Kinetic and structural analysis of the early oxidation products of dopamine -: Analysis of the interactions with α-synuclein
Kinetic and structural analysis of the early oxidation products of dopamine -: Analysis of the interactions with α-synuclein
复制标题
DOI：
10.1074/jbc.m610893200
复制
发表时间：
2007-05-25
影响因子：
4.8
通讯作者：
Bubacco, Luigi
中科院分区：
文献类型：
--
作者：
Bisaglia, Marco;Mammi, Stefano;Bubacco, Luigi
氧化应激似乎直接参与了几种神经退行性疾病的发病机制，包括阿尔茨海默病和帕金森病。黑质多巴胺能神经元特别暴露于氧化应激，因为胞质多巴胺的病理积累会产生各种有毒分子，包括自由基和活性醌。后者可以与蛋白质发生反应，阻止它们发挥生理功能。在醌类药物的可能靶点中，α -突触核蛋白因其直接参与多巴胺代谢而备受关注。与神经毒性过程相反，神经黑色素合成似乎通过其隔离各种潜在有害物质的能力发挥保护作用。在这项研究中，我们对多巴胺的早期氧化产物进行了动力学和结构分析。具体来说，考虑到氨基色素对细胞和线粒体的潜在高毒性，我们将注意力集中在其重排到5,6-二羟基吲哚上。在对多巴胺氧化产物进行光谱表征后，获得的结构信息被用于分析醌类对α -突触核蛋白的反应性。我们的结果表明，吲哚-5,6-醌，而不是多巴胺-邻醌或氨基色素，是反应物质。我们认为，观察到的反应性可以代表蛋白质中不存在半胱氨酸残基或受到空间保护时的一般反应途径。
Oxidative stress appears to be directly involved in the pathogenesis of several neurodegenerative disorders, including Alzheimer and Parkinson diseases. Nigral dopaminergic neurons are particularly exposed to oxidative stress because a pathological accumulation of cytosolic dopamine gives rise to various toxic molecules, including free radicals and reactive quinones. These latter species can react with proteins preventing them from exerting their physiological functions. Among the possible targets of quinones, alpha-synuclein is of primary interest because of its direct involvement in dopamine metabolism. Contrary to the neurotoxic processes, neuromelanin synthesis seems to play a protective role by its ability to sequester a variety of potentially damaging substances. In this study, we carried out a kinetic and structural analysis of the early oxidation products of dopamine. Specifically, considering the potential high toxicity of aminochrome for both cells and mitochondria, we focused our attention on its rearrangement to 5,6- dihydroxyindole. After the spectroscopic characterization of the products derived from the oxidation of dopamine, the structural information obtained was used to analyze the reactivity of quinones toward alpha-synuclein. Our results suggest that indole-5,6-quinone, rather than dopamine-o-quinone or aminochrome, is the reactive species. We propose that the observed reactivity could represent a general reaction pathway whenever cysteinyl residues are absent in proteins or if they are sterically protected.