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Kazuyuki Sugahara - One of the best experts on this subject based on the ideXlab platform.
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Development of a mouse monoclonal antibody against the chondroitin sulfate-protein linkage region derived from Shark Cartilage
Glycoconjugate Journal, 2010Co-Authors: Chizuru Akatsu, Shuhei Yamada, Jeanclaude Jacquinet, Duriya Fongmoon, Shuji Mizumoto, Prachya Kongtawelert, Kazuyuki SugaharaAbstract:Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) and heparan sulfate (HS) are synthesized on the tetrasaccharide linkage region, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1- O -Ser, of proteoglycans. The Xyl can be modified by 2- O -phosphate in both CS and HS, whereas the Gal residues can be sulfated at C-4 and/or C-6 in CS but not in HS. To study the roles of these modifications, monoclonal antibodies were developed against linkage glycopeptides of Shark Cartilage CS proteoglycans, and one was characterized in detail. This antibody bound hexa- and pentasaccharide-peptides more strongly than unsaturated tetrasaccharide-peptides with the unnatural fourth sugar residue (unsaturated hexuronic acid), suggesting the importance of the fifth and/or fourth saccharide residue GalNAc-5 and/or GlcA-4. Its reactivity was not affected by treatment with chondro-4-sulfatase or alkaline phosphatase, suggesting that 4- O -sulfate on the Gal residues and 2- O -phosphate on the Xyl residue were not recognized. Treatment with weak alkali to cleave the Xyl-Ser linkage completely abolished the binding activity, suggesting the importance of the peptide moiety of the hexasaccharide-peptide for the binding. Based on the amino acid composition and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analyses, it was revealed that the peptide moiety is composed of four amino acids, Ser, Pro, Gly, and Glu. Furthermore, the antibody stained wild-type CHO cells significantly, but much weakly mutant cells deficient in xylosyl- or galactosyltransferase-I required for the biosynthesis of the linkage region. These results suggest that the antibody recognizes the structure GalNAc(±6- O -sulfate)-GlcA-Gal-Gal-Xyl-Ser-(Pro, Gly, Glu). The antibody will be a useful tool for investigating the significance of the linkage region in the biosynthesis and/or intracellular transport of different GAG chains especially since such tools to study the linkage region are lacking.
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characteristic hexasaccharide sequences in octasaccharides derived from Shark Cartilage chondroitin sulfate d with a neurite outgrowth promoting activity
Journal of Biological Chemistry, 1998Co-Authors: Satomi Nadanaka, Albrecht M Clement, Kimiko Masayama, Andreas Faissner, Kazuyuki SugaharaAbstract:Abstract A mouse brain chondroitin sulfate (CS) proteoglycan, DSD-1-PG, bears the DSD-1 epitope and has neurite outgrowth promoting properties. Shark Cartilage CS-C inhibits the interactions between the DSD-1-specific monoclonal antibody 473HD and the CS chains of the DSD-1-PG, which is expressed on the mouse glial cells (Faissner, A., Clement, A., Lochter, A., Streit, A., Mandl, C., and Schachner, M. (1994) J. Cell Biol. 126, 783–799). On the other hand, several hexasaccharides isolated from commercial Shark Cartilage CS-D, which contains a higher proportion of characteristic D units (GlcUA(2-sulfate)β1–3GalNAc(6-sulfate)) as compared with CS-C, has the A-D tetrasaccharide sequence composed of an A disaccharide unit (GlcUAβ1–3GalNAc(4-sulfate)) and a D disaccharide unit (Nadanaka, S. and Sugahara, K. (1997) Glycobiology 7, 253–263). In this study, the biological activities and the structure of Shark Cartilage CS-D were investigated. CS-D inhibited the interactions between monoclonal antibody 473HD and DSD-1-PG and also promoted neurite outgrowth of embryonic day 18 hippocampal neurons. Eight octasaccharide fractions were isolated from CS-D after partial digestion with bacterial chondroitinase ABC by means of gel filtration chromatography and anion-exchange high performance liquid chromotography to investigate the frequency and the arrangement of the A-D tetrasaccharide unit in the polymer sequence. Structural analysis performed by a combination of enzymatic digestions with 500-MHz 1H NMR spectroscopy demonstrated that the isolated octasaccharides shared the common core structure ΔHexAα1–3GalNAcβ1–4(GlcUAβ1–3GalNAc)3 with four, five, and six sulfate esters at various hydroxyl groups in different combinations. In the structure, ΔHexA and GlcUA represent 4-deoxy-α-l-threo-hex-4-enepyranosyluronic acid and glucuronic acid, respectively. No D-D tetrasaccharide sequence was found, and discrete D disaccharide units were demonstrated exclusively as A-D tetrasaccharide units in either an A-D-A or an A-D-C hexasaccharide sequence in the five octasaccharides that represented about 5.0% (w/w) of the starting polysaccharides (C denotes the disaccharide GlcUAβ1–3GalNAc(6-sulfate)). It remains to be determined whether such characteristic hexasaccharide sequences present in Shark Cartilage CS-D serve as functional domain structures recognized by some protein ligands.
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Characteristic hexasaccharide sequences in octasaccharides derived from Shark Cartilage chondroitin sulfate D with a neurite outgrowth promoting activity
The Journal of biological chemistry, 1998Co-Authors: Satomi Nadanaka, Albrecht M Clement, Kimiko Masayama, Andreas Faissner, Kazuyuki SugaharaAbstract:A mouse brain chondroitin sulfate (CS) proteoglycan, DSD-1-PG, bears the DSD-1 epitope and has neurite outgrowth promoting properties. Shark Cartilage CS-C inhibits the interactions between the DSD-1-specific monoclonal antibody 473HD and the CS chains of the DSD-1-PG, which is expressed on the mouse glial cells (Faissner, A., Clement, A., Lochter, A., Streit, A., Mandl, C., and Schachner, M. (1994) J. Cell Biol. 126, 783-799). On the other hand, several hexasaccharides isolated from commercial Shark Cartilage CS-D, which contains a higher proportion of characteristic D units (GlcUA(2-sulfate)beta1-3GalNAc(6-sulfate)) as compared with CS-C, has the A-D tetrasaccharide sequence composed of an A disaccharide unit (GlcUAbeta1-3GalNAc(4-sulfate)) and a D disaccharide unit (Nadanaka, S. and Sugahara, K. (1997) Glycobiology 7, 253-263). In this study, the biological activities and the structure of Shark Cartilage CS-D were investigated. CS-D inhibited the interactions between monoclonal antibody 473HD and DSD-1-PG and also promoted neurite outgrowth of embryonic day 18 hippocampal neurons. Eight octasaccharide fractions were isolated from CS-D after partial digestion with bacterial chondroitinase ABC by means of gel filtration chromatography and anion-exchange high performance liquid chromotography to investigate the frequency and the arrangement of the A-D tetrasaccharide unit in the polymer sequence. Structural analysis performed by a combination of enzymatic digestions with 500-MHz 1H NMR spectroscopy demonstrated that the isolated octasaccharides shared the common core structure DeltaHexAalpha1-3GalNAcbeta1-4(GlcUAbeta1-3GalNAc)3 with four, five, and six sulfate esters at various hydroxyl groups in different combinations. In the structure, DeltaHexA and GlcUA represent 4-deoxy-alpha-L-threo-hex-4-enepyranosyluronic acid and glucuronic acid, respectively. No D-D tetrasaccharide sequence was found, and discrete D disaccharide units were demonstrated exclusively as A-D tetrasaccharide units in either an A-D-A or an A-D-C hexasaccharide sequence in the five octasaccharides that represented about 5.0% (w/w) of the starting polysaccharides (C denotes the disaccharide GlcUAbeta1-3GalNAc(6-sulfate)). It remains to be determined whether such characteristic hexasaccharide sequences present in Shark Cartilage CS-D serve as functional domain structures recognized by some protein ligands.
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preparation of a series of sulfated tetrasaccharides from Shark Cartilage chondroitin sulfate d using testicular hyaluronidase and structure determination by 500 mhz1h nmr spectroscopy
Glycoconjugate Journal, 1996Co-Authors: Kazuyuki Sugahara, Yukako Tanaka, Shuhei YamadaAbstract:Six tetrasaccharide fractions were isolated from Shark Cartilage chondroitin sulfate D by gel filtration chromatography followed by HPLC on an amine-bound silica column after exhaustive digestion with testicular hyaluronidase. Their structures were determined unambiguously by one- and two-dimensional 500 MHz1H NMR spectroscopy in conjunction with HPLC analysis of chondroitinase AC-II digests of the tetrasaccharides. One fraction was found to contain two tetrasaccharide components. All the seven tetrasaccharides shared the common core structure GlcAβ1-3GalNAcβ1-4GlcAβ1-3GalNAc with various sulfation profiles. Four were disulfated comprising of two monosulfated disaccharide units GlcAβ1-3GalNAc(4-sulfate) and/or GlcAβ1-3GalNAc(6-sulfate), whereas the other three were hitherto unreported trisulfated tetrasaccharides containing a disulfated disaccharide unit GlcA(2-sulfate)β1-3GalNAc(6-sulfate) and a monosulfated disaccharide unit GlcAβ1-3GalNAc(4-or 6-sulfate). These sulfated tetrasaccharides were demonstrated to serve as appropriate acceptor substrates for serum α-N-acetylgalactosaminyltransferase, indicating their usefulness as authentic oligosaccharide substrates or probes for the glycobiology of sulfated glycosaminoglycans.
Richard Béliveau - One of the best experts on this subject based on the ideXlab platform.
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Direct-acting fibrinolytic enzymes in Shark Cartilage extract: potential therapeutic role in vascular disorders.
Thrombosis research, 2005Co-Authors: David Ratel, Denis Gingras, Geneviève Glazier, Mathieu Provençal, Dominique Boivin, Edith Beaulieu, Richard BéliveauAbstract:Fibrinogen and fibrin are molecules with overlapping roles in blood clotting, fibrinolysis, wound healing, inflammation, matrix and cellular interactions and neoplasia. There is currently much interest in the possible use of fibrinolytic agents in human therapeutics. In this study, we report the presence of fibrinolytic activities in Shark Cartilage extract (SCE). In vitro, SCE at 100 microg/ml completely degraded fibrin gel in an aprotinin-insensitive manner, suggesting a non-plasmin molecular nature. SCE was able to cleave all chains of fibrinogen and fibrin and the cleavage was completely inhibited by 1,10-phenanthroline, suggesting an essential role for metalloprotease(s) in this process. Using fibrinogen zymography, we show that SCE contains two plasmin-independent fibrinolytic activities and that these activities are correlated with the presence of 58 and 62 kDa proteases in the extract. SCE-fibrinolytic activities are inhibited by dithiothreitol, suggesting that disulfide bonds are necessary for the protease structure. Finally, using thromboelastography, SCE markedly induced retraction of human platelet-rich plasma (PRP) clot, this process being completely abolished by 1,10-phenanthroline. These data suggest the presence of novel non-plasmin fibrinolytic activities within SCE. This extract may thus represent a potential source of new therapeutic molecules to prevent and treat vaso-occlusive and thromboembolic disorders.
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Shark Cartilage Extracts as Antiangiogenic Agents: Smart Drinks or Bitter Pills?
Cancer and Metastasis Reviews, 2000Co-Authors: Denis Gingras, Alain Renaud, Nathalie Mousseau, Richard BéliveauAbstract:The use of crude Cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of Cartilage. We then presented the properties of Æ-941, a novel standardized water-soluble extract derived from Shark Cartilage that represents less than 5% of the crude Cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. Æ-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer.
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Shark Cartilage extracts as antiangiogenic agents: smart drinks or bitter pills?
Cancer metastasis reviews, 2000Co-Authors: Denis Gingras, Alain Renaud, Nathalie Mousseau, Richard BéliveauAbstract:The use of crude Cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of Cartilage. We then presented the properties of AE-941, a novel standardized water-soluble extract derived from Shark Cartilage that represents less than 5% of the crude Cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. EA-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer.
Jeanclaude Jacquinet - One of the best experts on this subject based on the ideXlab platform.
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Development of a mouse monoclonal antibody against the chondroitin sulfate-protein linkage region derived from Shark Cartilage
Glycoconjugate Journal, 2010Co-Authors: Chizuru Akatsu, Shuhei Yamada, Jeanclaude Jacquinet, Duriya Fongmoon, Shuji Mizumoto, Prachya Kongtawelert, Kazuyuki SugaharaAbstract:Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) and heparan sulfate (HS) are synthesized on the tetrasaccharide linkage region, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1- O -Ser, of proteoglycans. The Xyl can be modified by 2- O -phosphate in both CS and HS, whereas the Gal residues can be sulfated at C-4 and/or C-6 in CS but not in HS. To study the roles of these modifications, monoclonal antibodies were developed against linkage glycopeptides of Shark Cartilage CS proteoglycans, and one was characterized in detail. This antibody bound hexa- and pentasaccharide-peptides more strongly than unsaturated tetrasaccharide-peptides with the unnatural fourth sugar residue (unsaturated hexuronic acid), suggesting the importance of the fifth and/or fourth saccharide residue GalNAc-5 and/or GlcA-4. Its reactivity was not affected by treatment with chondro-4-sulfatase or alkaline phosphatase, suggesting that 4- O -sulfate on the Gal residues and 2- O -phosphate on the Xyl residue were not recognized. Treatment with weak alkali to cleave the Xyl-Ser linkage completely abolished the binding activity, suggesting the importance of the peptide moiety of the hexasaccharide-peptide for the binding. Based on the amino acid composition and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analyses, it was revealed that the peptide moiety is composed of four amino acids, Ser, Pro, Gly, and Glu. Furthermore, the antibody stained wild-type CHO cells significantly, but much weakly mutant cells deficient in xylosyl- or galactosyltransferase-I required for the biosynthesis of the linkage region. These results suggest that the antibody recognizes the structure GalNAc(±6- O -sulfate)-GlcA-Gal-Gal-Xyl-Ser-(Pro, Gly, Glu). The antibody will be a useful tool for investigating the significance of the linkage region in the biosynthesis and/or intracellular transport of different GAG chains especially since such tools to study the linkage region are lacking.
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stereocontrolled total syntheses of Shark Cartilage chondroitin sulfate d related tetra and hexasaccharide methyl glycosides
European Journal of Organic Chemistry, 2002Co-Authors: Nathalie Karst, Jeanclaude JacquinetAbstract:Expeditious and stereocontrolled syntheses of β-D-GlcpA(2SO4)-(1⇄3)-[β-D-GalpNAc(6-SO4)-(1⇄4)-β-D-GlcpA(2-SO4)(1⇄3)]n-β-D-GalpNAc(6-SO4)-(1⇄OMe) (where n = 1 and 2), which represent structural elements of Shark Cartilage chondroitin sulfate D, are reported for the first time. The compounds were obtained from a common key disaccharide donor 15, which was used in an iterative way, and in which the 2-deoxy-2-trichloroacetamido group was used as an efficient stereocontrolling auxiliary. The D-glucuronyl donor 7 was easily prepared from D-glucose, whereas the D-galactosaminyl acceptor 11 was synthesized starting from D-glucosamine precursors. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, 2002)
Afshar Bargahi - One of the best experts on this subject based on the ideXlab platform.
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Effect of Shark Cartilage derived protein on the NK cells activity.
Immunopharmacology and immunotoxicology, 2010Co-Authors: Afshar Bargahi, Zuhair Mohammad Hassan, A. Rabbani, Ladan Langroudi, Shokoofe Noori, Elahe SafariAbstract:Context: Shark Cartilage has been used for its beneficial effects on various diseases. There are evidences, that Shark Cartilage stimulates cellular and humoral immune responses, which makes it an anti-tumor and immunomodulator candidate.Objective: The immunostimulatory effect of Shark Cartilage derived proteins on the cytotoxic activity of natural killer (NK) cells from healthy human peripheral blood mononuclear cells was studied.Material and methods: The Shark Cartilage was extracted and its bioactive proteins were purified using ion-exchange chromatography (DE-52) and sequential fractionation on Amicon ultrafiltration membranes. The effect of each protein fraction on the modulation of cytotoxic activity of NK cells, as effectors, against K562, as target cells, was assayed by enzymatic lactate dehydrogenase test.Results: The most immunostimulatory effect on the cytotoxic activity of NK cells was observed for AR10 fraction, containing proteins with molecular weight of about 14.5 kDa on the reducible disc...
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Angiogenic inhibitor protein fractions derived from Shark Cartilage.
Bioscience reports, 2008Co-Authors: Afshar Bargahi, Azra Rabbani-chadeganiAbstract:Development of therapies based on the growth inhibition of new blood vessels is among the most intensively studied approaches to the treatment of cancer and other angiogenesis-related diseases. Shark Cartilage has been proven to have inhibitory effects on the endothelial cell angiogenesis, metastasis, cell adhesion and MMP (matrix metalloprotease) activity. In the present study, we have used a chromatography-based procedure for the isolation and partial purification of a Shark Cartilage protein fraction containing anti-angiogenesis activity. Proteins were extracted in 4 M guanidinium chloride, followed by sequential anion- and cation-exchange column chromatography. Angiogenesis assays were performed using the rat aortic ring and chick CAM (chorioallantoic membrane) assay models. The results show that the final fraction contains two proteins with molecular masses of 14.7 and 16 kDa. The protein fraction is able to block microvessel sprouting in the collagen-embedded rat aortic ring assay in vitro and inhibition of capillary sprouting in the CAM assay in vivo. It is suggested that these are partially purified anti-angiogenesis proteins, which have further biotechnological or biomedical applications.
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Identification of low-molecular-weight protein (SCP1) from Shark Cartilage with anti-angiogenesis activity and sequence similarity to parvalbumin.
Journal of pharmaceutical and biomedical analysis, 2007Co-Authors: Azra Rabbani-chadegani, Afshar Bargahi, Sayeh Abdossamadi, Marzeih Yousef-masbooghAbstract:Cartilage was considered as a possible natural source of anti-angiogenesis compounds due to its known avascular nature. In this study, a low-molecular-weight protein with an anti-angiogenesis activity was isolated from Shark Cartilage using a mild extraction procedure. The protein was purified to homogeneity by gel filtration and electroelution techniques and its N-terminal amino acid sequence was determined. The purified protein, designated as SCP1, represented a molecular weight of 13.7 kDa, pI of 6.9-7 and its N-terminal sequence revealed sequence similarity to alpha parvalbumin family. The protein inhibited angiogenesis when subjected to microvessel sprouting of collagen-embedded rat aortic ring assay. It is suggested that SCP1 could be considered as a new angiogenesis inhibitor derived from Shark Cartilage.
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Low molecular weight fraction of Shark Cartilage can modulate immune responses and abolish angiogenesis
International immunopharmacology, 2005Co-Authors: Zuhair M. Hassan, Afshar Bargahi, Somayeh Shahrokhi, Tooba Ghazanfari, Reza Feyzi, Ali Mostafaie, Ali Sheikhian, Kamran Mansouri, Shahram ShahabiAbstract:Shark Cartilage has proven to have inhibitory effects on angiogenesis. In this research, we studied the effects of Shark Cartilage on the immune system. Firstly, we isolated and purified a Shark Cartilage protein fraction with the most immunostimulatory effects. Our fraction was composed of two proteins with molecular weights of about 14 and 15 kDa. This fraction highly augments delayed-type hypersensitivity response against sRBC in mice, and decreases the cytotoxic activity of Natural Killer cells. Furthermore, intraperitoneal injection of this fraction to tumor-bearing mice could increase T-cell infiltration into the tumor, and decrease the tumor lesion size. Also, this fraction has strong inhibitory effect on HBMEC proliferation and migration in fibrin matrix. According to these results, we suppose that this fraction is a good candidate for further studies in cancer therapy.
Shuhei Yamada - One of the best experts on this subject based on the ideXlab platform.
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Development of a mouse monoclonal antibody against the chondroitin sulfate-protein linkage region derived from Shark Cartilage
Glycoconjugate Journal, 2010Co-Authors: Chizuru Akatsu, Shuhei Yamada, Jeanclaude Jacquinet, Duriya Fongmoon, Shuji Mizumoto, Prachya Kongtawelert, Kazuyuki SugaharaAbstract:Glycosaminoglycans (GAGs) like chondroitin sulfate (CS) and heparan sulfate (HS) are synthesized on the tetrasaccharide linkage region, GlcAβ1-3Galβ1-3Galβ1-4Xylβ1- O -Ser, of proteoglycans. The Xyl can be modified by 2- O -phosphate in both CS and HS, whereas the Gal residues can be sulfated at C-4 and/or C-6 in CS but not in HS. To study the roles of these modifications, monoclonal antibodies were developed against linkage glycopeptides of Shark Cartilage CS proteoglycans, and one was characterized in detail. This antibody bound hexa- and pentasaccharide-peptides more strongly than unsaturated tetrasaccharide-peptides with the unnatural fourth sugar residue (unsaturated hexuronic acid), suggesting the importance of the fifth and/or fourth saccharide residue GalNAc-5 and/or GlcA-4. Its reactivity was not affected by treatment with chondro-4-sulfatase or alkaline phosphatase, suggesting that 4- O -sulfate on the Gal residues and 2- O -phosphate on the Xyl residue were not recognized. Treatment with weak alkali to cleave the Xyl-Ser linkage completely abolished the binding activity, suggesting the importance of the peptide moiety of the hexasaccharide-peptide for the binding. Based on the amino acid composition and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analyses, it was revealed that the peptide moiety is composed of four amino acids, Ser, Pro, Gly, and Glu. Furthermore, the antibody stained wild-type CHO cells significantly, but much weakly mutant cells deficient in xylosyl- or galactosyltransferase-I required for the biosynthesis of the linkage region. These results suggest that the antibody recognizes the structure GalNAc(±6- O -sulfate)-GlcA-Gal-Gal-Xyl-Ser-(Pro, Gly, Glu). The antibody will be a useful tool for investigating the significance of the linkage region in the biosynthesis and/or intracellular transport of different GAG chains especially since such tools to study the linkage region are lacking.
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preparation of a series of sulfated tetrasaccharides from Shark Cartilage chondroitin sulfate d using testicular hyaluronidase and structure determination by 500 mhz1h nmr spectroscopy
Glycoconjugate Journal, 1996Co-Authors: Kazuyuki Sugahara, Yukako Tanaka, Shuhei YamadaAbstract:Six tetrasaccharide fractions were isolated from Shark Cartilage chondroitin sulfate D by gel filtration chromatography followed by HPLC on an amine-bound silica column after exhaustive digestion with testicular hyaluronidase. Their structures were determined unambiguously by one- and two-dimensional 500 MHz1H NMR spectroscopy in conjunction with HPLC analysis of chondroitinase AC-II digests of the tetrasaccharides. One fraction was found to contain two tetrasaccharide components. All the seven tetrasaccharides shared the common core structure GlcAβ1-3GalNAcβ1-4GlcAβ1-3GalNAc with various sulfation profiles. Four were disulfated comprising of two monosulfated disaccharide units GlcAβ1-3GalNAc(4-sulfate) and/or GlcAβ1-3GalNAc(6-sulfate), whereas the other three were hitherto unreported trisulfated tetrasaccharides containing a disulfated disaccharide unit GlcA(2-sulfate)β1-3GalNAc(6-sulfate) and a monosulfated disaccharide unit GlcAβ1-3GalNAc(4-or 6-sulfate). These sulfated tetrasaccharides were demonstrated to serve as appropriate acceptor substrates for serum α-N-acetylgalactosaminyltransferase, indicating their usefulness as authentic oligosaccharide substrates or probes for the glycobiology of sulfated glycosaminoglycans.