Fucosylated Chondroitin Sulfates from the Body Wall of the Sea Cucumber Holothuria forskali: CONFORMATION, SELECTIN BINDING, AND BIOLOGICAL ACTIVITY

C. G. Panagos, D. S. Thomson, C. Moss, a. D. Hughes, M. S. Kelly, Y. Liu, W. Chai, R. Venkatasamy, D. Spina, C. P. Page, J. Hogwood, R. J. Woods, B. Mulloy, C. D. Bavington, D. Uhrin

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Abstract

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 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 Cu(2+)-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.
Original languageEnglish
Title of host publicationJournal of Biological Chemistry
Pages28284-28298
Number of pages15
DOIs
Publication statusPublished - 21 Aug 2014

Publication series

NameJournal of Biological Chemistry
Volume289

Keywords

  • Carbohydrate Structure
  • Carbohydrate-binding Protein
  • Glycosaminoglycan
  • Inflammation
  • Microarray
  • Molecular Dynamics
  • Nuclear Magnetic Resonance (NMR)
  • Selectin

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    Panagos, C. G., Thomson, D. S., Moss, C., Hughes, A. D., Kelly, M. S., Liu, Y., Chai, W., Venkatasamy, R., Spina, D., Page, C. P., Hogwood, J., Woods, R. J., Mulloy, B., Bavington, C. D., & Uhrin, D. (2014). Fucosylated Chondroitin Sulfates from the Body Wall of the Sea Cucumber Holothuria forskali: CONFORMATION, SELECTIN BINDING, AND BIOLOGICAL ACTIVITY. In Journal of Biological Chemistry (pp. 28284-28298). (Journal of Biological Chemistry; Vol. 289). https://doi.org/10.1074/jbc.M114.572297