Senol F Sezer, Khan M Tareq Hassan, Orhan Gurdal, Gurkas Erdem, Orhan Ilkay Erdogan, Oztekin Nese Subutay, Ak Fikri
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey.
Curr Top Med Chem. 2014;14(12):1469-72. doi: 10.2174/1568026614666140610121253.
Current evidence suggests that endogenous dopamine may act as a neurotoxin following its oxidation to an oquinone and reaction with cellular thiols, which are neutoxic, which may occur spontaneously or via reaction with tyrosinase or some other enzymes. Tyrosinase (E.C. 1.14.18.1) with two cupper ions coordinated by three histidines is a bifunctional enzyme that catalyses both the hydroxylation of tyrosine to L-DOPA and the consequent oxidation of the resulting catechol-containing species to an o-quinone. Therefore, tyrosinase may play a role in neuromelanin formation in the brain and could be central to dopamine neurotoxicity by contributing to the neurodegeneration associated with Parkinson's disease. In the present study, inhibitory effect of ascorbic acid against tyrosinase has been investigated and it has shown a remarkable inhibitory effect in in vitro assays. Then, the in silico-based experiments established through molecular docking calculations and scoring, docking search algorithm, and data plotting indicated that ascorbic acid is strong inhibitor of tyrosinase by interacting with four amino acid units (histidine 263, serine 282, phenylalanine 264, and valin 283) in the active site of the enzyme. The compound also had two long distant hydrogen bindings with Cu1 and Cu2 with distances of 3.57 and 3.41 A, respectively, through its O5 atom.
目前的证据表明，内源性多巴胺在氧化为邻醌并与具有神经毒性的细胞硫醇反应后，可能会作为一种神经毒素发挥作用，这种反应可能自发发生，也可能通过与酪氨酸酶或其他一些酶的反应发生。酪氨酸酶（E.C. 1.14.18.1）由三个组氨酸配位两个铜离子，是一种双功能酶，它既催化酪氨酸羟基化为L-多巴，又催化生成的含儿茶酚的物质氧化为邻醌。因此，酪氨酸酶可能在大脑中神经黑色素的形成中起作用，并且可能通过促成与帕金森病相关的神经退行性变而在多巴胺神经毒性中起核心作用。在本研究中，研究了抗坏血酸对酪氨酸酶的抑制作用，并且在体外试验中显示出显著的抑制作用。然后，通过分子对接计算和评分、对接搜索算法以及数据绘图建立的基于计算机模拟的实验表明，抗坏血酸通过与酶活性位点中的四个氨基酸单元（组氨酸263、丝氨酸282、苯丙氨酸264和缬氨酸283）相互作用，是酪氨酸酶的强抑制剂。该化合物还通过其O5原子与Cu1和Cu2分别有两个长距离氢键，距离分别为3.57和3.41埃。
