Physicochemical characteristics and anticoagulant activities of low molecular weight fractions by free-radical depolymerization of a fucosylated chondroitin sulphate from sea cucumber Thelenata ananas

Wu, Mingyi; Xu, Shen; Zhao, Jinhua; Kang, Hui Jung; Ding, Hui

doi:10.1016/j.foodchem.2010.03.042

Cited by 89 publications

(69 citation statements)

References 31 publications

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“…The native FG (HPLC purity 99.9%; average molecular mass 70 kDa) (1; Fig. 2A) was isolated and purified from the sea cucumber S. variegatus as previously described (24,31). Depolymerized 1 (i.e., 2) with an anTal-ol terminal was prepared via the partial deacetylation-deaminative cleavage of 1 as previously described (17).…”

Section: Methodsmentioning

confidence: 99%

“…For over 30 y since its discovery the detailed structures of native FG and its depolymerized products have not been elucidated, because these polysaccharides are heterogeneous, namely they are mixtures of isomers with different molecular weights, and because limitations exist in the available strategies for analyzing such molecules (17,20). For example, although it is assumed that a single fucose (Fuc) is linked to the C-3 position of glucuronic acid (GlcA) via an α-glycosidic bond, there is no direct evidence excluding the possibility that Fuc may be linked to the C-4 and C-6 positions of N-acetylgalactosamine (GalNAc) and that the Fuc side chain may exist as a di-or trisaccharide side chain (14,(21)(22)(23)(24). Because the polydisperse and structurally ambiguous native FG and its illdefined depolymerized products are not suitable for the precise evaluation of their structure-activity relationships, in general, the purification of FG-derived fragments is crucial for probing these structure-activity relationships with regard to the inhibition of the intrinsic tenase and for elucidating the detailed structure of FG.…”

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confidence: 99%

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Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylationdeaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.T hrombotic disease is seriously harmful to human health and is one of the major causes of death in modern society (1). Despite their long-term and widespread use as anticoagulants, heparin, low-molecular-weight heparin (LMWH), and coumarins still have a major unresolved issue: the risk of serious bleeding during therapy (1-3). It is generally recognized that the risk of bleeding associated with these agents is related to the nonselectivity of their anticoagulant activity. Therefore, selective inhibitors of human factor Xa (FXa) and thrombin (FIIa), such as dabigatran, rivaroxaban, and apixaban, which have predictable pharmacokinetics, have recently been developed; however, these agents have not effectively reduced the risk of bleeding in clinical applications (4-7).Components of the intrinsic coagulation pathway are promising targets for antithrombotic therapy because they are important for thrombosis but are not required for hemostasis (1,8). The development of new anticoagulant agents that inhibit components of the intrinsic pathway and that have a lower risk of causing bleeding has thus become a research focus (9-11). Factor IXa (FIXa), a serine protease, and factor VIIIa (FVIIIa), a protein cofactor, form a Ca 2+ -and phospholipid surface-dependent complex referred to as the intrinsic tenase complex, which efficiently converts zymogen factor X (FX) to FXa (1,12,13). Because the intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway, the development of inhibitors of this enzyme complex is important for meeting clinical demands (1). However, limited progress has been achieved due to the unavailability of selective inhibitors with welldefined structures.Fucosylated glycosaminoglycan (FG; 1 in Fig. 1), which is a complex acidic polysaccharide isolated from sea cucumber, has recently attracted considerable attention because of its various bioactivities (14). Notably, FG has potent anticoagula...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

116

152

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“…The degradation of polysaccharides was achieved by enzymatic (pectinase [11], pectin methyl esterase, polygalacturonase [12]), chemical (acid hydrolysis [13], ozonolysis [14], free radical depolymerization [15]), physical (sonochemistry [16], microwave, irradiation [17], etc.) and thermal processes [17].…”

Section: Introductionmentioning

confidence: 99%

Depolymerization of polysaccharides from Opuntia ficus indica: Antioxidant and antiglycated activities

Chaouch

Hafsa

Rihouey

et al. 2015

International Journal of Biological Macromolecules

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“…Previous studies have suggested that anticoagulant activity mostly depends on the molecular size of the polysaccharides and also relates to monosaccharide composition, sulfate content and position [9,10,11,12]. The anticoagulant activity of the FuCS from the sea cucumber Thelenota ananas as measured by the activated partial thromboplastin time assay varies in proportion to the molecular weight following a logarithmic-like function [10].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Physicochemical Characteristics and Anticoagulant Activities of Polysaccharides from Three Sea Cucumbers

et al. 2013

Marine Drugs

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In order to search for sulfated polysaccharides in different invertebrate connective tissues and to examine their biological activities, we have isolated three types of polysaccharides from the body wall of the three sea cucumbers Holothuria edulis, Apostichopus japonicas and Holothuria nobilis. The physicochemical properties and anticoagulant activities of these polysaccharides were examined and compared. The chemical composition analysis and nuclear magnetic resonance (NMR) analysis indicate that two types of polysaccharides, sulfated fucan and fucosylated chondroitin sulfate (FuCS), were found in all of the three species and in addition a neutral glycan was observed in H. edulis. The neutral α-glucan was firstly obtained from sea cucumber. The same type of polysaccharides from different species of sea cucumbers have similar physicochemical properties and anticoagulant activities, but those of different types of glycans are significantly different, possibly due to their different monosaccharide compositions, electric charges and average molecular weights. The FuCSs have stronger anticoagulant activities than the sulfated fucans, although the molecular sizes of the FuCSs are lower than those of the sulfated fucans, whereas the neutral glucan has no activity, as expected from the absence of sulfate. Thus, anticoagulant activities of the different type of polysaccharides are likely to relate to monosaccharide composition and sulfate content. Preliminary analysis suggests that the sulfation patterns of the FuCSs may result in the difference in anticoagulant activities. Our data could help elucidate the structure-activity relationship of the sea cucumber polysaccharides.

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Physicochemical characteristics and anticoagulant activities of low molecular weight fractions by free-radical depolymerization of a fucosylated chondroitin sulphate from sea cucumber Thelenata ananas

Cited by 89 publications

References 31 publications

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Depolymerization of polysaccharides from Opuntia ficus indica: Antioxidant and antiglycated activities

Comparison of Physicochemical Characteristics and Anticoagulant Activities of Polysaccharides from Three Sea Cucumbers

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