title: Comparison of N-acyl phosphatidylethanolamines with different N-acyl groups as activators of glucocerebrosidase in various forms of Gaucher's disease.
abstract: The acidic phospholipid requirement of the predominant particulate beta-glucosidase of mammalian spleen and liver was investigated using a series of N-acyl derivatives of dioleoyl phosphatidylethanolamine (PE). The PE, a neutral phospholipid, was converted to an acidic lipid, (N-acyl)-phosphatidylethanolamine (NAPE) by acylation of the amino group with different fatty acyl chains. Lysosomal beta-glucosidases from rat liver and spleens of controls and patients with various types of Gaucher's disease were solubilized and delipidated by extraction with sodium cholate and 1-butanol. All members of the NAPE series tested were effective activators of the delipidated rat liver beta-glucosidase, and the stimulatory power of the NAPE family increased with increasing chain length of the fatty acid substitution. In contrast, dioleoyl-PE had no effect on beta-glucosidase activity. A heat-stable factor (HSF) purified from the spleen of a patient with Gaucher's disease significantly increased the sensitivity of the rat liver beta-glucosidase to all of the NAPE derivatives. The maximum stimulation achieved in the presence of HSF was independent of N-acyl chain length. Compared to the potent activator, phosphatidylserine (PS), (N-acetyl)-PE and (N-linoleoyl)-PE were half as effective as activators of beta-glucosidase from control human spleen. PS stimulated the beta-glucosidase of type 1 nonneurologic Gaucher's disease, but none of the NAPE compounds activated it. Neither PS nor any of the (N-acyl)-PE compounds could activate a delipidated preparation of beta-glucosidase obtained from the spleen of a neurologic case. These results indicate that although the presence of a net negative charge on a phospholipid confers upon it an ability to reconstitute beta-glucosidase activity to the normal, nonmutant enzyme, it is insufficient to permit differentiation of the various types of Gaucher's disease.
mesh_terms: D000215:Acylation; D000368:Aged; D000818:Animals; D002648:Child; D004789:Enzyme Activation; D005776:Gaucher Disease / Q000201:enzymology*; D005959:Glucosidases / Q000378:metabolism*; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D051381:Rats; D013154:Spleen / Q000201:enzymology; D013329:Structure-Activity Relationship; D001617:beta-Glucosidase / Q000378:metabolism
chemical_list: D010714:Phosphatidylethanolamines; D005959:Glucosidases; D001617:beta-Glucosidase; D005962:Glucosylceramidase