INHIBITION OF NAD-DEPENDENT SYNTHASES

利用烟酰胺腺嘌呤二核苷酸(NAD)作为 催化剂而不是共底物构成了NAD的一个独特的子集- 需要酵素。这类酶的两个主要例子包括 3-脱氢奎宁酸(DHQ)合成酶和肌醇1-磷酸(MIP) 合成酶。建议的研究需要使用基于机制的酶学 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的合成酶。有待制定的新战略 抑制DHQ合酶将成为并行努力的范例 针对MIP合成酶的抑制。 MIP合酶在脑组织中产生的肌醇1-磷酸是 肌醇对人脑的重要来源，因为大脑的 获得膳食肌醇的机会极其有限。抑制 因此，大脑定位的MIP合成酶将降低肌醇浓度 并可能为治疗躁狂症提供另一种方法 精神错乱。这是因为有证据表明，控制躁狂抑郁 LI治疗是肌醇浓度降低的结果 在脑组织中。同时实现抑制剂的高效移位 走进大脑必须是一个长期的目标，精心制定的策略 通过这些分子抑制MIP合成酶可以从这个开始 研究努力。

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.