Activation of Membrane Cholesterol by 63 Amphipaths
Activation of Membrane Cholesterol by 63 Amphipaths
复制标题
DOI：
10.1021/bi900951r
复制
发表时间：
2009-09-15
期刊：
影响因子：
2.9
通讯作者：
Steck, Theodore L.
中科院分区：
文献类型：
--
作者：
Lange, Yvonne;Ye, Jin;Steck, Theodore L.
已经观察到一些膜插入的两亲分子刺激胆固醇与胆固醇氧化酶、皂苷和环糊精的相互作用，推测是通过从其磷脂复合物中横向置换胆固醇。我们现在报告说，这种效应，称为胆固醇活化，发生在几十个其他两亲分子，包括烷醇，饱和和顺式和反式不饱和脂肪酸，脂肪酸甲酯，鞘氨醇衍生物，萜烯，烷基醚，酮，芳香族化合物和环状烷基衍生物。所测试的试剂的表观效力范围为3 μ M至7 mM，并且通常大于它们的辛醇/水分配系数，除了具有> 10个碳的化合物的相对效力下降。一些小的两亲分子激活胆固醇在膜浓度类似于3摩尔每100摩尔的双层脂质，约等摩尔的胆固醇，他们取代，溶血磷脂酰丝氨酸反击所有这些代理商的影响，符合其能力，以减少池的活性膜胆固醇。各种两亲分子稳定红细胞对溶血引起的胆固醇消耗，大概是通过取代提取的甾醇。顺式和反式脂肪酸不饱和度的数量和位置以及对映体对的绝对立体化学对两亲性效力的影响很小。然而，在一组具有相似分配系数的不同药物中，效力变化接近7倍。我们推断，各种各样的两亲分子可以取代膜胆固醇竞争化学计量，但只有有限的特异性弱协会与磷脂。任何数量的其他药物和实验剂可能会做同样的事情。
A few membrane-intercalating amphipaths have been observed to stimulate the interaction of cholesterol with cholesterol oxidase, saponin and cyclodextrin, presumably by displacing cholesterol laterally from its phospholipid complexes. We now report that this effect, referred to as cholesterol activation, occurs with dozens of other amphipaths, including alkanols, saturated and cis- and trans-unsaturated fatty acids, fatty acid methyl esters, sphingosine derivatives, terpenes, alkyl ethers, ketones, aromatics and cyclic alkyl derivatives. The apparent potency of the agents tested ranged from 3 mu M to 7 mM and generally paralleled their octanol/water partition coefficients, except that relative potency declined for compounds with > 10 carbons. Some small amphipaths activated cholesterol at a membrane concentration of similar to 3 mol per 100 mol of bilayer lipids, about equimolar with the cholesterol they displaced, Lysophosphatidylserine countered the effects of all these agents, consistent with its ability to reduce the pool of active membrane cholesterol. Various amphipaths stabilized red cells against the hemolysis elicited by cholesterol depletion, presumably by substituting for the extracted sterol. The number and location of cis and trans fatty acid unsaturations and the absolute stereochemistry of enantiomer pairs had only small effects on amphipath potency. Nevertheless, potency varied similar to 7-fold within a group of diverse agents with similar partition coefficients. We infer that a wide variety of amphipaths can displace membrane cholesterol by competing stoichiometrically but with only limited specificity for weak association with phospholipids. Any number of other drugs and experimental agents might do the same.