At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to alpha-synuclein and prevents its fibrillation.
At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to alpha-synuclein and prevents its fibrillation.
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在低浓度下，3,4-二羟基苯乙酸 (DOPAC) 与 α-突触核蛋白非共价结合并防止其纤维化。
DOI：
10.1016/j.jmb.2009.03.053
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发表时间：
2009
影响因子：
5.6
通讯作者：
Uversky,VladimirN
中科院分区：
文献类型：
--
作者：
Zhou,Wenbo;Gallagher,Amy;Hong,Dong-Pyo;Long,Chunmei;Fink,AnthonyL;Uversky,VladimirN
几项研究表明，儿茶酚胺可以抑制α-突触核蛋白（α-Syn）的纤维化，α-Syn是一种小的突触前蛋白，其聚集被认为是帕金森病和其他几种神经退行性疾病病因学中的关键步骤。然而，这种抑制的机制是不确定的。我们在这里表明，亚化学计量浓度的3，4-二羟基苯乙酸（DOPAC），多巴胺代谢的正常产物，可以抑制α-Syn的纤维化，由于非共价结合的DOPAC的α-Syn单体。有趣的是，α-Syn的存在加速了DOPAC的自发氧化，并且DOPAC的氧化形式（醌）负责纤化抑制。此外，DOPAC的存在导致α-Syn的甲硫氨酸残基的氧化，可能是由于DOPAC氧化的副产物H2 O2的产生。缺乏原纤化是由于形成了稳定的低聚物，这与在α-Syn原纤化早期阶段观察到的瞬时低聚物非常相似。这种现象的一个可能的解释是，DOPAC稳定了通常短暂的低聚物，并防止它们随后形成原纤维。对α-Syn Y39 W变体的分析表明，DOPAC与脂质囊泡非共价结合于α-Syn的相同N-末端区域，可能在残基39附近。与具有1，2-二羟基苯基的化合物（DOPAC和邻苯二酚）相比，它们的1，4-二羟基苯基异构体（氢醌和尿黑酸）能够共价修饰α-Syn，这可能是由于Michael加成中的空间位阻较小。
Several studies have shown that catecholamines can inhibit the fibrillation of α-synuclein (α-Syn), a small presynaptic protein whose aggregation is believed to be a critical step in the etiology of Parkinson's disease and several other neurodegenerative disorders. However, the mechanism of this inhibition is uncertain. We show here that substoichiometric concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a normal product of the metabolism of dopamine, can inhibit the fibrillation of α-Syn, due to non-covalent binding of DOPAC to α-Syn monomer. Intriguingly, the presence of α-Syn accelerates the spontaneous oxidation of DOPAC, and the oxidized form of DOPAC (the quinone) is responsible for the fibrillation inhibition. In addition, the presence of DOPAC leads to the oxidation of the methionine residues of α-Syn, probably due to the H2O2production as a by-product of DOPAC oxidation. The lack of fibrillation results from the formation of stable oligomers, which are very similar to those observed transiently at early stages of the α-Syn fibrillation. A possible explanation for this phenomenon is that DOPAC stabilizes the normally transient oligomers and prevents them from subsequent fibril formation. The analysis of the α-Syn Y39W variant suggests that DOPAC binds non-covalently to the same N-terminal region of α-Syn as lipid vesicles, probably in the vicinity of residue 39. In contrast to the compounds with 1,2-dihydroxyphenyl groups (DOPAC and catechol), their 1,4-dihydroxyphenyl isomers (hydroquinone and homogentisic acid) are able to modify α-Syn covalently, probably due to the less steric hindrance in the Michael addition.