Fucosylated Chondroitin Sulfates from the Body Wall of the Sea Cucumber Holothuria forskali CONFORMATION, SELECTIN BINDING, AND BIOLOGICAL ACTIVITY
Author(s)
Type
Journal Article
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 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+-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.
Date Issued
2014-10-10
Date Acceptance
2014-08-09
Citation
Journal of Biological Chemistry, 2014, 289 (41), pp.28284-28298
ISSN
0021-9258
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
28284
End Page
28298
Journal / Book Title
Journal of Biological Chemistry
Volume
289
Issue
41
Copyright Statement
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Creative Commons Attribution Unported License applies to Author Choice Articles
Creative Commons Attribution Unported License applies to Author Choice Articles
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
MOLECULAR-DYNAMICS SIMULATIONS
FREE-RADICAL DEPOLYMERIZATION
RESIDUAL DIPOLAR COUPLINGS
HUMAN-LEUKOCYTE ELASTASE
STICHOPUS-JAPONICUS
P-SELECTIN
LEWIS-X
ANTICOAGULANT ACTIVITIES
NMR-SPECTROSCOPY
HEPARAN-SULFATE
Publication Status
Published