Regulatory-Mechanism of Monoamine Biosynthesis in Central Nervous System

在神经系统中儿茶酚胺生物合成途径中催化限速步骤的酪氨酸羟基酶被发现被酪氨酸羟基酶的终产物-儿茶酚胺转化为非活性/稳定形式。在各种儿茶酚或相关化合物中，只有侧链上有氨基和不带负电荷的儿茶酚才能在低至10^~(-7)M的浓度下有效地将酶转化为失活/稳定形式。该酶的失活形式被环AMP依赖的蛋白激酶显著激活。人的酶和大鼠的酶似乎受类似的机制调节。色氨酸羟基酶催化中枢神经系统5-羟色胺生物合成的限速步骤，在加入磷脂酰肌醇或磷脂酰丝氨酸后显着激活，一旦激活，通过随后与磷脂的孵育逐渐失活。亚铁离子和二硫苏糖醇的加入可阻断该酶的失活。凝胶过滤分析表明，被磷脂激活的酶与磷脂结合，而随后孵育失活的酶不与磷脂结合。这些结果提示细胞膜可能参与了这种酶的调节。钙调蛋白依赖的蛋白激酶II已被证明参与了中枢神经系统中酪氨酸羟基酶和色氨酸羟基酶的调节。分离了三种不同类型的大鼠脑钙调蛋白依赖蛋白激酶II的cDNA克隆，并测定了其编码区的cDNA序列。预测的氨基酸序列揭示了该激酶的结构域结构。

Tyrosine hydroxylase which catalyzes the rate-limiting step in the biosynthetic pathway of catecholamines in the nervous system was found to be converted to inactive/stable form by catecholamines, end-products of tyrosine hydroxylase. Among a variety of catechols or related compounds tested for their ability to convert the enzyme to inactive/stable form, only catechols possessing amino group on the side chain and no negatively charged side chain were effective at a concentration as low as 10^<-7> M. The inactive form of the enzyme was dramatically activated by the action of cyclic AMP-dependent protein kinase. The human enzyme as well as the rat enzyme appeared to be regulated by similar mechanism.Tryptophan hydroxylase which catalyzes the rate-limiting step in the biosynthesis of serotonin in the central nervous system was markedly activated by the addition of phosphatidylinositol or phosphatidylserine and the enzyme once activated was gradually inactivated by subsequent incubation with the phospholipids. The inactivation was found to be blocked by the addition of ferrous ion and dithiothreitol. Gel filtration analysis revealed that the enzyme activated by the phospholipids was bound to the phospholipids and that the enzyme inactivated by the subsequent incubation was not bound to the phospholipids. the results suggest The possible involvement of cellular membranes in the regulation of this enzyme.Calmodulin-dependent protein kinase II has been demonstrated to be involved in the regulation of both tyrosine hydroxylase and tryptophan hydroxylase in the central nervous system. cDNA clones for three distinct types of rat brain calmodulin-dependent protein kinase II were isolated and a cDNA sequence for the coding region was determined. The predicted amino acid sequence of this kinase revealed the domain structure of the kinase.