Regulatory-Mechanism of Monoamine Biosynthesis in Central Nervous System

酪氨酸羟化酶催化神经系统中儿茶酚胺生物合成途径中的限速步骤，被发现被酪氨酸羟化酶的终产物儿茶酚胺转化为无活性/稳定形式。在测试其将酶转化为无活性/稳定形式的能力的多种儿茶酚或相关化合物中，仅在侧链上具有氨基且不带负电荷的侧链的儿茶酚在低至10 μ M的浓度下有效<-7>。环腺苷酸依赖性蛋白激酶的作用显着激活的酶的非活性形式。人酶以及大鼠酶似乎受到类似的机制。色氨酸羟化酶，催化在中枢神经系统中的5-羟色胺的生物合成的限速步骤显着激活的添加磷脂酰肌醇或磷脂酰丝氨酸和酶一旦激活逐渐灭活随后与磷脂孵育。失活被认为是通过加入亚铁离子和二硫苏糖醇阻断。凝胶过滤分析表明，被磷脂激活的酶与磷脂结合，而通过随后的孵育失活的酶不与磷脂结合。结果表明，在中枢神经系统中，钙调素依赖性蛋白激酶II参与酪氨酸羟化酶和色氨酸羟化酶的调节。分离了三种不同类型的大鼠脑钙调素依赖性蛋白激酶II的cDNA克隆，并确定了编码区的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.