A specific fluorescent probe reveals compromised activity of methionine sulfoxide reductases in Parkinson's disease.
A specific fluorescent probe reveals compromised activity of methionine sulfoxide reductases in Parkinson's disease.
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一种特定的荧光探针揭示了帕金森病中甲硫氨酸亚砜还原酶的活性受损
DOI：
10.1039/c6sc04708d
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发表时间：
2017-04-01
期刊：
影响因子：
8.4
通讯作者：
Fang J
中科院分区：
文献类型：
--
作者：
Zhang L;Peng S;Sun J;Yao J;Kang J;Hu Y;Fang J
报道了一种设计蛋氨酸亚砜还原酶探针的一般策略，并公开了第一个开启的探针。甲硫氨酸残基氧化成甲硫氨酸亚砜(Metso)可能会引起蛋白质结构和功能的改变，最终可能导致细胞损伤。蛋氨酸亚砜还原酶(MSR)是目前已知的唯一一种酶，它通过从硫氧还蛋白系统中提取还原的等价物来催化Metso还原为蛋氨酸，从而保护细胞免受氧化损伤。然而，缺乏方便的酶分析方法阻碍了对其功能的探索。我们报道了MSR-BLUE的发现，这是第一个开启的MSR荧光探针，通过对一个设计合理的小文库的筛选，荧光增加了100倍。深入的研究证实了这些酶对MSR-Blue的特异性还原。MSR-Blue已准备好测定生物样品和活细胞中的MSR活性。重要的是，我们在帕金森氏症模型中揭示了MSR活性的下降，从而提供了MSR功能丧失和神经退行性变发展之间的机制联系。发现MSR-Blue的战略还将为开发具有更长激发/发射波长的新型探针和针对MSR异构体的特定探针提供指导。
A general strategy for designing probes of methionine sulfoxide reductases was reported and a first turn on probe was disclosed. Oxidation of methionine residues to methionine sulfoxide (MetSO) may cause changes in protein structure and function, and may eventually lead to cell damage. Methionine sulfoxide reductases (Msrs) are the only known enzymes that catalyze the reduction of MetSO back to methionine by taking reducing equivalents from the thioredoxin system, and thus protect cells from oxidative damage. Nonetheless, a lack of convenient assays for the enzymes hampers the exploration of their functions. We report the discovery of Msr-blue, the first turn-on fluorescent probe for Msr with a >100-fold fluorescence increment from screening a rationally-designed small library. Intensive studies demonstrated the specific reduction of Msr-blue by the enzymes. Msr-blue is ready to determine Msr activity in biological samples and live cells. Importantly, we disclosed a decline of Msr activity in a Parkinson's model, thus providing a mechanistic linkage between the loss of function of Msrs and the development of neurodegeneration. The strategy for the discovery of Msr-blue would also provide guidance for developing novel probes with longer excitation/emission wavelengths and specific probes for Msr isoforms.