Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali. Conformation, selectin binding and biological activity

Charalambos Panagos, Derek S. Thomson, Claire Moss, Adam D. Hughes, Maeve S. Kelly, Yan Liu, Wengang Chai, Radhakrishnan Venkatasamy, Domenico Spina, Clive P. Page, John Hogwood, Robert J. Woods, Barbara Mulloy, Charles D. Bavington, D. Uhrin

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Fucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of the following repeating trisaccharide unit: →3)GalNAcβ4,6S(1→4) [FucαX(1→3)]GlcAβ(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 MD simulations, the fCS repeating unit adopts a conformation similar to that of the Lex 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+ catalysed 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. While the polysaccharide shows some anti-coagulant activity, small oligosaccharide fCS fragments have much reduced anticoagulant properties, with activity mainly via heparin cofactor II. The fCS polysaccharides showed prekallikrein activation comparable to 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 presented data 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 may open new avenues for therapeutic intervention using fCS fragments or their mimetics.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume289
Issue number41
Early online date21 Aug 2014
DOIs
Publication statusPublished - 10 Oct 2014

Keywords / Materials (for Non-textual outputs)

  • carbohydrate structure
  • carbohydrate-binding protein
  • glycosaminoglycan
  • inflammation
  • microarray
  • molecular dynamics
  • nuclear magnetic resonance
  • NMR
  • GAG
  • selectin

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