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dc.contributor.authorPanagos, Charalampos G.
dc.contributor.authorThomson, Derek S.
dc.contributor.authorMoss, Claire
dc.contributor.authorHughes, Adam D.
dc.contributor.authorKelly, Maeve S.
dc.contributor.authorLiu, Yan
dc.contributor.authorChai, Wengang
dc.contributor.authorVenkatasamy, Radhakrishnan
dc.contributor.authorSpina, Domenico
dc.contributor.authorPage, Clive P.
dc.contributor.authorHogwood, John
dc.contributor.authorWoods, Robert J.
dc.contributor.authorMulloy, Barbara
dc.contributor.authorBavington, Charlie D.
dc.contributor.authorUhrín, Dušan
dc.date.accessioned2018-09-20T16:21:02Z
dc.date.available2018-09-20T16:21:02Z
dc.date.issued2014-08-21
dc.identifier.citationPanagos, Charalampos G. Thomson, Derek S.; Moss, Claire; Hughes, Adam D.; Kelly, Maeve S.; Liu, Yan; Chai, Wengang; Venkatasamy, Radhakrishnan; Spina, Domenico; Page, Clive P.; Hogwood, John; Woods, Robert J.; Mulloy, Barbara; Bavington, Charlie D.; Uhrín, Dušan (2014). Fucosylated chondroitin sulfates from the body wall of the sea cucumberholothuria forskali. Journal of Biological Chemistry 289 (41), 28284-28298
dc.identifier.issn0021-9258,1083-351X
dc.identifier.urihttp://hdl.handle.net/10379/13395
dc.description.abstractFucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of the following repeating trisaccharide unit: -> 3)GalNAc beta 4,6S(1 -> 4) [Fuc alpha X(1 -> 3)]GlcA beta(1 ->, where X stands for different sulfation patterns of fucose (X = 3,4S (46%), 2,4S (39%), and 4S (15%)). As revealed by NMR and molecular dynamics simulations, the fCS repeating unit adopts a conformation similar to that of the Le(x) blood group determinant, bringing several sulfate groups into close proximity and creating large negative patches distributed along the helical skeleton of the CS backbone. This may explain the high affinity of fCS oligosaccharides for L-and P-selectins as determined by microarray binding of fCS oligosaccharides prepared by Cu2+-catalyzed Fenton-type and photochemical depolymerization. No binding to E-selectin was observed. fCS poly- and oligosaccharides display low cytotoxicity in vitro, inhibit human neutrophil elastase activity, and inhibit the migration of neutrophils through an endothelial cell layer in vitro. Although the polysaccharide showed some anti-coagulant activity, small oligosaccharide fCS fragments had much reduced anticoagulant properties, with activity mainly via heparin cofactor II. The fCS polysaccharides showed prekallikrein activation comparable with dextran sulfate, whereas the fCS oligosaccharides caused almost no effect. The H. forskali fCS oligosaccharides were also tested in a mouse peritoneal inflammation model, where they caused a reduction in neutrophil infiltration. Overall, the data presented support the action of fCS as an inhibitor of selectin interactions, which play vital roles in inflammation and metastasis progression. Future studies of fCS-selectin interaction using fCS fragments or their mimetics may open new avenues for therapeutic intervention.
dc.publisherAmerican Society for Biochemistry & Molecular Biology (ASBMB)
dc.relation.ispartofJournal of Biological Chemistry
dc.subjectmolecular-dynamics simulations
dc.subjectfree-radical depolymerization
dc.subjectresidual dipolar couplings
dc.subjecthuman-leukocyte elastase
dc.subjectstichopus-japonicus
dc.subjectp-selectin
dc.subjectlewis-x
dc.subjectanticoagulant activities
dc.subjectnmr-spectroscopy
dc.subjectheparan-sulfate
dc.titleFucosylated chondroitin sulfates from the body wall of the sea cucumberholothuria forskali
dc.typeArticle
dc.identifier.doi10.1074/jbc.m114.572297
dc.local.publishedsourcehttp://www.jbc.org/content/289/41/28284.full.pdf
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