Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite
Antioxidant-Mediated Modulation of Protein Reactivity for 3,4-Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite
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DOI：
10.1021/acs.chemrestox.5b00528
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发表时间：
2016-07-01
影响因子：
4.1
通讯作者：
Doorn, Jonathan A.
中科院分区：
文献类型：
--
作者：
Anderson, David G.;Florang, Virginia R.;Doorn, Jonathan A.
3，4-二羟基苯乙醛（DOPAL）是一种内源性产生的有毒醛。它是一种双功能亲电体，与帕金森病和神经变性伴随的多巴胺能细胞损失有关。已知DOPAL与蛋白质和氨基酸如N-乙酰基赖氨酸（NAL）反应; DOPAL的儿茶酚部分氧化成醌增加了这种反应性。在这里，我们证明了抗氧化剂N-乙酰半胱氨酸，谷胱甘肽和抗坏血酸以剂量依赖性方式减轻DOPAL与蛋白质和氨基酸的反应性的能力。相反，Trolox没有减少观察到的与蛋白质的反应性。有趣的是，在这些系统中使用tricine，缓冲剂和还原剂，也降低了DOPAL与胺的反应性，产生tricine衍生的自由基物质。用醛修饰胺通常涉及席夫碱化学;然而，对自由基的观察表明DOPAL与赖氨酸的反应涉及氧化步骤。此外，虽然席夫碱形成通常在pH 5下是最佳的，但是DOPAL与NAL的反应速率在pH 5下是可忽略的，并且在碱性条件下（例如，pH 9）。高pH条件也有利于邻苯二酚自动氧化，已知DOPAL会发生这种氧化。这里证明的抗氧化剂介导的保护表明，氧化应激可能会赋予细胞的脆弱性蛋白质修饰的DOPAL。因此，耗尽的抗氧化剂和脂质过氧化产物水平的增加，已知可以阻止DOPAL的解毒代谢，可能对帕金森病中靶向的多巴胺能细胞提出生存挑战。
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is an endogenously produced toxic aldehyde. It is a bifunctional electrophile implicated in the loss of dopaminergic cells concomitant with Parkinson's disease and neurodegeneration. DOPAL is known to react with proteins and amino acids such as N-acetyl lysine (NAL); oxidation of the catechol moiety to the quinone of DOPAL increases this reactivity. Here, we demonstrate the ability of the antioxidants N-acetylcysteine, glutathione, and ascorbic acid to mitigate the reactivity of DOPAL with proteins and amino acids in a dose-dependent fashion. Conversely, Trolox did not lessen the observed reactivity with proteins. Interestingly, use of tricine, a buffer and reducing agent, in these systems also decreased the reactivity of DOPAL with amines, yielding tricine-derived free radical species. Modification of amines with aldehydes typically involves Schiff base chemistry; however, the observance of free radicals suggests that an oxidative step is involved in the reaction of DOPAL with lysine. Furthermore, while Schiff base formation is usually optimal at pH 5, the reaction rate of DOPAL with NAL is negligible at pH 5 and is enhanced under basic conditions (e.g., pH 9). Conditions of high pH are also favorable for catechol auto-oxidation, known to occur for DOPAL. The antioxidant-mediated protection demonstrated here suggests that oxidative stress may impart cellular vulnerability to protein modification by DOPAL. Therefore, depleted antioxidants and increased levels of lipid peroxidation products, known to prevent the detoxifying metabolism of DOPAL, may present a survival challenge to dopaminergic cells targeted in Parkinson's disease.