Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.99.6 (sialyltransferase)
1,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Keto-3-deoxy-D- glycero -D- galacto -nononic acid (KDN) was introduced into asialotransferrin and N -acetyllactosamine (LacNAc) from CMP-KDN by using rat liver Galbeta1-->4GlcNAc alpha2, 6-sialyltransferase to form KDN-transferrin and KDN-LacNAc. These structures contain terminal KDNalpha2-->6Gal-residues, a glycotope that has not yet been described in natural glycoconjugates. KDN was transferred to all four Gal residues in asialotransferrin by this enzyme. The incorporation efficiency of KDN from CMP-KDN into asialotransferrin was about half that of Neu5Ac from CMP-Neu5Ac, based on the V max/ K m values for these donor substrates, 0.0527 min-1and 0.119 min-1, respectively. The KDNalpha2-->6Gal linkage was resistant to exosialidase treatment, in contrast to the sensitivity of the Neu5Acalpha2-->6Gal linkage. Interestingly, Sambucus sieboldiana agglutinin (SSA) was shown to prefer KDN-transferrin to the corresponding Neu5Ac-transferrin, as estimated by slot-blot analysis. The use of an alpha2,6-sialyltransferase to synthesize neoglycoproteins containing KDN has not been previously reported. Their facile synthesis using CMP-KDN and sialyltransferases with different specificities offers new possibilities to study the function of neo-KDN-glycoconjugates, and to explore their use in glycotechnology.
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PMID:Synthesis of neoglycoconjugates containing deaminated neuraminic acid (KDN) using rat liver alpha2,6-sialyltransferase. 945 Oct 37

We have previously shown that chronic ethanol treatment impairs the glycosylation of proteins in the rat liver. Changes in the microheterogeneity of transferrin, a N-sialoprotein under chronic alcohol consumption are well established. Apolipoprotein J, another N-glycoprotein, is a normal component of plasma high-density lipoproteins in the rat and human. Apo J is also highly sialylated and, thus, may be vulnerable to the deleterious actions of ethanol. Therefore, to understand the specific nature of alterations of Apo J sialylation as a consequence of chronic ethanol treatment, we have determined: (1) the sialylation index of Apo J (moles sialic acid per mole Apo J protein) in rats administered ethanol for 4, 6, and 8 weeks and a gradual withdrawal and a follow-up abstinence for 1, 2, and 4 weeks; and (2) enzymatic activities of hepatic sialyltransferase and plasma sialidase during the same periods of alcohol treatment and abstinence in rats. Although no significant differences in the Apo J sialylation index between rats of the control and ethanol groups were found at the 4th week of alcohol treatment, a highly significant loss of 24% (p < 0.001) and 44% (p < 0.001) was found after 6 and 8 weeks, respectively, of alcohol feeding of these animals. Furthermore, a significant recovery of 38% (p < 0.001), 78% (p < 0.001), 84% (p < 0.001) and 96% (p < 0.001) in the sialylation index of Apo J were found, respectively, during withdrawal and 1, 2, and 4 weeks of subsequent alcohol abstinence in these animals. These changes in the sialic acid content of Apo J were accompanied by a similar pattern of changes in the enzyme activities of hepatic sialyltransferase and plasma sialidase in animals undergoing chronic ethanol treatment, withdrawal, and abstinence periods. The analysis of the sialylation index of Apo J seems to be a simple and feasible method to use to evaluate the extent of ethanol exposure.
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PMID:Long-term ethanol exposure alters the sialylation index of plasma apolipoprotein J (Apo J) in rats. 1023 9

Chronic alcohol exposure leads to the appearance of carbohydrate-deficient transferrin (CDT), a N-glycosylated protein and sialic acid-deficient apolipoprotein E (apoE), an O-glycosylated protein. We show that chronic ethanol treatment destabilizes sialyltransferase (ST) mRNA resulting in a concomitant decreased steady-state level of ST mRNA. As a result, alcohol markedly decreases the hepatic synthetic rate of ST. This leads to impaired sialylation of transferrin and apoE. Consequently, apoE content in plasma high-density lipoproteins (HDL) is decreased. ApoE plays a significant role in the delivery of HDL cholesterol to the liver via apo B/E receptor, a process called reverse cholesterol transport (RCT). Desialylation of apoE results in its decreased association with HDL. Thus, the dissociation constant of HDL for binding to sialo-apoE is 90 +/- 35 nM, whereas that for desialo-apoE is 1010 +/- 250 nM. More importantly, the uptake of labeled cholesterol by human HepG2 cells is decreased by 30-40% from reconstituted HDL particles (rHDL)-containing desialo-apoE compared to rHDL with sialo-apoE. We conclude that chronic alcohol exposure down-regulates the expression of sialyltransferase genes resulting in impaired sialylation of apoE. This leads to its decreased binding to plasma HDL and thereby, impairs the RCT function of HDL.
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PMID:Alcohol and molecular regulation of protein glycosylation and function. 1058 May 14

Insulin regulates glucose transport in muscle and adipose tissue by triggering the translocation of a facilitative glucose transporter, GLUT4, from an intracellular compartment to the cell surface. It has previously been suggested that GLUT4 is segregated between endosomes, the trans-Golgi network (TGN), and a postendosomal storage compartment. The aim of the present study was to isolate the GLUT4 storage compartment in order to determine the relationship of this compartment to other organelles, its components, and its presence in different cell types. A crude intracellular membrane fraction was prepared from 3T3-L1 adipocytes and subjected to iodixanol equilibrium sedimentation analysis. Two distinct GLUT4-containing vesicle peaks were resolved by this procedure. The lighter of the two peaks (peak 2) was comprised of two overlapping peaks: peak 2b contained recycling endosomal markers such as the transferrin receptor (TfR), cellubrevin, and Rab4, and peak 2a was enriched in TGN markers (syntaxin 6, the cation-dependent mannose 6-phosphate receptor, sortilin, and sialyltransferase). Peak 1 contained a significant proportion of GLUT4 with a smaller but significant amount of cellubrevin and relatively little TfR. In agreement with these data, internalized transferrin (Tf) accumulated in peak 2 but not peak 1. There was a quantitatively greater loss of GLUT4 from peak 1 than from peak 2 in response to insulin stimulation. These data, combined with the observation that GLUT4 became more sensitive to ablation with Tf-horseradish peroxidase following insulin treatment, suggest that the vesicles enriched in peak 1 are highly insulin responsive. Iodixanol gradient analysis of membranes isolated from other cell types indicated that a substantial proportion of GLUT4 was targeted to peak 1 in skeletal muscle, whereas in CHO cells most of the GLUT4 was targeted to peak 2. These results indicate that in insulin-sensitive cells GLUT4 is targeted to a subpopulation of vesicles that appear, based on their protein composition, to be a derivative of the endosome. We suggest that the biogenesis of this compartment may mediate withdrawal of GLUT4 from the recycling system and provide the basis for the marked insulin responsiveness of GLUT4 that is unique to muscle and adipocytes.
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PMID:Characterization of insulin-responsive GLUT4 storage vesicles isolated from 3T3-L1 adipocytes. 1059 43

Five variants of mouse serum transferrin (mTf, designated mTf-I to mTf-V) with respect to carbohydrate composition have been isolated by DEAE-cellulose chromatography in the following relative percentages: mTf-I: 0.55; mTf-II: 0.79; mTf-III: 71.80; mTf-VI: 21. 90 and mTf-V: 4.96. The primary structures of the major glycans from mTf-III and mTf-IV were determined by methylation analysis and 1H-nuclear magnetic resonance (NMR) spectroscopy. All glycans possessed a common trimannosyl-N,N'-diacetylchitobiose core. From the glycovariant mTf-III two isomers of a conventional biantennary N-acetyllactosamine type were isolated, in which two N-glycolylneuraminic acid (Neu5Gc) residues are linked to galactose either by a (alpha 2-6) or (alpha 2-3) linkage. A subpopulation of this glycovariant contains a fucose residue (alpha 1-6)-linked to GlcNAc-1. The structure of the major glycan found in variant mTf-IV contained an additional Neu5Gc and possessed the following new type of linkage: Neu5Gc(alpha 2-3)Gal(beta 1-3)[Neu5Gc(alpha 2-6)]GlcNAc(beta 1-2 )Man(alpha 1-3). In addition to this glycan, a minor compound contained the same antennae linked to Man(alpha 1-6). In fraction mTf-V, which was found to be very heterogeneous by (1)H NMR analysis, carbohydrate composition and methylation analysis suggested the presence of tri'-antennary glycans sialylated by Neu5Gc alpha-2,6- and alpha-2, 3-linked to the terminal galactose residues. In summary, mTf glycans differed from those of other analyzed mammalian transferrins by the presence of Neu5Gc and by a Neu5Gc(alpha 2-6)GlcNAc linkage in trisialylated biantennary structures, reflecting in mouse liver, a high activity of CMP-Neu5Ac hydroxylase and (alpha 2-6)GlcNAc sialyltransferase.
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PMID:Structural analysis of trisialylated biantennary glycans isolated from mouse serum transferrin. Characterization of the sequence Neu5Gc(alpha 2-3)Gal(beta 1-3)[Neu5Gc(alpha 2-6)]GlcNAc(beta 1-2)Man. 1091 32

The science of antiviral research was well advanced when HIV/AIDS appeared as a major new virus disease in the early 1980s. The first effective antiviral compound (AZT, azidothymidine, zidovudine) was already among the library of compounds screened and was promptly reported to be a specific inhibitor of retroviruses, including HIV. Due to the pivotal role of AZT in HIV treatment, this review summarizes the most known effects -some of which are toxic side effects- induced by AZT a drug which is still used in the combined therapy of HIV-infected patients. Among the toxic side effects, a severe bone marrow toxicity manifested as anemia, neutropenia and siderosis, and caused by inhibition of heme and globin synthesis together with a general derangement of iron supply, have been reported. In this regard, we proved that while AZT and its monophosphorylated derivative AZTMP were unable to chelate iron, the triphosphate form AZTTP displayed a significant capacity to remove iron from transferrin. Moreover, we have previously demonstrated that AZT-exposed K562 cells showed an increase of transferrin receptors located on the cell membrane without affecting their biosynthesis, but slowing down their endocytotic pathway. Interestingly, literature data report the impairement of glycosylation reactions by AZT. Indeed, we have shown that AZT-treated K562 cells exhibited a reduced sialylation of proteins and lipids, and a strong inhibition of alpha,(2-->8) sialyltransferase activity while beta,(1-->4)galactosyltransferase and beta-galactosidase activities were significantly increased. These latter observations could be of clinical relevance since alterations of intracellular and cell surface carbohydrate expression and composition, often are associated with several diseases. However, contrarily to previous reports by other authors on AZT as an inhibitor of plant and bacterial toxins activity, we have demonstrated that AZT not only did not inhibit saporin toxicity, but even increased the cytotoxic activity of this plant toxin on K562 cells. Furthermore, the review enlightens the potential utilization of AZT as a tool in proteomics since in the recent years several genes responding to this drug have been identified in different cell lines. We have shown, for the first time, an over-expression of two proteins (PDI-A3 and sthatmin), and a full repression of two others (HSP-60 and SOD1) in AZT-exposed K562 cells. At present, we are investigating if the above reported alterations are a general feature of AZT-treatment of cultured cells, or they represent a peculiar characteristic of a specific cell line. Finally, the paper reviews a number of novel methodologies aimed at enhancing the AZT plasma levels and its bioavailability in all human organs in order to improve its therapeutic efficacy against HIV infection. These new possibilities, namely the AZT prodrug strategy, the AZT transdermal delivery and the targeted brain delivery, are yet not in use for humans but they are under experimental studies.
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PMID:AZT: an old drug with new perspectives. 1869 Aug 75

Assessment of influenza virus disease progression and efficacy of antiviral therapy in the widely used mouse models relies mostly on body weight loss and lung virus titers as markers of disease. However, both parameters have their shortcomings. Therefore, the aim of our study was to find non-invasive markers in the murine model of severe influenza that could detect disease early and predict disease outcome. BALB/c mice were lethally infected with influenza A(H1N1)pdm09 virus and serum samples were collected at various time points. Enzyme-linked immunosorbent assays were performed to quantify amounts of serum amyloid A (SAA), C-reactive protein, complement 3, transferrin, corticosterone, prostaglandin E2, H2O2, and alpha-2,6-sialyltransferase. We found that SAA was the most promising candidate with levels acutely and temporarily elevated by several hundred-fold 3 days post virus inoculation. Upon treatment with oseltamivir phosphate, levels of SAA were significantly decreased. High levels of SAA were associated with poor disease prognosis, whereas body weight loss was not as a reliable predictor of disease outcome. SAA levels were also transiently increased in BALB/c mice infected with influenza A(H3N2) and influenza B virus, as well as in C57BL/2, Swiss-Webster, and DBA.2 mice infected with influenza A(H1N1)pdm09 virus. High levels of SAA often, but not always, were associated with disease outcome in these other influenza virus mouse models. Therefore, SAA represents a valid biomarker for influenza disease detection in all tested mouse strains but its prognostic value is limited to BALB/c mice infected with influenza A(H1N1)pdm09 virus.
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PMID:Serum amyloid A (SAA) is an early biomarker of influenza virus disease in BALB/c, C57BL/2, Swiss-Webster, and DBA.2 mice. 2752 92


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