单糖-凝集素之间的相互作用非常弱(解离常数在毫摩尔范围),并且专一性不强。但在生物学过程中,凝集素表现出了针对细胞表面寡糖高度的亲和性和优越的专一性。可见,体内可能存在一些补偿亲和力的机制,例如,通过配基多价性(multivalency)或凝集素簇集(cluster),更多的糖残基参与寡糖与凝集素的相互作用。凝集素的寡聚体可以同时结合不同的、适合空间位置的、分支的寡糖或者相同糖复合物的不同寡糖分支。多价寡糖与簇集的凝集素之间的相互作用与单糖同凝集素之间的相互作用相比,亲和力强十倍到千倍,这种现象称为多价效应或者糖(苷)簇效应(glycocluster effect or cluster glycoside effect)。
从理论的角度,多价效应提供给生命一种新的调控方式--即通过糖基化,调节蛋白信号、调节蛋白周转等。
多价性的概念已经应用到了开发基于糖分子的药物和疫苗开发中,以利于增强它与靶分子的相互作用。比较成功的例子是加拿大科学家Roy等开发的glycodendrimer. 如图所示:
上图:Amplification of specific carbohydrate-protein recognition processes via multivalent interactions: ( a ) and ( b ) soluble di- and tetra-valent receptors, e.g. galectins and phytohemagglutinins, ( c ) clustered monovalent receptors at the cell surface, e.g. hepatic asialoglycoprotein receptor, ( d ) and ( e ) oligomeric receptors, e.g. macrophage mannose receptor, and ( f ) receptors that bind more than one carbohydrate simultaneously.
下图:
Multivalent carbohydrate ligands: possible shapes and valencies, ( a ) glycopolymers, ( b ) liposomes, ( c ) glycotelomers and glycopeptoids, ( d ) glycoclusters, ( e ) cyclic glycopeptides, ( f )glycodendrimers (dendrons), ( g ) spherical glycodendrimers, and ( h ) cyclodextrins and glycocalixarenes. 图片版权属于Wiley.
最近没有阅读,不过,糖生物学领域的确是一个令人振奋的领域。读Unusual sugar biosynthesis and natural product glycodiversification这篇文章的文摘的时候,立刻想到同学的一个课题,他想开发一种环糖,类似于环糊精。自然界给了我们很多甚至化学家也望而生畏的工具。这些工具在这几个领域有应用潜力:(1) Drug target; (2) Tool in bioconversion----Catalyst in oligosaccharide systhesis; (3) Modification drug structure.(4) Oligosaccharide library for drug screening. (细看以后再写。怎么没有其他人发言?)作者: ukonptp 时间: 2013-7-24 11:56
Heparan sulphate proteoglycans fine-tune mammalian physiology
我读到The dark side of heparan sulphate proteoglycans这一段的时候,联想了很多。想到现在肿瘤学有一个理论:肿瘤干细胞理论。这个领域的人认为:肿瘤之所以不容易杀掉、容易metastasis、可发生去分化等等,统统是因为存在肿瘤干细胞。我们知道,干细胞的生长是需要一个niche的,而这个niche或者叫microenvironment,其实主要是ECM成份。ECM成份的重要组分就是多糖和糖蛋白。这样,理解了微环境中,粘多糖参与的生物活动,或许就可以揭开很多关于肿瘤发生发展、干细胞活动等等的机密。利用这些机密或许可以在治疗癌症中发挥重大作用。文章中提到的其他疾病Alzheimer’s病都与HSPG有关。
Bringing you the latest on the glycobiology of the immune system, this Immunology & Cell Biology special feature and the accompanying web focus explore the current understanding of how glycans play a role in activating the adaptive and innate immune responses. This focus also features how carbohydrates are involved in a range of interactions related to immune responses.
Articles featured in this focus include those from: Immunology & Cell Biology, Nature, Nature Immunology, Nature Methods, EMBO Reports, Nature Protocols, Nature Reviews Drug Discovery and Nature Reviews Cancer.
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Such metabolic interference can block the expression of oligosaccharides or alter the structures of the sugars presented on cells. Collectively, these chemical approaches are contributing great insight into the myriad biological functions of oligosaccharides. 通过结构的变化,研究功能的改变。