INTERACTIONS OF A VERY LONG-CHAIN FATTY-ACID WITH MODEL MEMBRANES AND SERUM-ALBUMIN - IMPLICATIONS FOR THE PATHOGENESIS OF ADRENOLEUKODYSTROPHY
INTERACTIONS OF A VERY LONG-CHAIN FATTY-ACID WITH MODEL MEMBRANES AND SERUM-ALBUMIN - IMPLICATIONS FOR THE PATHOGENESIS OF ADRENOLEUKODYSTROPHY
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DOI：
10.1172/jci118182
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发表时间：
1995-09-01
影响因子：
15.9
通讯作者：
HAMILTON, JA
中科院分区：
文献类型：
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作者：
HO, JK;MOSER, H;HAMILTON, JA
肾上腺脑白质营养不良（ALD）是一种遗传性脂肪酸代谢疾病，其特征是长链饱和脂肪酸（VLCFA），特别是26碳的六糖酸（HA）在膜和组织中积累。我们利用C-13核磁共振光谱研究了富含C-13的透明质酸与模型膜（磷脂双层囊泡）和牛血清白蛋白（BSA）的相互作用，并将其与典型膳食脂肪酸的特性进行了比较。在磷脂双分子层中，HA的羧基定位于水界面，其表观pK(a)（7.4）与其他脂肪酸相似；然后酰基链必须非常深入地渗透到膜中。HA从囊泡的解吸（t1/2 = 3小时）比短链脂肪酸慢几个数量级。在囊泡和牛血清白蛋白的混合物中，透明质酸比典型脂肪酸更有利于磷脂双分子层的分离，牛血清白蛋白在一个结合位点上最多只能结合1mol的透明质酸。量热实验表明，透明质酸对磷脂酰基链有很强的扰动作用。我们预测VLCFA对细胞膜结构和功能的破坏作用可能解释ALD患者的神经学表现。由于VLCFA从膜上的缓慢解吸和与血清白蛋白的无效结合，这些影响将进一步放大。
Adrenoleukodystrophy (ALD) is an inherited disorder of fatty acid metabolism marked by accumulation of very long chain saturated fatty acids (VLCFA), especially the 26-carbon acid, hexacosanoic acid (HA), in membranes and tissues. We have studied interactions of C-13-enriched HA with model membranes (phospholipid bilayer vesicles) and bovine serum albumin (BSA) by C-13 NMR spectroscopy to compare properties of HA with those of typical dietary fatty acids. In phospholipid bilayers the carboxyl group of HA is localized in the aqueous interface, with an apparent pK(a) (7.4) similar to other fatty acids; the acyl chain must then penetrate very deeply into the membrane. Desorption of HA from vesicles (t1/2 = 3 h) is orders of magnitude slower than shorter chain fatty acids. In mixtures of vesicles and BSA, HA partitions much more favorably to phospholipid bilayers than typical fatty acids, BSA binds a maximum of only 1 mole of HA at one binding site. Calorimetric experiments show strong perturbations of acyl chains of phospholipids by HA. We predict that disruptive effects of VLCFA on cell membrane structure and function may explain the neurological manifestations of ALD patients. These effects will be further amplified by slow desorption of VLCFA from membranes and by the ineffective binding to serum albumin.