Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.99.7 (sialyltransferase)
 1,534 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four different glycolipid:glycosyltransferase activities involved in the biosynthesis in vitro of gangliosides and blood group-related glycosphingolipids have been tested in a simian virus 40-transformed glial cell culture derived from the cerebrum of a fetus with Tay-Sachs disease (TSD). The TSD cultured brain cells contained little activity of either UDP-Gal:GM2(beta 1-3)galactosyltransferase (GalT-3; EC 2.4.1.62), which catalyzes the formation of GM1a from GM2 (tay-Sachs) ganglioside, or GDP-Fuc:nLcOse4Cer (alpha 1-2)fucosyltransferase (FucT-2; EC 2.4.1.89), which catalyzes the formation of H1 glycolipid from nLcOse4Cer. These cells contained a potent inhibitor of the second reaction (catalyzed by a Golgi-rich membrane fraction from bovine spleen), whereas no inhibition of the first reaction (catalyzed by a membrane fraction from 14-day-old embryonic chicken brain) was observed. The activity of UDP-Gal:LcOse3Cer(beta 1-4)galactosyltransferase (GalT-4; EC 2.4.1.86) was 30- to 80-fold higher than the activity of GalT-3. The presence of CMP-AcNeu:nLcOse4Cer sialyltransferase activity and the absence of either GalT-3 or FucT-2 suggested a probable pathway for the synthesis of sialylneolactotetraosylceramide [GM1b(GlcNAc)] in addition to a specific blockage of GM1a ganglioside synthesis from GM2 in these TSD transformed cells.
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PMID:Differential activities of glycolipid glycosyltransferases in Tay-Sachs disease: studies in cultured cells from cerebrum. 29 63

The developmental pattern of gangliosides in human fetal brain should reflect the activities of the respective glycosyltransferases. LA2-synthase activity, along with that of GM3-, GD3-, GM2-, and GM1-synthases, was determined in human fetal brain at 10-22 weeks of gestation. LA2-synthase is the pivotal enzyme in lacto series ganglioside formation. LA2-synthase activity decreased during the study period, mirroring a similar temporal decline in levels of the lacto series gangliosides, particularly 3'-isoLM1. The developmental profiles of the ganglio series glycosyltransferase activities demonstrate distinct changes that correspond to the ganglioside pattern between fetal weeks 10 and 22. In particular, the marked increase in GM2-synthase activity at 20 and 22 weeks of gestation and the decline in GD3-synthase activity after 15 weeks could explain the prominent expression of the a series gangliosides in this period of rapid neuronal outgrowth. However, a similar decline (two- to 2.5-fold) in GM3-synthase activity suggests a more likely conclusion, namely, that the two sialyltransferase activities are derived mainly from astroglial cells, which show a marked proliferation during the 10-15th fetal weeks. The data do not negate the hypothesis that GM3- and GD3-synthase are the critical enzymes in the regulation of ganglioside biosynthesis but do indicate a need to reevaluate the significance of GM2-synthase in expression of the a series gangliosides.
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PMID:Glycosphingolipid glycosyltransferases in human fetal brain. 190 91

The role of acidic glycosphingolipids in cell growth and differentiation was investigated using the multipotent leukemia cell line K562. When GM3 was added to cell culture media, the growth of K562 cells was remarkably inhibited and the cells were shown to have megakaryocytoid morphology. Ultrastructural study demonstrated that K562 cells treated with GM3 had platelet peroxidase-positive structures, which were considered to be the specific marker of megakaryocyte. Furthermore, AP-3 directed against an epitope present on membrane glycoprotein IIIa reacted with the GM3-treated cells. Free N-acetylneuraminic acid, GM1, GM2, GD1a, and a mixture of bovine brain gangliosides containing GD1a and GT1b did not affect growth of K562 cells or show morphological changes. According to chemical analyses, GM3 content increased in megakaryocytoid differentiation induced by tetradecanoylphorbol-13-acetate, whereas GM3 decreased in erythroid differentiation induced by hemin. Enzymatic analysis showed that the GM3 increase during megakaryocytoid differentiation was a result of the sialyltransferase activation. These results indicated that exogenous GM3 induced differentiation of K562 cells into a "GM3-rich" lineage, i.e., mainly megakaryocytoid lineage, and that GM3 accumulation in the GM3-rich lineage was the result of the activation of GM3 synthase. These findings strongly suggested that GM3 ganglioside, a minor membrane component, has a crucial role in not only the differentiation induction but also the determination of the differentiation direction in pluripotent K562 cells.
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PMID:Ganglioside GM3 can induce megakaryocytoid differentiation of human leukemia cell line K562 cells. 200 80

The patterns of acidic and neutral glycosphingolipids (GSLs) were examined in a syngeneic tumour system in Balb/c mice consisting of closely related cell lines with different colonisation potentials directed to the murine lungs (in vivo selected highly metastatic sublines of L1-fibrosarcoma cells and their WGA-resistant mutants with low metastatic potential). GSLs were analysed by high-performance thin-layer chromatography and structurally identified by fast atom bombardment mass spectrometry combined with compositional analyses and exo-glycosidase digestion. The results suggest that highly metastatic sublines L1-LM and L1-LM12 derived by in vivo selection from mouse fibrosarcoma cells (cell line L1) exhibit a drastic increase of polar ganglioside expression and a restriction to globo-series GSLs. Contrasting with this the low metastatic mutant cells (L1-LM13WGA) express a reduced portion of acidic GSLs and exhibit a shift to less polar ganglioside components. Total cellular and plasma membrane-integrated GSLs were demonstrated to exhibit largely identical patterns. Concomitant with a significant decrease in LacCer expression a substantial reduction of GM2 and a complete lack of GM3 expression can be assigned to the highly metastatic sublines of L1-cells. On the other hand, the more polar gangliosides GM1a and, to an even greater extent, GD1a (exceeding 70% of total gangliosides) accumulate on L1-LM and their clonal sublines. The shift to acidic GSLs of higher polarity is less pronounced on the low metastatic WGA-resistant mutant cells (L1-LM13WGA) showing a preponderance of GM1a. The portion of GD1a within the fractions of acidic GSLs does not correspond to the cellular activities of CMP-NeuAc/GM1 (alpha 2-3) sialyltransferase measured for high and low metastatic cell variants. Total sialic acid content of the various cell lines differs, but is not associated with the metastatic potential. Gangliosides on L1-cells exhibit a significant substitution of N-glycolyl for N-acetylneuraminic acid (13%) compared to their metastatic sublines and to mutant cells (less than 1%). A conversion of surface exposed GD1a to GM1a on membranes of metastatic cells by in situ treatment with Vibrio cholerae sialidase is associated with a significant reduction of tumour cell colonisation directed to the murine lungs.
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PMID:Glycosphingolipid expression on murine L1-fibrosarcoma cells: analysis of clonal in vivo and in vitro selected sublines with different lung colonisation potential. 237 82

The enrichment of gangliosides in neuronal membranes suggests that they play an important role in CNS development. We recently found a marked tetrasialoganglioside deficiency in twl/twl mutant mouse embryos at embryonic day (E)-11. The recessive twl/twl mutants die at embryonic ages E-9 to E-18 from failed neural differentiation in the ventral portion of the neural tube. In the present study, we examined the composition and distribution of gangliosides in twl/twl mutant mouse embryos at E-12. The total ganglioside sialic acid concentration was significantly lower in the mutants than in normal (+/-) embryos. The mutants also expressed significant deficiencies of gangliosides in the "b" metabolic pathway (GD3, GD1b, GT1b, and GQ1b) and elevations in levels of gangliosides in the "a" metabolic pathway (GM3, GM2, GM1, and GD1a). These findings suggest that the mutants have a partial deficiency in the activity of a specific sialyltransferase in the b pathway. Regional ganglioside distribution was also studied in E-12 normal mouse embryos. The ganglioside composition in heads and bodies was similar to each other and to whole embryos. Total ganglioside concentration and the distribution of b pathway gangliosides were significantly higher in neural tube regions than in nonneural tube regions. These findings suggest that b pathway gangliosides accumulate in differentiating neural cells and that the deficiency of these gangliosides in the twl/twl mutants is closely associated with failed neural differentiation.
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PMID:Ganglioside composition of normal and mutant mouse embryos. 291 Oct 26

Developmental changes in ganglioside composition and biosynthesis was studied in rat brain between embryonic day (E) 14 and birth. In E14 brains, GM3 and GD3 were predominant. At E16, "b" series gangliosides, such as GD1b, GT1b, and GQ1b, increased in content. After E18, "a" series gangliosides such as GM1, GD1a, and GT1a increased in content, and the content of GM3 and GD3 markedly decreased. Because of these changes in composition, we determined the activities, in homogenates of embryonic brains, of two key enzymes of ganglioside synthesis: sialyltransferase for the synthesis of GD3 from GM3 and N-acetylgalactosaminyltransferase for GM2 synthesis from GM3. The sialyltransferase activity (GM3----GD3) was constant between E14 and E18 but decreased rapidly from E18 to birth. In contrast, the N-acetylgalactosaminyltransferase activity (GM3----GM2) increased between E14 and E18 but was constant from E18 to birth. These changes in ganglioside composition and enzymatic activities indicate that during development there is a shift from synthesis of the simplest gangliosides of the "a" and "b" pathways to synthesis of the more complex gangliosides.
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PMID:Developmental changes in ganglioside composition and synthesis in embryonic rat brain. 313 85

Competition experiments using lactosylceramide, ganglioside GM3 and ganglioside GD3 as substrates, as well as mutual inhibitors for ganglioside N-acetylgalactosaminyltransferase, in Golgi vesicles derived from rat liver suggested that N-acetylgalactosamine transfer to these three respective compounds, leading to gangliosides GA2, GM2, and GD2, respectively, is catalyzed by one enzyme. Analogous studies with gangliosides GA1, GM1, and GD1b as glycolipid acceptors in sialyltransferase assays indicated GM1b, GD1a, and GT1b synthases to be identical. These results are incorporated into a model for ganglioside biosynthesis and its regulation.
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PMID:Both GA2, GM2, and GD2 synthases and GM1b, GD1a, and GT1b synthases are single enzymes in Golgi vesicles from rat liver. 314 Feb 34

In order to better understand the role of cell surface glycolipids in T lymphocyte activation, heparin was used to simultaneously modulate the expression of glycolipids and the lytic capacity of lymphocytes activated by interleukin-2. Results presented here show that heparin added at the start of a 3 day culture inhibited the formation of lymphokine activated killer cells by up to 50%. Heparin also has a profound effect on the synthesis of glycolipids during this three day period. Asialo GM1, a useful cell surface marker for subsets of murine cytotoxic cells, is reduced in amount, as are the other two major neutral glycolipids lactosylceramide and asialo GM2. In addition, the synthesis of some gangliosides is affected by heparin treatment. Comparison of the glycosyltransferase activities of untreated and heparin-treated cells shows that the activities of a 2-3-sialyltransferase and a beta 1-3 galactosyltransferase are inhibited dramatically, while a third enzyme, N-acetyl-galactosaminyltransferase is unaffected. The two heparin inhibitable enzymes bind to heparin affinity columns but the galactosaminyltransferase does not. These studies suggest that the proper regulation of the activities of specific glycosyltransferases may be important events in lymphocyte activation.
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PMID:Heparin inhibits specific glycosyltransferase activities in interleukin 2 activated murine T cells. 314 30

We have conducted a quantitative analysis of the gangliosides extracted from brain, spleen, thymus, and liver tissue of 8-week-old male mice from H-2 congenic mouse strains on the B10 background, using high performance thin-layer chromatography (HPTLC). An analysis of variance of replicate samples of liver from strains B10, B10.A, and B10.G revealed that the time of sample and colony of origin were not sources of significant variance but that for N-glycolylated gangliosides GM2, GM1, and GD1a, the differences detected between strains were significant. Particularly important were the differences for GM1: the values of 0.0% for B10, 19.0% for B10.A, and 36.0% for B10.G were each significantly different from the others (P less than 0.0005). Further studies with liver tissue from B10/A H-2 recombinant strains also revealed three significantly different levels of GD1a: less than or equal to 4.0% [B10, B10.A (3R), B10.A (5R), B10.A (18R)], 11.0% (B10.A), and 33% [B10.A (1R), B10.A (2R), B10.A (4R)]. Our findings support prior studies which indicate that a gene linked to the H-2 complex affects hepatic GM2 galactosyltransferase activity. However, they also indicate that the current model, which classifies all strains as possessing either an allele for "high" enzyme activity or a single alternative allele for "low" enzyme activity, is probably oversimplified, since at least three levels of enzyme activity appear to exist as stable phenotypic markers. Moreover, the current model cannot readily account for the three different levels of GD1a observed with B10/A H-2 recombinants. Alternative models are proposed, including the novel suggestion that a distinct H-2 linked gene may affect hepatic GM1 sialyltransferase activity. These findings demonstrate that further study of H-2 linked genes affecting the activities of glycosyltransferases is indicated.
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PMID:A quantitative analysis of H-2 linked effects on hepatic ganglioside composition. 362 37

Golgi vesicles were isolated and purified from rat liver, in which the specific activities of glycosyltransferases (e.g. GM3: CMP-NeuAc sialyltransferase, GD3-synthase; GM3: UDP-GalNAc galactosaminyltransferase, GM2-synthase) were 50-60 times enriched relative to microsomes or total homogenate. Synthesis of gangliosides GM2 and GM1 in such Golgi vesicles is, in the absence of any detergents, stimulated 6- and 20-fold, respectively, by phosphatidylglycerol. Other phospholipids like dolichyl phosphate, phosphatidylethanolamine and phosphatidylserine are also significantly stimulatory. Tunicamycin inhibits the synthesis of gangliosides GM2 and GM1 in isolated Golgi vesicles, but only in the absence of detergents. The dependence on phosphatidylglycerol and the degree of inhibition by tunicamycin of the synthetic activities are strictly dependent on the intactness of the Golgi vesicles: both phenomena become increasingly less evident when the vesicles are pelleted, and frozen and thawed several times, and completely disappear when the vesicles are solubilized by the detergents or disrupted by ultrasonication. Furthermore, tunicamycin inhibition is reversible by increased concentration of phosphatidylglycerol. In pronase-treated Golgi vesicles, which retain full enzyme activity, both phospholipid-dependence and tunicamycin inhibition of the synthetic activity disappear completely. When freshly prepared Golgi vesicles are incubated with 125 microM UDP [3H]Gal for 10 min at 30 degrees C, the nucleotide sugar is found to be transported into the vesicles at the rate of about 85 pmoles/mg protein/min, 92% of radiolabel remaining firmly bound with membrane. Tunicamycin inhibits this transport in a concentration-dependent manner. The results show that, while the mechanism of phosphatidylglycerol induced stimulation of the synthetic activity remains unclear, tunicamycin inhibits ganglioside biosynthesis by blocking the transport of the nucleotide sugar across Golgi vesicles and not inhibiting the transferase enzyme directly.
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PMID:Ganglioside biosynthesis in rat liver golgi apparatus: stimulation by phosphatidylglycerol and inhibition by tunicamycin. 674 31


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