INTERACTIONS OF A VERY LONG-CHAIN FATTY-ACID WITH MODEL MEMBRANES ANDSERUM-ALBUMIN - IMPLICATIONS FOR THE PATHOGENESIS OF ADRENOLEUKODYSTROPHY

Adrenoleukodystrophy (ALD) is an inherited disorder of fatty acid meta bolism marked by accumulation of very long chain saturated fatty acids (VLCFA), especially the 26-carbon acid, hexacosanoic acid (HA), in me mbranes 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 wit h those of typical dietary fatty acids. In phospholipid bilayers the c arboxyl group of HA is localized in the aqueous interface, with an app arent pK(a) (7.4) similar to other fatty acids; the acyl chain must th en penetrate very deeply into the membrane. Desorption of HA from vesi cles (t1/2 = 3 h) is orders of magnitude slower than shorter chain fat ty acids. In mixtures of vesicles and BSA, HA partitions much more fav orably to phospholipid bilayers than typical fatty acids, BSA binds a maximum of only 1 mole of HA at one binding site. Calorimetric experim ents 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 patie nts. These effects will be further amplified by slow desorption of VLC FA from membranes and by the ineffective binding to serum albumin.