Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: conformation, selectin binding, and biological activity.
Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: conformation, selectin binding, and biological activity.
复制标题
来自海参 Holothuria forskali 体壁的岩藻糖化硫酸软骨素：构象、选择素结合和生物活性。
DOI：
10.1074/jbc.m114.572297
复制
发表时间：
2014-10-10
期刊：
影响因子：
--
通讯作者：
Uhrín D
中科院分区：
文献类型：
--
作者：
Panagos CG;Thomson DS;Moss C;Hughes AD;Kelly MS;Liu Y;Chai W;Venkatasamy R;Spina D;Page CP;Hogwood J;Woods RJ;Mulloy B;Bavington CD;Uhrín D
背景：海参中提取的一种酸性多糖FCS具有一系列生物活性。结果：确定了FCS的构象，所得到的寡糖具有良好的生物学特性。结论：FCS重复单位构象支持与L选择素和P选择素的结合。意义：利用FCS-选择素相互作用可能为使用FCS片段或其模拟物进行治疗干预开辟新的途径。从海参海参中提取的岩藻糖化硫酸软骨素由以下三糖单元组成：→3)GalNAcβ4，6S(1→4)[FucαX(1→3)]Glcaβ(1→，其中X代表岩藻糖不同的硫化模式(X=3，4S(46%)，2，4S(39%)，4S(15%))。如核磁共振和分子动力学模拟所揭示的那样，FCS重复单元采用与Lex血型决定簇相似的构象，使几个硫酸盐基团紧密接近，并沿着CS主干的螺旋骨架产生大的负斑块。这可能解释了FCS寡糖对L-和P-选择素的高亲和力，这可以通过Cu2+催化的Fenton型FCS寡糖与光化学解聚制备的FCS寡糖微阵列结合来确定。未观察到与E-选择素的结合。FCS多糖和寡糖在体外表现出低的细胞毒性，抑制人中性粒细胞弹性蛋白酶的活性，并在体外抑制中性粒细胞通过内皮细胞层的迁移。虽然多糖具有一定的抗凝血活性，但小分子寡糖FCS片段的抗凝血活性明显降低，主要通过肝素辅因子II发挥作用。FCS多糖具有与葡聚糖硫酸盐相当的激肽释放酶原活性，而FCS寡糖几乎没有作用。Forskali FCS寡糖还在小鼠腹膜炎症模型中进行了测试，在该模型中，它们可以减少中性粒细胞的渗透。总体而言，所提供的数据支持FCS作为选择素相互作用的抑制物的作用，选择素相互作用在炎症和转移进展中发挥重要作用。未来利用FCS片段或其模拟物研究FCS与选择素的相互作用可能会为治疗干预开辟新的途径。
Background: An acidic polysaccharide, fCS, from the sea cucumber Holothuria forskali has a range of biological activities. Results: The conformation of fCS was determined, and resulting oligosaccharides were shown to retain desirable biological properties. Conclusion: The conformation of the fCS repeating unit underpins binding to L- and P-selectins. Significance: Exploitation of the fCS-selectin interaction may open new avenues for therapeutic intervention using fCS fragments or their mimetics. 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.