Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.99.6 (sialyltransferase)
 1,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human diploid fibroblastic cell line, TIG-3, has a finite life span of about 80 population doubling levels (PDL), and is used for in vitro aging studies. Young cells (PDL 23) grew to higher cell densities at a higher growth rate than aged cells (PDL 77). When the electrophoretic mobility of cells was determined, the negative surface charge of the aged cells decreased significantly when compared to that of young cells. Lectin blot analysis of membrane glycoproteins showed that the alpha-2-6-sialylation but not the alpha-2-3-sialylation of N-glycans decreases markedly in the aged cells when compared to the young cells. In support of this observation, the cDNA microarray assay and reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the gene expression of the alpha-2,6-sialyltransferase I (ST6Gal I), which transfers sialic acid to galactose residues of N-glycans, decreases in the aged cells. These results indicate that the concordant decrease of the alpha-2,6-sialylation of N-glycans with the ST6Gal I gene expression is induced in TIG-3 cells by in vitro aging.
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PMID:Preferential reduction of the alpha-2-6-sialylation from cell surface N-glycans of human diploid fibroblastic cells by in vitro aging. 1689 85

The addition of sialic acid to glycoproteins and glycolipids requires Golgi sialyltransferases to have access to their glycoconjugate substrates and nucleotide sugar donor, CMP-sialic acid. CMP-sialic acid is transported into the lumen of the Golgi complex through the CMP-sialic acid transporter, an antiporter that also functions to transport CMP into the cytosol. We localized the transporter using immunofluorescence and deconvolution microscopy to test the prediction that it is broadly distributed across the Golgi stack to serve the many sialyltransferases involved in glycoconjugate sialylation. The transporter co-localized with ST6GalI in the medial and trans Golgi, showed partial overlap with a medial Golgi marker and little overlap with early Golgi or trans Golgi network markers. Endoplasmic reticulum-retained forms of sialyltransferases did not redistribute the transporter from the Golgi to the endoplasmic reticulum, suggesting that transporter-sialyltransferase complexes are not involved in transporter localization. Next we evaluated the role of the transporter's N- and C-terminal cytoplasmic tails in its trafficking and localization. The N-tail was not required for either endoplasmic reticulum export or Golgi localization. The C-tail was required for endoplasmic reticulum export and contained di-Ile and terminal Val motifs at its very C terminus that function as independent endoplasmic reticulum export signals. Deletion of the last four amino acids of the C-tail (IIGV) eliminated these export signals and prevented endoplasmic reticulum export of the transporter. This form of the transporter supplied limited amounts of CMP-sialic acid to Golgi sialyltransferases but was unable to completely rescue the transporter defect of Lec2 Chinese hamster ovary cells.
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PMID:The CMP-sialic acid transporter is localized in the medial-trans Golgi and possesses two specific endoplasmic reticulum export motifs in its carboxyl-terminal cytoplasmic tail. 1692 16

The hemagglutinins of influenza viruses isolated from humans typically prefer binding to sialic acid in an alpha2,6 linkage. Presumably, the virus uses the presence of these receptors on the respiratory tract to gain entrance into the host cell. The ST6Gal I sialyltransferase knock-out mouse lacks the main enzyme necessary for the attachment of alpha2,6 sialic acid to N-linked glycoproteins on the cell surface. Yet even in the absence of detectable alpha2,6 sialic acid in the mouse respiratory tract, human influenza viruses can still infect these mice and grow to similar titers in the lung and trachea as compared to wild-type animals. This work demonstrates that the presence of a major alpha2,6 sialic acid on N-linked glycoproteins is not essential for human influenza virus infection in mice.
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PMID:Effective replication of human influenza viruses in mice lacking a major alpha2,6 sialyltransferase. 1731 86

Structural data on mammalian proteins are often difficult to obtain by conventional NMR approaches because of an inability to produce samples with uniform isotope labeling in bacterial expression hosts. Proteins with sparse isotope labels can be produced in eukaryotic hosts by using isotope-labeled forms of specific amino acids, but structural analysis then requires information from experiments other than nuclear Overhauser effects. One source of alternate structural information is distance-dependent perturbation of spin relaxation times by nitroxide spin-labeled analogs of natural protein ligands. Here, we introduce spin-labeled analogs of sugar nucleotide donors for sialyltransferases, specifically, CMP-TEMPO (CMP-4-O-[2,2,6,6-tetramethylpiperidine-1-oxyl]) and CMP-4carboxyTEMPO (CMP-4-O-[4-carboxy-2,2,6,6-tetramethylpiperidinine-1-oxyl]). An ability to identify resonances from active site residues and produce distance constraints is illustrated on a (15)N phenylalanine-labeled version of the structurally uncharacterized, alpha-2,6-linked sialyltransferase, ST6Gal I.
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PMID:Spin-labeled analogs of CMP-NeuAc as NMR probes of the alpha-2,6-sialyltransferase ST6Gal I. 1746 76

Sialic acids are negatively charged acidic sugars, and sialylglycoconjugates often play important roles in various biological phenomena. Sialyltransferases are involved in the synthesis of sialylglycoconjugates, and 20 members of the mammalian sialyltransferase family have been identified to date. These sialyltransferases are grouped into four families according to the carbohydrate linkages they synthesize: beta-galactoside alpha2,3-sialyltransferases (ST3Gal I-VI), beta-galactoside alpha2,6-sialyltransferases (ST6Gal I and II), GalNAc alpha2,6-sialyltransferases (ST6GalNAc I-VI), and alpha2,8-sialyltransferases (ST8Sia I-VI). Analysis of the amino acid sequence similarities, substrate specificities, and gene structures of mouse sialyltransferases has revealed that they can be further divided into seven subfamilies. The genomic structural resemblance of members of the same subfamily suggests that they arose from a common ancestral gene through gene duplication events. These multiple sialyltransferase genes are needed for fine control of the expression of sialylglycoconjugates, resulting in a variety of developmental stage- and tissue-specific glycosylation patterns.
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PMID:Characterization of mouse sialyltransferase genes: their evolution and diversity. 1846 Jul 88

Thymocyte development is accompanied by sequential changes in cell surface glycosylation. For example, medullary thymocytes have increased levels of alpha2,3-linked sialic acid and a loss of asialo core 1 O-glycans as compared to cortical thymocytes. Some of these changes have been linked to fine tuning of the T cell receptor avidity. We analyzed ST6Gal I transcript abundance and levels of alpha2,6-linked sialic acid across thymocyte subsets. We found that ST6Gal I transcript levels increased following T cell receptor beta-selection suggesting that this sialyltransferase may influence the development of early thymocyte populations. Indeed, low levels of alpha2,6-linked sialic acid were found in the earliest T lineage cells, and then increased in T cell receptor beta-selected cells. To determine whether ST6Gal I influences T cell development, we analyzed ST6Gal I-deficient mice for disruptions in thymocyte populations. We found reduced thymic cellularity in the ST6Gal I-deficient mice starting in the early thymocyte compartments.
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PMID:Disruption of thymopoiesis in ST6Gal I-deficient mice. 1853 87

Previously, we identified beta-galactoside alpha(2,6)-sialyltransferase (ST6Gal I) as a candidate biomarker for ionizing radiation. The expression of ST6Gal I and the level of protein sialylation increased following radiation exposure in a dose-dependent manner. Radiation induced ST6Gal I cleavage and the cleaved form of ST6Gal I was soluble and secreted. Sialylation of integrin beta1, a glycosylated cell surface protein, was stimulated by radiation exposure and this increased its stability. Overexpression of ST6Gal I in SW480 colon cancer cells that initially showed a low level of ST6Gal I expression increased the sialylation of integrin beta1 and also increased the stability of the protein. Inhibition of sialylation by transfection with neuraminidase 2 or neuraminidase 3 or by treatment with short interfering RNA targeting ST6Gal I reversed the effects of ST6Gal I overexpression. In addition, ST6Gal I overexpression increased clonogenic survival following radiation exposure and reduced radiation-induced cell death and caspase 3 activation. However, removal of sialic acids by neuraminidase 2 or knockdown of expression by short interfering RNA targeting ST6Gal I restored radiation-induced cell death phenotypes. In conclusion, radiation exposure was found to increase the sialylation of glycoproteins such as integrin beta1 by inducing the expression of ST6Gal I, and increased protein sialylation contributed to cellular radiation resistance.
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PMID:Protein sialylation by sialyltransferase involves radiation resistance. 1870 63

Hepatic steatosis and steatohepatitis are frequent results of long-term ethanol exposure. We have previously demonstrated that long-term ethanol down-regulates Galbetal, 4GlcNAc alpha2, 6-sialyltransferase (ST6Gal1), leading to defective glycosylation of a number of proteins including apolipoprotein (apo) E and apo J and the appearance of asialoconjugates in the blood of continuously alcohol-fed animals as well as in human alcoholics. In the current study, we have explored the possibility of whether ethanol-induced down-regulation of ST6Gal1 could contribute toward alcoholic steatosis in human alcoholics presumably because of impaired lipid and lipoprotein transport caused by this down-regulation. Real-time quantitative polymerase chain reaction analyses of liver samples from nondrinkers, moderate drinkers, and heavy drinkers as well as from subjects with and without alcoholic liver disease revealed direct evidence that the down-regulation of ST6Gal1 may be due to ethanol per se. The ST6Gal1 messenger RNA level was reduced by as much as 70% in moderate and heavy drinkers as well as in patients with alcoholic liver disease, but was not changed in subjects with liver disease due to causes other than alcohol exposure. Biochemical and histopathologic analysis demonstrated that the liver total cholesterol was increased by more than 30% (P < .05) and 75% (P < .01), respectively, in moderate and heavy drinkers compared with nondrinkers, with even more dramatic changes in triglyceride levels. Significantly, there was a strong inverse correlation between ST6Gal1 messenger RNA level and liver lipid deposit (F = 8.68, P < .001) by statistical analysis. Thus, it is suggested that alcohol-mediated down-regulation of hepatic ST6Gal1 gene leads to defective glycosylation of lipid-carrying apolipoproteins such as apo E and apo J, resulting in defective intracellular lipid and lipoprotein transport, which in turn may contribute to alcoholic steatosis.
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PMID:Down-regulation of liver Galbeta1, 4GlcNAc alpha2, 6-sialyltransferase gene by ethanol significantly correlates with alcoholic steatosis in humans. 1901 88

Previous reports, including our work, have shown that plasma beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) activity is significantly increased in particular hepatopathological situations, suggesting that it may represent a sensitive biomarker for diagnosing hepatic diseases. So far, activity of ST6Gal I have been measured by using radioactive tracer method in place of measuring amount of ST6Gal I. However, this method is tangled and cannot exclude other sialyltransferase activities. Thus, simple and specific methods for measuring plasma ST6Gal I had been unavailable. Here, we developed two kinds of sandwich enzyme-linked immunosorbent assay (ELISA) systems that specifically detect the soluble cleaved form of ST6Gal I in plasma. In one sandwich ELISA, we detected rat specific sequence, EFQMPK, which is N-terminus of soluble ST6Gal I. In the other sandwich ELISA, we detected internal common sequence among rat, mouse and human ST6Gal I in plasma (M2 ELISA). Using the M2 ELISA, we observed that elevation of plasma ST6Gal I was much faster than elevation of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in a carbon tetrachloride (CCl(4))-induced mouse liver injury model. Our data suggest that these ELISA systems are very useful tools for measuring plasma ST6Gal I, which represents a potential biomarker for diagnosing hepatic diseases.
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PMID:Development of sandwich enzyme-linked immunosorbent assay systems for plasma beta-galactoside alpha2,6-sialyltransferase, a possible hepatic disease biomarker. 1904 88

Cell surface glycosylation patterns are markers of cell type and status. However, the mechanisms regulating surface glycosylation patterns remain unknown. Using a panel of carbohydrate markers, we have shown that cell surface sialylation and fucosylation are upregulated in L1-transfected embryonic stem cells (L1-ESCs). Consistently, the mRNA levels of sialyltransferase ST6Gal1 and ST3Gal4, and fucosyltransferase FUT9 were significantly increased in L1-transfected ESCs. Activation of L1 signaling promoted cell survival and inhibited cell proliferation. ShRNAs knocking down FUT9, ST6Gal1 and ST3Gal4 blocked these effects. A phospholipase Cgamma (PLCgamma) inhibitor and shRNA reduced ST6Gal1, ST3Gal4 and FUT9 mRNA levels in the L1-ESCs. Thus, embryonic stem cell surface sialylation and fucosylation are regulated via PLCgamma by L1, with which they cooperate to modulate cell survival and proliferation.
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PMID:Cell surface sialylation and fucosylation are regulated by the cell recognition molecule L1 via PLCgamma and cooperate to modulate embryonic stem cell survival and proliferation. 1916 42


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