Fucosylated chondroitin sulfate oligosaccharides exert anticoagulant activity by targeting at intrinsic tenase complex with low FXII activation: importance of sulfation pattern and molecular size

Authors
Li, Junhui
Li, Shan
Yan, Lufeng
Ding, Tian
Linhardt, Robert J.
Yu, Yanlei
Liu, Xinyue
Liu, Donghong
Ye, Xingqian
Chen, Shiguo
ORCID
https://orcid.org/0000-0003-2219-5833
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Other Contributors
Issue Date
2017-01-01
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Degree
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Full Citation
Fucosylated chondroitin sulfate oligosaccharides exert anticoagulant activity by targeting at intrinsic tenase complex with low FXII activation: importance of sulfation pattern and molecular size, J. Li, S. Li, L. Yan, T. Ding, R. J. Linhardt, Y. Yu, X. Liu, D. Liu, X. Ye, S. Chen, European Journal of Medicinal Chemistry, 139, 191-200, 2017
Abstract
Fucosylated chondroitin sulfates (fCSs) are structurally unusual glycosaminoglycans isolated from sea cucumbers that exhibit potent anticoagulant activity. These fCSs were isolated from sea cucumber, Isostichopus badionotus and Pearsonothuria graeffei. Fenton reaction followed by gel filtration chromatography afforded fCS oligosaccharides, with different sulfation patterns identified by mass and NMR spectroscopy, and these were used to clarify the relationship between the structures and the anticoagulant activities of fCSs. In vitro activities were measured by activated partial thromboplastin time (APTT), thrombin time (TT), thrombin and factor Xa inhibition, and activation of FXII. The results showed that free radicals preferentially acted on GlcA residues affording oligosaccharides that were purified from both fCSs. The inhibition of thrombin and factor X activities, mediated through antithrombin III and heparin cofactor II of fCSs oligosaccharides were affected by their molecular weight and fucose branches. Oligosaccharides with different sulfation patterns of the fucose branching had a similar ability to inhibit the FXa by the intrinsic factor Xase (factor IXa-VIIIa complex). Oligosaccharides with 2,4-O-sulfo fucose branches from fCS-Ib showed higher activities than ones with 3,4-O-disulfo branches obtained from fCS-Pg. Furthermore, a heptasaccharide is the minimum size oligosaccharide required for anticoagulation and FXII activation. This activity was absent for fCS oligosaccharides smaller than nonasaccharides. Molecular size and fucose branch sulfation are important for anticoagulant activity and reduction of size can reverse the activation of FXII caused by native fCSs.
Description
European Journal of Medicinal Chemistry, 139, 191-200
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Department
The Linhardt Research Labs.
The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
Publisher
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The Linhardt Research Labs Online Collection
Rensselaer Polytechnic Institute, Troy, NY
European Journal of Medicinal Chemistry
https://harc.rpi.edu/
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