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PubMed1988

Evidence that trans-bilayer interdigitation of glycosphingolipid long chain fatty acids may be a general phenomenon.

'Interdigitation' is a term coined to describe the phenomenon whereby pure phosphatidylcholines with intramolecular fatty acid chain length heterogeneity when hydrated to form bilayers may insert the methyl ends of long fatty acids from one side across more than half of the membrane thickness to protrude amongst the acyl chains of the opposite side of the bilayer (Keough, K.M.W. and Davis, P.J. (1979) Biochemistry 18, 1453-1459; Huang, C. and Mason, J.T. (1986) Biochim. Biophys. Acta 864, 423-470). In this article we address the fate of long fatty acid chains of glycosphingolipids present as minor components in membranes of non-interdigitating phosphatidylcholines. In this pursuit, derivatives of galactosyl ceramide, lactosyl ceramide, globoside and GM1 were synthesized having either 18-carbon or 24-carbon fatty acid with a spin label covalently attached at C-16. Labelled glycolipids were incorporated at 1-2 mol% into bilayers of synthetic phosphatidylcholines, their mixtures with cholesterol, or natural egg phosphatidylcholine. In each case the C-16 carbon of the glycolipid long chain fatty acid showed considerably greater 'order' and immobility than did C-16 of the fatty acid which was similar in length to the host matrix phospholipids. We interpret this as strong evidence that the long chain fatty acid interdigitates across the mid point of the bilayer in the systems studied. Clearly this phenomenon did not require that the phospholipid host matrix have mixed chain lengths. Furthermore it was totally independent of glycolipid family: for a given host matrix and (glycolipid) fatty acid chain length the order parameter values found were the same amongst all four glycolipid families tested.

Fatty Acids↗
PubMed1976

Effects of uridine nucleotides and nucleotide pyrophosphatase on glycolipid alpha and beta-N-acetylgalactosaminyltransferase activities in guinea pig microsomes.

Membrane-bound alpha and beta-N-acetylgalactosaminyltransferases (EC 2.4.1.0) which catalyze formation of non-reducing terminal linkages of Forssman hapten and globoside, respectively, could be differentiated with respect to the different effects of UDP on the two enzyme activities. UDP markedly inhibited the alpha-transferase activity, in contrast to its stimulatory action on the beta-transferase. These effects of UDP were similar to those of UDPglucose, which was demonstrated to be a competitive inhibitor (Ki, 3.3 - 10(-5) M for UDP-N-acetylgalactosamine) for the alpha-transferase reaction. Other uridine derivatives tested suppressed both the transferase activities, being more inhibitory for the alpha-transferase than for the beta-transferase. Under the synthetic conditions of these aminoglycolipids, UDP-N-acetylgalactosamine as a donor was simultaneously degraded into N-acetylgalactosamine-1-phosphate and finally into N-acetylgalactosamine by UDP-N-acetylgalactosamine pyrophosphatase, which is part of the membrane system. UDPglucose was confirmed as being able to prevent the enzymatic hydrolysis of UDP-N-acetylgalactosamine. UDPglucose, therefore, acts to suppress both the alpha-N-acetylgalactosaminyltransferase (but not the beta-transferase) and the pyrophosphatase activities. The inhibitory effect of UDPglucose on the alpha-transferase activity was most probably due to its direct action on the transferase rather than its function in protecting UDP-N-acetylgalactosamine donor from pyrophosphatase action.

Animals↗
PubMed1976

Localization of neutral glycosphingolipids in human plasma.

1. The localization of the neutral glycosphingolipids glucosylceramide, lactosylceramide, trihexosylceramide and globoside in human plasma was investigated. Glycosphingolipids were isolated and analysed by gas-liquid chromatography. 2. After Sephadex gel chromatography of human plasma, about 75% of the glycosphingolipids were found in the fraction containing most of the lipoproteins. 3. After fractionation of the lipoproteins by ionic precipitation, 15-25% of each glycosphingolipid was found in the very low-density lipoprotein + chylomicron fraction, 30-45% in the low density lipoprotein fraction and 40-50% in the high density lipoprotein fraction. 4. After fractionation of lipoproteins by density-gradient ultracentrifugation, 15% of each glycosphingolipid was found in the very low-density lipoprotein + chylomicron fraction and 85% in the low density and high density lipoprotein fractions. No glycosphingolipids could be detected in the ultracentrifugal residue which contains the bulk of the albumin.

Ceramides↗
PubMed1978

Structures and fatty acid compositions of neutral glycosphingolipids of human plasma.

Major neutral glycosphingolipids were isolated from human plasma and their structures and fatty acid compositions studied. The four neutral glycosphingolipids of plasma were characterized as Glc beta(1 leads to 1)ceramide, Gal beta(1 leads to 1)- ceramide, Gal beta(1 leads to 4) Glc beta (1 leads to 1)ceramide, Gal alpha(1 leads to 4) Gal beta(1 leads to 4) Glc beta(1 leads to 1)ceramide and GalNAc beta(1 leads to 3) Gal (1 leads to 4) Gal (1 leads to 4) Glc beta(1 leads to 1)-ceramide. The glycosphingolipids contained mostly short chain fatty acids of which most prominent was C16. Erythrocyte glucosylceramide and lactosylceramide exhibited similar fatty acid compositions as their plasma counterparts. Triglycosylceramide and globoside of erythrocytes contained almost exclusively long-chain fatty acids. In lactosylceramide obtained from "p" erythrocytes, an accumulation of long-chain fatty acids was found; this accumulation was not observed, however, in lactosylceramide isolated from "p" plasma. It was concluded that plasma and erythrocyte glycosphingolipids are synthesized at separate sites where short- and long-chain fatty acids, respectively, are available. Plasma and erythrocyte glucosylceramide, and probably a fraction of lactosylceramide, exchange between plasma and erythrocyte pools. The latter conclusion is discussed in the light of the relative roles of carbohydrate and lipid moieties of the glycosphingolipids in maintaining their association with erythrocyte membranes.

Erythrocyte Membrane↗
PubMed1985

GM2-ganglioside metabolism in cultured human skin fibroblasts: unambiguous diagnosis of GM2-gangliosidosis.

The metabolism of GM2-ganglioside was studied in situ using cultured skin fibroblasts from normal individuals and patients with different forms of GM2-gangliosidosis. [3H]Sphingosine-labeled GM2 was provided in the culture medium to confluent cells in 6-cm petri dishes. After 10 days, the cells were washed free of radioactivity and harvested by trypsinization. The cellular lipids were extracted and analyzed for radioactivity in GM2 and its metabolic products. In fibroblasts from healthy subjects, 50-60% of the total cellular radioactivity was found in the neutral glycosphingolipids, ceramide, sphingomyelin and fatty acids. Degradation of the labeled GM2 progressed rapidly via GM3, ceramide dihexoside and ceramide monohexoside with a build-up of radioactivity mainly in the ceramide pool of the cell. The labeled ceramide is also reutilized for the synthesis of ceramide trihexoside, globoside and sphingomyelin or is converted to fatty acid and incorporated in ester linkages. In contrast, cells from patients with GM2-gangliosidosis representing Tay-Sachs, Sandhoff and AB variant forms of the disease did not metabolize the ingested labeled GM2-like controls. Nearly all of the radioactivity was present in the ganglioside fraction in the lipid extracts from these cells and consisted of unhydrolyzed GM2. High-performance liquid chromatographic analysis of monosialogangliosides from cells grown without added labeled GM2 in the medium indicated accumulation of endogenously synthesized GM2 in cell lines from all patients with GM2 gangliosidosis compared to healthy controls. This approach provides a reliable tool for pre- and post-natal diagnosis of all forms of GM2-gangliosidosis without ambiguity.

Cells, Cultured↗
PubMed1986

Gangliosides and neutral glycosphingolipids of normal tissue and oat cell carcinoma of human lung.

Concentration and composition of gangliosides and neutral glycosphingolipids of adult human lung, and lung small cell carcinoma were studied. The structures of the glycolipids were determined by quantitative component determination, enzymic degradation, permethylation and fast atom bombardment mass spectrometry. Adult human lung contained mainly gangliosides with lactosylceramide as the basic core, GM3, GD3 and GT3, and approx. equal proportions (10%) of gangliosides of the gangliotetraosyl- and lactotetraosylceramide series. 18 gangliosides with different carbohydrate moieties were identified: four of them were only found in the tumor tissue. The adult human lung contained 85 nmol (77-120) gangliosides and 140 nmol neutral glycosphingolipids per g wet weight. Globoside was the major neutral glycolipid and there were only minor amounts of glycolipids of the lactotetraose series. In small cell carcinoma tissue the concentration of neutral glycosphingolipids was approximately twice as high than in normal lung tissue, and there was a markedly larger concentration of both lactosylceramide and glycolipids of the lactotetraose series and fucose derivatives of these. The concentration of gangliosides varied between 202 and 415 nmol per g wet weight. Compared to normal lung tissue, the tumor tissue had a lower proportion of GD3, and a higher proportion of complex gangliosides, and they contained five tumor-associated gangliosides: Fuc-GM1, Fuc-GD1b, 3'-LM1, Fuc-3'-LM1 and 6'-nLM1.

Adult↗
PubMed1988

Glycosphingolipids of cultured human colon carcinoma cells and their drug-resistant sublines.

Human colon carcinoma cells were analyzed for lipid phosphorus, cholesterol and glycosphingolipids. Ceramide mono-, di- and trihexosides and sulfatides were isolated by column and thin-layer chromatography and determined quantitatively on the basis of their hexose content. The complex lipid fractions so isolated were only partially resolved with the material available. Gangliosides GM2 and GM3 and globoside were major components of the fraction and were determined on the basis of their hexose, hexosamine and neuraminic acid content. The HCT 116, 116a and 116b cells contained no fucolipids. Cell lines resistant to mitomycin C, teniposide and etoposide were developed and analyzed. Over the 5 year period of the study sulfatides declined to about one-fourth of their original amounts in both parent and drug-adapted cells. HCT 116 cells adapted to mitomycin C and teniposide had 30% less ceramide monohexoside and a 45% greater cholesterol to lipid phosphorus ratio than the parent cells. Reductions in ceramide dihexoside in the drug-adapted cells were greater than those of the ceramide monohexoside. Galabiosyl ceramide was the major ceramide dihexoside in all the cells and accumulated in HCT 116a to levels 4-6-fold greater than that of the other lines as the only dihexoside.

Cholesterol↗
PubMed1989

Liberation of oligosaccharides from glycosphingolipids on PC12 cell surface with endoglycoceramidase.

Endoglycoceramidase (EGCase) cleaves the linkage between the oligosaccharide and ceramide of glycosphingolipids (Ito, M., and Yamagata, T., J. Biol. Chem. 261, 14278-14282, ibid, 264, in press). Intact cells of rat pheochromocytoma line PC12 were treated with the highly purified EGCase I and the oligosaccharides released were analyzed by HPLC. Cleavage of the oligosaccharides with the enzyme reached a plateau as the amount of the enzyme was increased. At maximum, 42% of the oligosaccharides from globoside, 40% from GalGb3Cer, and 60% from Gb3Cer were liberated during 1h of incubation without impairing the viability of cells. The only partial liberation indicates that not all oligosaccharides of cell surface glycosphingolipids are accessible to the enzyme. The use of EGCase offers an important new method to access the functions of glycosphingolipids on cell surface in situ.

Adrenal Gland Neoplasms↗
PubMed1991

Solution conformation of Forssman antigen probed by NOE and exchange interactions.

The conformation of Forssman glycolipid, GalNAc alpha 1-3GalNAc beta 1-3Gal alpha 1-4Gal beta 1-4Glc beta 1-1ceramide, was analysed with the aid of the rotating frame NOE and Hartmann-Hahn spectroscopy. NOE contacts between C-, O-, and N-linked protons were used for distance mapping. The glycosidic bonds that are common to globotriaosylceramide and globoside showed a similar flexibility as found for these compounds [Poppe et al., (1990) Eur. J. Biochem. 189, 313-325; J. Am. Chem. Soc. 112, 7762-7771]. In contrast, the conformational mobility of the terminal GalNAc alpha 1-3GalNAc beta linkage appears to be restrained. A new approach, based on 2D exchange spectroscopy, was proposed for revealing of spatial proximities between exchangeable protons in Me2SO solution.

Carbohydrate Conformation↗
PubMed1992

Binding specificity of lung surfactant protein SP-D for glucosylceramide.

The specificities of the binding of lung surfactant protein SP-D to glycolipids were examined using 125I-labeled SP-D as a probe. When the binding study was performed on TLC plates, SP-D bound exclusively to GlcCer, whereas it failed to bind to GalCer, GM1, GM2, asialo-GM1, asialo-GM2, sulfatide, Forssman antigen, ceramide dihexoside, ceramide trihexoside, globoside, paragloboside or ceramide. Excess native SP-D competed with 125I-SP-D for the binding to GlcCer. Antibody to rat SP-D inhibited 125I-SP-D binding to GlcCer. Ca2+ was absolutely required for the binding of SP-D to GlcCer; Mg2+ failed to substitute for Ca2+. SP-D bound to ceramide monohexoside in glycolipids isolated from rat lung and bronchoalveolar lavage fluids of rats.

Animals↗
PubMed1976

GM2 ganglioside in fetal Tay-Sachs disease brain cultures: a model system for the disease.

Cultured cells derived from Tay-Sachs disease (TSD) fetal cerebellum were shown to accumulate GM2 ganglioside when compared with control cultures. In contrast, fibroblasts derived from TSD fetal lung do not contain GM2. GM2 was identified by thin-layer chromatography (TLC) and confirmed by gas-liquid chromatography (GLC). Unlike fetal TSD brain, the cell cultures established from fetal TSD brain have high concentrations of globoside and GD3 and little or no asialo GM2(GA2). The GM2 and related glycosphingolipids in these cultured cells contain a high percentage of C24:0 and C24:1 fatty acids. In spite of these differences, this TSD cell strain is unique in that it accumulates GM2, and can therefore serve as a useful in vitro model for the study of TSD.

Cells, Cultured↗
PubMed1979

Cell-type-specific markers for distinguishing and studying neurons and the major classes of glial cells in culture.

We have used 4 cell-type-specific markers to identify individual glial and neuronal cells in dissociated cell cultures of neonatal rat sciatic nerve, dorsal root ganglia (DRG), optic nerve, cerebellum, corpus callosum, cerebral cortex and leptomeninges. Schwann cells were identified with antibodies against rat neural antigen-1 (Ran-1), neurons with tetanus toxin, astrocytes with antibody against the glial fibrillary acidic protein (GFAP) and oligodendrocytes with antibody against galactocerebroside. All of these ligands react with cell surface molecules except for anti-GFAP antibody which binds to intracellular glial filaments. Using two-fluorochrome immunofluorescence we have studied the distribution of various glycoproteins and glycolipids on these 4 major neural cell types in short-term cultures. We have found that (1) although Ran-1 is expressed on glial and neuronal tumours, it was not found on normal astrocytes, oligodendrocytes or neurons; (2) Thy-1 was present on fibroblasts and some neurons but not on the majority of leptomeningeal cells or on oligodendrocytes or astrocytes in short-term cultures (however, it was expressed on some astrocytes in longer term cultures); (3) the 'large external transformation sensitive' (LETS) protein could be detected on fibroblasts and leptomeningeal cells but not on neurons or glial cells; (4) GM1 was present on all neurons, most oligodendrocytes and approx. 50% of other cell types; sulfatide and GM3 were only detectable on oligodendrocytes, while globoside was only found on some neurons. In addition, we were able to identify putative microglial cells by the presence of cell surface receptors for IgG and by their phagocytic activity; they did not express and of the cell-type-specific defining markers.

Animals↗
PubMed1991

Subsets of olfactory and vomeronasal sensory epithelial cells and axons revealed by monoclonal antibodies to carbohydrate antigens.

Cell surface glycoconjugates are believed to play an important role in cell-cell interactions during development of CNS pathways. In order to identify developmentally regulated glycoconjugates in the nervous system, monoclonal antibodies were raised and selected for reactivity with carbohydrate antigens. Three monoclonal antibodies were identified, each of which reacts with a defined carbohydrate epitope and reveals a unique pattern of immunoreactivity within the olfactory sensory epithelia, vomeronasal and olfactory nerves and their terminal regions in rats. Antibody CC1 reacts with a globoside-like glycolipid which contains a terminal N-acetylgalactosamine residue. CC1-immunoreactivity is present in just the vomeronasal organ, vomeronasal nerve and in the rostral half of the accessory olfactory bulb. Antibody CC2 reacts with a complex glycolipid which contains a branched chain oligosaccharide terminating with alpha-galactose and alpha-fucose. CC2-immunoreactivity is seen throughout the vomeronasal organ, in dorsomedial regions of the olfactory sensory epithelia, in the vomeronasal and olfactory nerves, the accessory olfactory bulb and dorsomedial glomeruli of the main olfactory bulb. Antibody 1B2 reacts with lacto-N-glycosyl ceramides. 1B2-immunoreactivity is highest at the luminal surfaces of receptor cells throughout the vomeronasal organ and in portions of the olfactory sensory epithelia. 1B2 is also expressed on the surface of a subset of receptor cell bodies, their dendrites and the proximal region of their axons in dorsomedial regions of the main olfactory epithelium.

Animals↗
PubMed1976

Mass spectrometric analysis of permethylated glycosphingolipids II. Comparative studies on different blood-group active and related erythrocyte membrane glycosphingolipids.

Three isomeric ceramide tetrasaccharides--P blood-group active globoside, lacto-N-neotetraosyl ceramide as ABH blood-group precursor, both isolated from human erythrocytes and "asialo ganglioside" from human brain as reference standard--and two ceramide pentasaccharides--H blood-group active glycosphingolipid, obtained from blood-group B active ceramide hexasaccharide of human B erythrocytes after alpha-galactosidase treatment and ceramide pentasaccharide from rabbit erythrocytes with B-like blood-group activity--were investigated by mass spectrometry after permethylation. The carbohydrate moiety exhibits differences not only concerning the sugar sequence but also with regard to the position of some glycosidic linkages: Oligosaccharides containing N-acetylhexosamine substituted at position 4 produce spectra that are distinctly different from those containing C-3 substituted N-acetylhexosamines, thus allowing the differentation between type 1 and type 2 carbohydrate chains. Moreover, oligosaccharide ions with a hexose at the cleavage site exhibit a fragmentation pattern different from those with a N-acetylhexosamine at the "reducing terminal". The intensity ratio between parent ion and parent ion -32 mass units is Q greater than or equal to 3 in the first case, whereas in the latter case Q is less than 1. The Q-values are given for 14 oligosaccharide ions. Differences in the composition of the ceramide residues can also be deduced from the mass spectra.

ABO Blood-Group System↗
PubMed1978

Isolation and purification of Lea blood-group active and related glycolipids from human plasma of blood-group A Lea individuals.

From 81 of human plasma of blood-group A Lea nonsecretors three different Lea blood-group active ceramide pentasaccharides (a total of 4.65 mg) have been isolated, all revealing glucose, galactose, N-acetylglucosamine and fucose in molar ratios of 1 : 2 : 1 : 1 as determined by gas liquid chromatography. A fourth blood-group active fraction (0.72 mg) represents a mixture of a Lea active ceramide pentasaccharide and an A active ceramide hexasaccharide (molar ration 7.7 : 2.3 as calculated from the content of different aminosugars). Additionally, two different globosides, two different hematosides and a new N-acetylglucosamine containing ceramide tetrasaccharide were obtained. All 9 glycolipid fractions demonstrated homogeneity in analytical high performance thin layer chromatography (HPTLC) using 4 different solvent systems. 0.2 microgram of each Lea active glycolipid completely inhibited the agglutination of O Le(a+b-) erythrocytes by 50 microliter of 4 hemagglutinating units of caprine anti Lea serum. At least 0.04 microgram of each Lea antigen are sufficient for incubation to convert 9 x 10(7) O Le(a-b-) erythrocytes into Lea-positive cells. Mainly due to the relatively low content of the blood-group A glycolipid in plasma (0.17 mg/81), previously negative erythrocytes readily become agglutinable by anti Lea sera and not by anti A sera after incubation with appropriate plasma.

ABO Blood-Group System↗
PubMed1980

The bile salt activation of leucocyte sphingolipid hydrolase activity and the modifying effects of triton X-100.

The activation of sphingomyelinase, galactosyl- and lactosylceramide beta-galactosidases, GM1, beta-galactosidase, cerebroside sulphate sulphatase, trihexosylceramide alpha-galactosidase and globoside beta-hexosaminidase by a number of bile salts was studied. Most of the salts examined, except glycolithocholate and deoxycholate, were effective activators of enzyme activity. Pure, but not crude, taurocholate elicited poor trihexosylceramide alpha-galactosidase and cerebroside sulphate sulphatase activities. The bile salt activation was often dependent on a number of parameters including the bile salt concentraion, pH, protein to bile salt ratio, and the nature of the enzyme preparation. In the absence of bile salts, Triton X-100 induced little activity of any of the hydrolases except sphingomyelinase; in their presence however, Triton either promoted or inhibited the activation depending on the enzyme. Our data suggest that bile salt structure is an important factor in determining the degree of activation of individual hydrolases and that this may be due to intramicellar lipid substrate/bile salt interactions, which either facilitate or inhibit the corresponding enzyme reaction.

Adult↗
PubMed1984

Lectins facilitate calcium-induced fusion of phospholipid vesicles containing glycosphingolipids.

Ca2+-induced fusion of phospholipid vesicles containing globoside (GL-4) or disialoganglioside (GDla) is several-fold slower than the fusion of the pure phospholipid vesicles. Lectins specific for these glycosphingolipids, soybean agglutinin and wheat germ agglutinin, respectively, enhance the rate of fusion when added to the vesicle suspension before the introduction of Ca2+. The enhancement depends on the lectin concentration and the time of preincubation with the lectin. We propose that lectins facilitate membrane fusion by inducing intermembrane contact, which is the first step in the overall process of membrane fusion, or by laterally phase separating the inhibitory glycolipids.

Calcium↗
PubMed1990

Juvenile Sandhoff disease: a Japanese patient carrying a mutation identical to that found earlier in a Canadian patient.

A 35-year-old Japanese man with juvenile Sandhoff disease is described. He showed progressive neurogenic muscular atrophy, cerebellar ataxia and mental deterioration, beginning at age 10 years. The accumulation of GM2 ganglioside in the submucosal nerve cell was confirmed by positive immunostaining using anti-GM2 ganglioside antibody. Biochemical evaluation revealed nearly absent beta-hexosaminidase A and B activities in leukocytes and cultured fibroblasts. Hydrolysis of [3H]globoside I in the intact fibroblasts was apparently disturbed but the rate of hydrolysis was higher than those seen in cells from patients with infantile Sandhoff disease. Analysis of the beta-hexosaminidase beta-subunit gene of the patient disclosed a point mutation (a G-to-A transition) within intron 12. The mutation generates a new splice junction resulting in a 24-base insertion between exons 12 and 13 in the processed mRNA and consequently an 8-amino acid insertion in the translation product. This mutation is identical to that originally found in a Canadian patient with juvenile Sandhoff disease. A possible relationship with the clinical phenotype and the gene abnormality is discussed.

Adult↗