Phytochemicals perturb membranes and promiscuously alter protein function.
Phytochemicals perturb membranes and promiscuously alter protein function.
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DOI：
10.1021/cb500086e
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发表时间：
2014-08-15
影响因子：
4
通讯作者：
Andersen, Olaf S.
中科院分区：
文献类型：
--
作者：
Ingolfsson, Helgi I.;Thakur, Pratima;Herold, Karl F.;Hobart, E. Ashley;Ramsey, Nicole B.;Periole, Xavier;de Jong, Djurre H.;Zwama, Martijn;Yilmaz, Duygu;Hall, Katherine;Maretzky, Thorsten;Hemmings, Hugh C., Jr.;Blobel, Carl;Marrink, Siewert J.;Kocer, Armagan;Sack, Jon T.;Andersen, Olaf S.
各种各样的植物化学物质被消费，以获得它们所认为的健康益处。许多这些植物化学物质已经被发现改变了许多细胞功能，但其生物活性背后的机制往往知之甚少。酚类植物化学物质尤其是膜蛋白功能的混杂修饰物，这表明它们的一些作用可能是由于共同的膜双层介导的机制。为了测试双层扰动是否可能是这种多样性作用的基础，我们研究了五种据报道具有药用价值的生物活性酚：来自辣椒的辣椒素、来自姜黄的姜黄素、来自绿茶的EGCG、来自大豆的染料木素和来自葡萄的白藜芦醇。我们发现，这些广泛使用的植物化学物质中的每一种都会改变脂双层性质和不同膜蛋白的功能。分子动力学模拟表明，这些植物化学物质通过定位于双分子层/溶液界面来改变双分子层的性质。通过基于革兰西丁的实验验证了双层修饰的倾向，并证明了四种蛋白质对膜蛋白功能的无差别调节：膜锚定的金属蛋白酶、机械敏感离子通道和电压依赖的钾和钠通道。每种蛋白质对多种植物化学物质都表现出相似的反应，符合共同的双层介导机制。我们的结果表明，两亲性植物化学物质的许多作用是由于细胞膜的扰动，而不是特定的蛋白质结合。
A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding.
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