Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite.
Inhibition and covalent modification of tyrosine hydroxylase by 3,4-dihydroxyphenylacetaldehyde, a toxic dopamine metabolite.
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DOI：
10.1016/j.neuro.2011.03.013
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发表时间：
2011-08
期刊：
影响因子：
3.4
通讯作者：
Doorn JA
中科院分区：
文献类型：
--
作者：
Mexas LM;Florang VR;Doorn JA
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能神经元选择性丧失，导致神经递质多巴胺（DA）减少。DA被单胺氧化酶代谢为3,4-二羟基苯乙醛（DOPAL）。虽然PD的发病机制尚不清楚，但DOPAL已被证明能够共价修饰蛋白质，并在高于生理水平的浓度下导致细胞死亡。目前，醛的蛋白靶点的身份尚不清楚，但先前的研究已经证明儿茶酚和其他da分解代谢产物能够与酪氨酸羟化酶（TH）相互作用并抑制TH。鉴于DOPAL在结构上与DA相关，并且是一种高活性的亲电试剂，假设它可以修饰和抑制TH。本研究的数据证实TH是DOPAL修饰和抑制的蛋白靶点。此外，western blot分析表明，抗体识别TH的浓度依赖性降低。通过降低左旋多巴的产生来测定细胞裂解液中的多巴显著抑制TH活性。TH的抑制是半可逆的，活性的恢复取决于DOPAL的去除时间和浓度。这些数据表明DOPAL是一种活性DA代谢物，具有修饰和抑制对DA合成重要的酶的能力。
Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective loss of dopaminergic neurons, leading to a decrease of the neurotransmitter dopamine (DA). DA is metabolized by monoamine oxidase to 3,4-dihydroxyphenyacetaldehyde (DOPAL). While the mechanism of pathogenesis of PD is unknown, DOPAL has demonstrated the ability to covalently modify proteins and cause cell death at concentrations elevated from physiologic levels. Currently, the identities of protein targets of the aldehyde are unknown, but previous studies have demonstrated the ability of catechols and other DA-catabolism products to interact with and inhibit tyrosine hydroxylase (TH). Given that DOPAL is structurally related to DA and is a highly reactive electrophile, it was hypothesized to modify and inhibit TH. The data presented in this study positively identified TH as a protein target of DOPAL modification and inhibition. Furthermore, western blot analysis demonstrated a concentration-dependent decrease in antibody recognition of TH. DOPAL in cell lysate significantly inhibited TH activity as measured by decreased L-DOPA production. Inhibition of TH was semi-reversible, with the recovery of activity being time and concentration-dependent upon removal of DOPAL. These data indicate DOPAL to be a reactive DA-metabolite with the capability of modifying and inhibiting an enzyme important to DA synthesis.
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影响因子：
56.9
作者：
Conway, KA;Rochet, JC;Lansbury, PT
通讯作者：
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影响因子：
2.3
作者：
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作者：
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3.4
作者：
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作者：
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