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Hakon Leffler - One of the best experts on this subject based on the ideXlab platform.
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the β galactoside binding immunomodulatory lectin galectin 3 reverses the desensitized state induced in neutrophils by the chemotactic peptide f met leu phe role of reactive oxygen species generated by the nadph oxidase and inactivation of the agonis
Glycobiology, 2008Co-Authors: Huamei Forsman, Hakon Leffler, Emma Salomonsson, Karin Onnheim, Jennie Karlsson, Ase Bjorstad, Johan Bylund, Anna Karlsson, Claes DahlgrenAbstract:Neutrophils interacting with a chemoattractant gradually become nonresponsive to further stimulation by the same agonist, a process known as desensitization. Receptor desensitization is a highly regulated process that involves different mechanisms depending on which receptor-ligand pair that is studied. Galectin-3, a member of a large family of beta-galactoside-binding lectins, has been suggested to be a regulator of the inflammatory process, augmenting or directly triggering the neutrophil functional repertoire. We show here that the desensitized state of neutrophils interacting with the chemotactic peptide fMLF is broken by galectin-3 and that this is achieved through an oxygen radical-mediated inactivation of the chemoattractant. The effect was inhibited by the competitor lactose and required the affinity of galectin-3 for N-Acetyllactosamine, a saccharide typically found on cell surface glycoproteins. The latter was shown using a galectin-3 mutant that lacked N-Acetyllactosamine binding activity, and this protein was not active. The mechanism behind the inactivation of the chemoattractant was found to depend on the ability of galectin-3 to induce a neutrophil generation/secretion of reactive oxygen species which in combined action with myeloperoxidase inactivated the peptides.
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galectin 1 2 and 3 exhibit differential recognition of sialylated glycans and blood group antigens
Journal of Biological Chemistry, 2008Co-Authors: Sean R Stowell, David F Smith, Hakon Leffler, Connie M Arthur, Padmaja Mehta, Kristen A Slanina, Ola Blixt, Richard D. CummingsAbstract:Human galectins have functionally divergent roles, although most of the members of the galectin family bind weakly to the simple disaccharide lactose (Galβ1-4Glc). To assess the specificity of galectin-glycan interactions in more detail, we explored the binding of several important galectins (Gal-1, Gal-2, and Gal-3) using a dose-response approach toward a glycan microarray containing hundreds of structurally diverse glycans, and we compared these results to binding determinants on cells. All three galectins exhibited differences in glycan binding characteristics. On both the microarray and on cells, Gal-2 and Gal-3 exhibited higher binding than Gal-1 to fucose-containing A and B blood group antigens. Gal-2 exhibited significantly reduced binding to all sialylated glycans, whereas Gal-1 bound α2-3- but not α2-6-sialylated glycans, and Gal-3 bound to some glycans terminating in either α2-3- or α2-6-sialic acid. The effects of sialylation on Gal-1, Gal-2, and Gal-3 binding to cells also reflected differences in cellular sensitivity to Gal-1-, Gal-2-, and Gal-3-induced phosphatidylserine exposure. Each galectin exhibited higher binding for glycans with poly-N-Acetyllactosamine (poly(LacNAc)) sequences (Galβ1-4GlcNAc)n when compared with N-Acetyllactosamine (LacNAc) glycans (Galβ1-4GlcNAc). However, only Gal-3 bound internal LacNAc within poly(LacNAc). These results demonstrate that each of these galectins mechanistically differ in their binding to glycans on the microarrays and that these differences are reflected in the determinants required for cell binding and signaling. The specific glycan recognition by each galectin underscores the basis for differences in their biological activities.
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galectin 1 2 and 3 exhibit differential recognition of sialylated glycans and blood group antigens
Journal of Biological Chemistry, 2008Co-Authors: Sean R Stowell, David F Smith, Hakon Leffler, Connie M Arthur, Padmaja Mehta, Kristen A Slanina, Ola Blixt, Richard D. CummingsAbstract:Human galectins have functionally divergent roles, although most of the members of the galectin family bind weakly to the simple disaccharide lactose (Galbeta1-4Glc). To assess the specificity of galectin-glycan interactions in more detail, we explored the binding of several important galectins (Gal-1, Gal-2, and Gal-3) using a dose-response approach toward a glycan microarray containing hundreds of structurally diverse glycans, and we compared these results to binding determinants on cells. All three galectins exhibited differences in glycan binding characteristics. On both the microarray and on cells, Gal-2 and Gal-3 exhibited higher binding than Gal-1 to fucose-containing A and B blood group antigens. Gal-2 exhibited significantly reduced binding to all sialylated glycans, whereas Gal-1 bound alpha2-3- but not alpha2-6-sialylated glycans, and Gal-3 bound to some glycans terminating in either alpha2-3- or alpha2-6-sialic acid. The effects of sialylation on Gal-1, Gal-2, and Gal-3 binding to cells also reflected differences in cellular sensitivity to Gal-1-, Gal-2-, and Gal-3-induced phosphatidylserine exposure. Each galectin exhibited higher binding for glycans with poly-N-Acetyllactosamine (poly(LacNAc)) sequences (Galbeta1-4GlcNAc)(n) when compared with N-Acetyllactosamine (LacNAc) glycans (Galbeta1-4GlcNAc). However, only Gal-3 bound internal LacNAc within poly(LacNAc). These results demonstrate that each of these galectins mechanistically differ in their binding to glycans on the microarrays and that these differences are reflected in the determinants required for cell binding and signaling. The specific glycan recognition by each galectin underscores the basis for differences in their biological activities.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
ChemInform, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-beta-D-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 microM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-β-d-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 μM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
Ulf J Nilsson - One of the best experts on this subject based on the ideXlab platform.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
ChemInform, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-beta-D-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 microM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-β-d-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 μM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
Richard D. Cummings - One of the best experts on this subject based on the ideXlab platform.
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galectin 1 2 and 3 exhibit differential recognition of sialylated glycans and blood group antigens
Journal of Biological Chemistry, 2008Co-Authors: Sean R Stowell, David F Smith, Hakon Leffler, Connie M Arthur, Padmaja Mehta, Kristen A Slanina, Ola Blixt, Richard D. CummingsAbstract:Human galectins have functionally divergent roles, although most of the members of the galectin family bind weakly to the simple disaccharide lactose (Galβ1-4Glc). To assess the specificity of galectin-glycan interactions in more detail, we explored the binding of several important galectins (Gal-1, Gal-2, and Gal-3) using a dose-response approach toward a glycan microarray containing hundreds of structurally diverse glycans, and we compared these results to binding determinants on cells. All three galectins exhibited differences in glycan binding characteristics. On both the microarray and on cells, Gal-2 and Gal-3 exhibited higher binding than Gal-1 to fucose-containing A and B blood group antigens. Gal-2 exhibited significantly reduced binding to all sialylated glycans, whereas Gal-1 bound α2-3- but not α2-6-sialylated glycans, and Gal-3 bound to some glycans terminating in either α2-3- or α2-6-sialic acid. The effects of sialylation on Gal-1, Gal-2, and Gal-3 binding to cells also reflected differences in cellular sensitivity to Gal-1-, Gal-2-, and Gal-3-induced phosphatidylserine exposure. Each galectin exhibited higher binding for glycans with poly-N-Acetyllactosamine (poly(LacNAc)) sequences (Galβ1-4GlcNAc)n when compared with N-Acetyllactosamine (LacNAc) glycans (Galβ1-4GlcNAc). However, only Gal-3 bound internal LacNAc within poly(LacNAc). These results demonstrate that each of these galectins mechanistically differ in their binding to glycans on the microarrays and that these differences are reflected in the determinants required for cell binding and signaling. The specific glycan recognition by each galectin underscores the basis for differences in their biological activities.
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galectin 1 2 and 3 exhibit differential recognition of sialylated glycans and blood group antigens
Journal of Biological Chemistry, 2008Co-Authors: Sean R Stowell, David F Smith, Hakon Leffler, Connie M Arthur, Padmaja Mehta, Kristen A Slanina, Ola Blixt, Richard D. CummingsAbstract:Human galectins have functionally divergent roles, although most of the members of the galectin family bind weakly to the simple disaccharide lactose (Galbeta1-4Glc). To assess the specificity of galectin-glycan interactions in more detail, we explored the binding of several important galectins (Gal-1, Gal-2, and Gal-3) using a dose-response approach toward a glycan microarray containing hundreds of structurally diverse glycans, and we compared these results to binding determinants on cells. All three galectins exhibited differences in glycan binding characteristics. On both the microarray and on cells, Gal-2 and Gal-3 exhibited higher binding than Gal-1 to fucose-containing A and B blood group antigens. Gal-2 exhibited significantly reduced binding to all sialylated glycans, whereas Gal-1 bound alpha2-3- but not alpha2-6-sialylated glycans, and Gal-3 bound to some glycans terminating in either alpha2-3- or alpha2-6-sialic acid. The effects of sialylation on Gal-1, Gal-2, and Gal-3 binding to cells also reflected differences in cellular sensitivity to Gal-1-, Gal-2-, and Gal-3-induced phosphatidylserine exposure. Each galectin exhibited higher binding for glycans with poly-N-Acetyllactosamine (poly(LacNAc)) sequences (Galbeta1-4GlcNAc)(n) when compared with N-Acetyllactosamine (LacNAc) glycans (Galbeta1-4GlcNAc). However, only Gal-3 bound internal LacNAc within poly(LacNAc). These results demonstrate that each of these galectins mechanistically differ in their binding to glycans on the microarrays and that these differences are reflected in the determinants required for cell binding and signaling. The specific glycan recognition by each galectin underscores the basis for differences in their biological activities.
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thermodynamics of carbohydrate binding to galectin 1 from chinese hamster ovary cells and two mutants a comparison with four galactose specific plant lectins
Biochemistry, 1996Co-Authors: Dipti Gupta, Richard D. Cummings, C F BrewerAbstract:The thermodynamics of carbohydrate binding to the 14 kDa dimeric β-galactoside-binding lectin galectin-1 (Gal-1) from Chinese hamster ovary cells and four galactose-specific plant lectins were investigated by isothermal titration microcalorimetry. Recombinant Gal-1 from Escherichia coli, a Cys→Ser mutant with enhanced stability (C2S-Gal-1), and a monomeric mutant of the lectin (N-Gal-1) were studied along with the soybean agglutinin and the lectins from Erythrina indica, Erythrina crystagalli, and Erythrina corollodendrum. Although the pattern of association constants of the Erythrina lectins was similar for mono- and disaccharides, variations exist in their enthalpy of binding (−ΔH) values for individual carbohydrates. While the Erythrina lectins show greater affinities and −ΔH values for lactose and N-Acetyllactosamine, the soybean agglutinin possesses similar affinities for methyl β-galactopyranoside, lactose, and N-Acetyllactosamine and a greater −ΔH value for the monosaccharide. Gal-1 and the plant l...
Bader A Salameh - One of the best experts on this subject based on the ideXlab platform.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
ChemInform, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-beta-D-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 microM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
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3 1 2 3 triazol 1 yl 1 thio galactosides as small efficient and hydrolytically stable inhibitors of galectin 3
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Bader A Salameh, Hakon Leffler, Ulf J NilssonAbstract:Copper(I)-catalyzed addition of alkynes to methyl 3-azido-3-deoxy-1-thio-β-d-galactopyranoside afforded stable and structurally simple 3-deoxy-3-(1H-1,2,3-triazol-1-yl)-1-thio-galactosides carrying a panel of substituents at the triazole C4 in high yields. The 3-(1H-[1,2,3]-triazol-1-yl)-1-thio-galactoside collection synthesized contained inhibitors of the tumor- and inflammation-related galectin-3 with Kd values as low as 107 μM, which is as potent as the natural disaccharide inhibitors lactose and N-Acetyllactosamine.
Minoru Fukuda - One of the best experts on this subject based on the ideXlab platform.
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poly n acetyllactosamine extension in n glycans and core 2 and core 4 branched o glycans is differentially controlled by i extension enzyme and different members of the beta 1 4 galactosyltransferase gene family
Journal of Biological Chemistry, 2000Co-Authors: Minoru Ujita, Joseph Mcauliffe, Ole Hindsgaul, Anup Kumar Misra, Minoru FukudaAbstract:Poly-N-Acetyllactosamines are attached to N-glycans, O-glycans, and glycolipids and serve as underlying glycans that provide functional oligosaccharides such as sialyl Lewis(X). Poly-N-acetyllactosaminyl repeats are synthesized by the alternate addition of beta1,3-linked GlcNAc and beta1,4-linked Gal by i-extension enzyme (iGnT) and a member of the beta1,4-galactosyltransferase (beta4Gal-T) gene family. In the present study, we first found that poly-N-Acetyllactosamines in N-glycans are most efficiently synthesized by beta4Gal-TI and iGnT. We also found that iGnT acts less efficiently on acceptors containing increasing numbers of N-Acetyllactosamine repeats, in contrast to beta4Gal-TI, which exhibits no significant change. In O-glycan biosynthesis, N-Acetyllactosamine extension of core 4 branches was found to be synthesized most efficiently by iGnT and beta4Gal-TI, in contrast to core 2 branch synthesis, which requires iGnT and beta4Gal-TIV. Poly-N-Acetyllactosamine extension of core 4 branches is, however, less efficient than that of N-glycans or core 2 branches. Such inefficiency is apparently due to competition between a donor substrate and acceptor in both galactosylation and N-acetylglucosaminylation, since a core 4-branched acceptor contains both Gal and GlcNAc terminals. These results, taken together, indicate that poly-N-Acetyllactosamine synthesis in N-glycans and core 2- and core 4-branched O-glycans is achieved by iGnT and distinct members of the beta4Gal-T gene family. The results also exemplify intricate interactions between acceptors and specific glycosyltransferases, which play important roles in how poly-N-Acetyllactosamines are synthesized in different acceptor molecules.
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synthesis of poly n acetyllactosamine in core 2 branched o glycans the requirement of novel β 1 4 galactosyltransferase iv and β 1 3 n acetylglucosaminyltransferase
Journal of Biological Chemistry, 1998Co-Authors: Minoru Ujita, Joseph Mcauliffe, Tilo Schwientek, Ole Hindsgaul, Raquel Almeida, Henrik Clausen, Minoru FukudaAbstract:Abstract Poly-N-Acetyllactosamine is a unique carbohydrate composed of N-Acetyllactosamine repeats and provides the backbone structure for additional modifications such as sialyl Lex. Poly-N-Acetyllactosamines in mucin-type O-glycans can be formed in core 2 branched oligosaccharides, which are synthesized by core 2 β-1,6-N-acetylglucosaminyltransferase. Using a β-1,4-galactosyltransferase (β4Gal-TI) present in milk and the recently cloned β-1,3-N-acetylglucosaminyltransferase, the formation of poly-N-Acetyllactosamine was found to be extremely inefficient starting from a core 2 branched oligosaccharide, GlcNAcβ1→6(Galβ1→3)GalNAcα→R. Since the majority of synthesized oligosaccharides containedN-acetylglucosamine at the nonreducing ends, galactosylation was judged to be inefficient, prompting us to test novel members of the β4Gal-T gene family for this synthesis. Using various synthetic acceptors and recombinant β4Gal-Ts, β4Gal-TIV was found to be most efficient in the addition of a single galactose residue to GlcNAcβ1→6(Galβ1→3)GalNAcα→R. Moreover, β4Gal-TIV, together with β-1,3-N-acetylglucosaminyltransferase, was capable of synthesizing poly-N-Acetyllactosamine in core 2 branched oligosaccharides. On the other hand, β4Gal-TI was found to be most efficient for poly-N-Acetyllactosamine synthesis inN-glycans. In contrast to β4Gal-TI, the efficiency of β4Gal-TIV decreased dramatically as the acceptors contained moreN-Acetyllactosamine repeats, consistent with the fact that core 2 branched O-glycans contain fewer and shorter poly-N-Acetyllactosamines than N-glycans in many cells. These results, as a whole, indicate that β4Gal-TIV is responsible for poly-N-Acetyllactosamine synthesis in core 2 branched O-glycans.
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expression cloning of cdna encoding a human β 1 3 n acetylglucosaminyltransferase that is essential for poly n acetyllactosamine synthesis
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Katsutoshi Sasaki, Minoru Ujita, Tatsunari Nishi, Kazumi Kuratamiura, Kiyohiko Angata, Satoshi Nakagawa, Susumu Sekine, Minoru FukudaAbstract:Abstract The structure and biosynthesis of poly-N-Acetyllactosamine display a dramatic change during development and oncogenesis. Poly-N-Acetyllactosamines are also modified by various carbohydrate residues, forming functional oligosaccharides such as sialyl Lex. Herein we describe the isolation and functional expression of a cDNA encoding β-1,3-N-acetylglucosaminyltransferase (iGnT), an enzyme that is essential for the formation of poly-N-Acetyllactosamine. For this expression cloning, Burkitt lymphoma Namalwa KJM-1 cells were transfected with cDNA libraries derived from human melanoma and colon carcinoma cells. Transfected Namalwa cells overexpressing the i antigen were continuously selected by fluorescence-activated cell sorting because introduced plasmids containing Epstein–Barr virus replication origin can be continuously amplified as episomes. Sibling selection of plasmids recovered after the third consecutive sorting resulted in a cDNA clone that directs the increased expression of i antigen on the cell surface. The deduced amino acid sequence indicates that this protein has a type II membrane protein topology found in almost all mammalian glycosyltransferases cloned to date. iGnT, however, differs in having the longest transmembrane domain among glycosyltransferases cloned so far. The iGnT transcript is highly expressed in fetal brain and kidney and adult brain but expressed ubiquitously in various adult tissues. The expression of the presumed catalytic domain as a fusion protein with the IgG binding domain of protein A enabled us to demonstrate that the cDNA encodes iGnT, the enzyme responsible for the formation of GlcNAcβ1 → 3Galβ1 → 4GlcNAc → R structure and poly-N-Acetyllactosamine extension.
