Facilitated phospholipid translocation across vesicle membranes using low-molecular-weight synthetic flippases
Facilitated phospholipid translocation across vesicle membranes using low-molecular-weight synthetic flippases
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DOI：
10.1021/ja9933285
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发表时间：
1999-12-22
影响因子：
15
通讯作者：
Smith, BD
中科院分区：
文献类型：
--
作者：
Boon, JM;Smith, BD
磷脂在大多数细胞膜上的分布是不对称的。例如，红细胞膜中约80%的鞘磷脂和磷脂酰胆碱位于外（外）小叶中，而80-85%的磷脂酰乙醇胺和> 96%的磷脂酰丝氨酸位于内（内）小叶中。1细胞消耗大量的化学能来维持这些不对称分布，因为它们控制着一系列重要的过程，如酶激活、膜融合、凝血和凋亡。1，2通常认为自发磷脂移位（也称为翻转）穿过双层膜是一个非常缓慢的过程，并通过称为移位酶或翻转酶的膜结合酶促进。在红细胞膜的情况下，已经确定了许多不同的磷脂移位活动，包括ATP依赖性内向移位酶与氨基磷脂的选择性，选择性较低的ATP依赖性外向移位酶，和Ca 2+依赖性非选择性scramblase。2其他细胞类型包含其他类型的翻转酶。一些翻转酶蛋白已被克隆并显示出体外活性，但目前还不知道易位如何在分子水平上起作用。4已经讨论过的机制特征包括蛋白质孔5和局部膜缺陷; 6，7然而，尚不清楚这些模型是否适用于可以区分磷脂头基的翻转酶。目前，文献中包含的化学诱导磷脂易位的例子很少。1，7，8合理设计的合成翻转酶可能是其更复杂的生物学对应物的有用的机械模型。它们也可能被用作药物或生物膜研究的化学工具。Moss、Ringsdorf和同事9报道了人工翻转酶的唯一先前实例，他们表明高分子量疏水改性聚合物可以促进磷脂移位。数据支持膜破裂机制，这表明该系统不太可能区分磷脂
The distribution of phospholipids across most, if not all, cell membranes is asymmetric. For example, around 80% of the sphingomyelin and phosphatidylcholine in erythrocyte membranes is localized in the exo (outer) leaflet, whereas 80-85% of the phosphatidylethanolamine and> 96% of the phosphatidylserine is in the endo (inner) leaflet. 1 A cell consumes significant amounts of chemical energy to maintain these asymmetric distributions, as they control a range of important processes such as enzyme activation, membrane fusion, coagulation, and apoptosis. 1, 2 It is generally accepted that spontaneous phospholipid translocation (also known as flip-flop) across a bilayer membrane is a very slow process and is facilitated by membrane-bound enzymes known as translocases or flippases. In the case of erythrocyte membranes, a number of different phospholipid translocation activities have been identified, including an ATP-dependent inward translocase with selectivity for aminophospholipids, a less-selective ATP-dependent outward translocase, and a Ca2+-dependent nonselective scramblase. 2 Other cell types contain additional classes of flippases. 3 Some of the flippase proteins have been cloned and shown to have in vitro activity, but presently it is not known how translocation works at the molecular level. 4 Mechanistic features that have been discussed include protein pores5 and localized membrane defects; 6, 7 however, it is not clear if these models apply to flippases that can discriminate between phospholipid headgroups.At present, the literature contains few examples of chemically induced phospholipid translocation. 1, 7, 8 Rationally designed, synthetic flippases are likely to be useful mechanistic models of their more complex biological counterparts. They also may find employment as pharmaceuticals or as chemical tools for biological membrane research. The only previous example of an artificial flippase was reported by Moss, Ringsdorf, and co-workers, 9 who showed that a high-molecular-weight, hydrophobically modified polymer can facilitate phospholipid translocation. The data are in favor of a membrane disruption mechanism, which suggests that this system is unlikely to discriminate between phospholipid