出版社：American Society for Biochemistry and Molecular Biology
摘要：Skin fibroblast cultures from patients with inherited lysosomal enzymopathies, α- N -acetylgalactosaminidase (α-NAGA) and α-galactosidase A deficiencies (Schindler and Fabry disease, respectively), and from normal controls were used to study in situ degradation of blood group A and B glycosphingolipids. Glycosphingolipids A-6-2 (Gal N Ac (α1 → 3)[Fucα1 → 2]Gal(β1 → 4)Glc N Ac(β1 → 3)Gal(β1 → 4)Glc (β1 → 1′)Cer, IV2-α-fucosyl-IV3-α- N -acetylgalactosaminylneolactotetraosylceramide), B-6-2 (Gal(α1 → 3)[Fucα1 → 2] Gal (β1 → 4)Glc N Ac(β1 → 3)Gal(β1 → 4)Glc(β1 → 1′)Cer, IV2- α-fucosyl-IV3-α-galactosylneolactotetraosylceramide), and globoside (Gal N Ac(β1 → 3)Gal(α1 → 4)Gal(β1 → 4)Glc(β1 → 1′) Cer, globotetraosylceramide) were tritium labeled in their ceramide moiety and used as natural substrates. The degradation rate of glycolipid A-6-2 was very low in fibroblasts of all the α-NAGA-deficient patients (less than 7% of controls), despite very heterogeneous clinical pictures, ruling out different residual enzyme activities as an explanation for the clinical heterogeneity. Strongly elevated urinary excretion of blood group A glycolipids was detected in one patient with blood group A, secretor status (five times higher than upper limit of controls), in support of the notion that blood group A-active glycolipids may contribute as storage compounds in blood group A patients. When glycolipid B-6-2 was fed to α-galactosidase A-deficient cells, the degradation rate was surprisingly high (50% of controls), while that of globotriaosylceramide was reduced to less than 15% of control average, presumably reflecting differences in the lysosomal enzymology of polar glycolipids versus less-polar ones. Relatively high-degree degradation of substrates with α- d -Galactosyl moieties hints at a possible contribution of other enzymes.
