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At least 505 records · Page 28Linked to original sources
PubMed1991

Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.

Niemann-Pick disease, an autosomal recessive lysosomal storage disorder, is caused by deficiency of acid sphingomyelinase. Sequence analysis of mRNA and genomic DNA of fibroblasts of a type A patient showed a single G1729 to A nucleotide transition. This mutation resulted in a substitution of serine for normal glycine at position 577 of the peptide sequence. Amplification of the genomic DNA region around the mutation and subsequent sequencing yielded exclusively the same base change found at the cDNA level. Expression studies with this abnormal cDNA in COS-1 cells revealed a complete loss of enzymatic activity of the mutated protein. These findings indicate that this mutation is responsible for the clinical disease of the patient.

Animals↗
PubMed1992

Biosynthesis of sphingolipids: dihydroceramide and not sphinganine is desaturated by cultured cells.

Radioactively labeled N-[1-14C]-octanoyl-sphinganine and D-erythro-[3-3H]-sphinganine were administered in parallel experiments to neuroblastoma cells B 104. A time dependent formation of ceramide with a double bond in its sphingoid backbone was observed in both cases. In the presence of fumonisin B1 (25 microM), a strong inhibitor of sphinganine N-acyltransferase, desaturated ceramide was formed only when cells were fed with N-[1-14C]-octanoyl-sphinganine but not with [3-3H]-sphinganine. Thus, the introduction of the double bond occurs only at the level of dihydroceramide, after N-acylation of sphinganine. It is now obvious that sphingosine is not a biosynthetic intermediate but exclusively a catabolic product of cellular sphingolipids.

Animals↗
PubMed1990

Distribution of ectopic neurite growth and other geometrical distortions of CNS neurons in feline GM2 gangliosidosis.

Golgi and combined Golgi-electron microscopic (EM) studies were carried out on cats in the terminal stages of GM2 ganglioside storage disease and the resulting data were compared with those from similar studies of other neuronal storage diseases in cats, including GM1 gangliosidosis. The results support the view that only limited types of neurons affected by the lysosomal hydrolase deficiency and subsequent intracellular storage have the capacity to sprout new dendritic-like growth processes from their axon hillocks, and that these neurons are essentially the same in all of these diseases studied to date. Golgi studies of CNS tissues from GM2 gangliosidosis cats revealed ectopic neurite growth on pyramidal neurons of cerebral cortex and multipolar cells of amygdala and claustrum, whereas other types of neurons responded to the metabolic defect with aspiny meganeurite formation or somatic enlargement, or appeared normal in terms of soma-dendritic morphology. Combined Golgi-EM studies of cortical pyramidal neurons revealed that ectopic, axon hillock neurites commonly possessed asymmetrical synapses which were similar to those observed in other storage disorders.

Animals↗
PubMed1993

[Synthesis of 2-acetamido-1,4-imino-1,2,4-tridesoxy-D-galactitol and competitive inhibition of human lysosomal beta-hexosaminidase A].

The synthesis of 2-acetamido-1,4-imino-1,2,4-trideoxy-D-galactitol (1; 2-acetamido-4-amino-1,4-anhydro-2,4-dideoxy-D-galactitol) by two different routes starting from 2-acetamido-2-deoxy-D-glucose is described. Compound 1 is a competitive inhibitor of human lysosomal beta-hexosaminidase A with K(i) values of 18 microM (beta-subunit) and 220 microM (alpha-subunit). Similar properties were found for the already known 2-acetamido-2-deoxy-D-gluco-hydroximo-1,4-lactone.

Binding, Competitive↗
PubMed1990

Evidence for the presence of water within the hydrophobic core of membranes.

The photoreactive ganglioside derivative N-diazirinyl-lyso-GM1 was incorporated into liposomes and calf brain microsomes. After photoactivation at 350 nm it was found to dimerize with phospholipids such as phosphatidylcholine and phosphatidylserine and with cholesterol. The predominant covalent reaction product, however, was the alcohol, resulting from the reaction with water. It amounted to about 45% of the covalent reaction products in calf brain microsomes and to about 58% in pure phosphatidylcholine liposomes. Based on the temperature dependence of the photoreaction of N-diazirinyl-lyso-GM1 in liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphoryl-choline or 1,2-distearoyl-sn-glycero- 3-phosphorylcholine and on affinity labeling experiments with cholera toxin we propose that the predominant reaction of N-diazirinyl-lyso-GM1 with water is due to the presence of water within the hydrophobic core of artificial and biological membranes.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

The determination of phytosphingosine-containing globotriaosylceramide from human kidney in the presence of lactosylceramide.

Globotriaosylceramide, the natural substrate of alpha-galactosidase A (the enzyme deficient in Fabry's disease) was prepared from human kidney by repeated medium pressure chromatography on Lichroprep Si 60 (E. Merck) before and after peracetylation. The apparently homogeneous preparation migrating as a single band on HPTLC was analysed by fast atom bombardment mass spectrometry and 1H-NMR at 500 MHz. It was found that in this fraction two major molecular species were comigrating: Gal alpha 1-4Gal beta 1-4Glc beta 1-1ceramide with nervonic and lignoceric acid linked to phytosphingosine and Gal beta 1-4Glc beta 1-1 ceramide with palmitic acid linked to sphingosine.

Antigens, CD↗
PubMed1992

Detection of protein mediated glycosphingolipid clustering by the use of resonance energy transfer between fluorescent labelled lipids. A method established by applying the system ganglioside GM1 and cholera toxin B subunit.

Glycosphingolipids labelled in the ceramide moiety with 3-(p-(6-phenyl)-1,3,5-hexatrienyl)phenylpropionic acid (DPH) or 6-(4-nitrobenz-2-oxa-1,3-diazole-7-yl)aminohexanoic acid (NBD) were incorporated into small unilamellar lecithin liposomes. They were used in resonance energy transfer (RET) experiments between the donor fluorophore DPH and the acceptor NBD to study glycosphingolipid distribution. In pure lecithin liposomes the fluorescent derivatives of GM1, GA1, galactosylceramide and sulfatide behaved almost identically and Ca2+ ions (5 microM or 150 mM) did not influence their transfer efficiencies. But cholera toxin B subunit (CTB) specifically clustered GM1 and enhanced the transfer efficiency. This RET-based method facilitated determination of binding specificity, complex stoichiometry (CTB/GM1 = 1:5), halftime of complex formation (5 s), cooperativity in binding and had a maximal sensitivity at a liposome dotation rate of just 0.25 mol%. In contrast to this, anisotrophy of the fluorophores and the excimer to monomer ratio of pyrene-GM1 were not affected by CTB. This demonstrates the advantage of the presented technique in detection of protein mediated glycosphingolipid clustering.

Cholera Toxin↗
PubMed1980

Assay of ganglioside GM2-N-acetyl-beta-D-galactosaminidase activity in human fibroblasts employing the natural activator protein--diagnosis of variant forms of GM2 gangliosidosis.

The physiological activator protein for the degradation of ganglioside GM2 by hexosaminidase A has been employed to assess the capability of cultured human fibroblast extracts to catalyze this ganglioside. This method permits a more reliable diagnosis of the different variants of GM2 gangliosidoses than the methods hitherto used. These either rely on artificial substrates or, when natural substrates are used, on detergents. Our method avoids a number of possible sources of error introduced by the unphysiological detergents, such as alteration of the isoenzymes' substrate specificity or inactivation of the enzymes. The range of application of the new method is discussed.

Cells, Cultured↗