Tyrosine hydroxylase and regulation of dopamine synthesis.
Tyrosine hydroxylase and regulation of dopamine synthesis.
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DOI：
10.1016/j.abb.2010.12.017
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发表时间：
2011-04-01
影响因子：
3.9
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Daubner SC;Le T;Wang S
酪氨酸羟化酶是儿茶酚胺生物合成的限速酶，它利用四氢生物蝶呤和分子氧将酪氨酸转化为多巴。它的氨基末端150个氨基酸组成一个结构域，其结构参与调节酶的活性。调节方式包括4个不同丝氨酸残基的多个激酶的磷酸化和2个磷酸酶的去磷酸化。这种酶被儿茶酚胺类神经递质以反馈的方式抑制。多巴胺通过四氢生物蝶呤与TyrH竞争性结合，并与R结构域相互作用。TyrH活性受蛋白质-蛋白质相互作用的调节，酶与相同途径或四氢生物蝶呤途径中的酶相互作用，结构蛋白被认为是介导神经元氧化状态的伴侣蛋白，以及将多巴胺转移到分泌囊泡中的蛋白质。酪氨酸H在NO存在的情况下被修饰，导致酪氨酸残基的硝化和半胱氨酸残基的谷胱甘肽基化。
Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine biosynthesis; it uses tetrahydrobiopterin and molecular oxygen to convert tyrosine to DOPA. Its amino terminal 150 amino acids comprise a domain whose structure is involved in regulating the enzyme’s activity. Modes of regulation include phosphorylation by multiple kinases at 4 different serine residues, and dephosphorylation by 2 phosphatases. The enzyme is inhibited in feedback fashion by the catecholamine neurotransmitters. Dopamine binds to TyrH competitively with tetrahydrobiopterin, and interacts with the R domain. TyrH activity is modulated by protein-protein interactions with enzymes in the same pathway or the tetrahydrobiopterin pathway, structural proteins considered to be chaperones that mediate the neuron’s oxidative state, and the protein that transfers dopamine into secretory vesicles. TyrH is modified in the presence of NO, resulting in nitration of tyrosine residues and the glutathionylation of cysteine residues.