的同时 必须保持一个长期的目标，制定战略， 这些分子抑制MIP合酶的作用可以从这一点开始开始 研究工作。

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.