Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives.
Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives.
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取代模式和阳离子结合对肝素衍生物构象和活性的影响。
DOI：
10.1093/glycob/cwm062
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发表时间：
2007
期刊：
影响因子：
4.3
通讯作者：
Rudd TR
中科院分区：
文献类型：
--
作者：
Rudd TR
作为具有重要生物学意义的硫酸乙酰肝素的模型化合物，我们通过对糖醛酸构象敏感的同步辐射圆二色性（SRCD）研究了八种系统修饰的肝素衍生物。即使相邻的葡萄糖胺残基发生结构变化（例如 6-O-脱硫）并且不涉及发色团，取代模式也会改变糖醛酸构象。这些衍生物转化为 Na+、K+、Mg2+、Ca2+、Mn2+、Cu2+ 和 Fe3+ 阳离子形式后的 SRCD 光谱表明，几乎所有取代/阳离子组合都会产生独特的光谱，表明每种组合在结构上都不同。还通过 NMR 研究了结合 Na+、K+、Mg2+ 和 Ca2+ 离子对 2-de-O-硫酸化衍生物的详细影响，揭示了构象（通过 NOE）和灵活性（通过 T2 测量）的细微变化。在基于细胞的成纤维细胞生长因子受体 (FGF2/FGFR1c) 信号转导测定中，转化为 K+ 和 Cu2+ 离子形式也极大地改变了生物活性，从无活性变为活性，并且游离阳离子无法重现这种效应。这些观察结果可以解释文献中有关这些衍生物的结构-活性关系的经常相互矛盾的数据，此外，强烈反对将序列视为完整结构定义的既定趋势。它还提供了改变这些多糖活性的额外方法，并提出了生物系统中可能的额外控制水平。这些发现在生物技术领域也有明显的潜在应用。
As model compounds for the biologically important heparan sulfate, eight systematically modified heparin derivatives were studied by synchrotron radiation circular dichroism (SRCD), which is sensitive to uronic acid confor- mation. Substitution pattern altered uronic acid conformation, even when structural changes were made in adjacent glucosamine residues (e.g. 6-O-desulfation) and did not involve a chromophore. SRCD spectra of these derivatives following conversion to the Na+, K+, Mg2+, Ca2+, Mn2+, Cu2+and Fe3+cation forms revealed that almost all substitution/cation combinations resulted in unique spectra, showing that each was structurally distinct. The detailed effects that binding Na+, K+, Mg2+and Ca2+ions had on a 2-de-O-sulfated derivative was also studied by NMR, revealing that subtle changes in conformation (by NOE) and flexibility (byT2measurements) resulted. Conversion to the K+and Cu2+ion forms also drastically modified biological activity, from inactive to active, in a cell-based assay of fibroblast growth factor-receptor (FGF2/FGFR1c) signalling and this effect was not reproduced by free cations. These observations could explain the often-contradictory data concerning structure–activity relationships for these derivatives in the literature and, furthermore, argue strongly against the established trend of considering sequence as a complete structural definition. It also provides additional means of modifying the activity of these polysaccharides and suggests a possible additional level of control in biological systems. There are also obvious potential applications for these findings in the biotechnology sphere.
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蛋白质-GAG 相互作用：新的表面技术、光谱学和纳米技术探针。
影响因子：
3.9
作者：
E. Yates;C. J. Terry;C. Rees;T. Rudd;L. Duchesne;M. Skidmore;R. Lévy;N. Thanh;R. Nichols;D. Clarke;D. Fernig
通讯作者：
D. Fernig
从肝素中提取的工程生物活性多糖。
影响因子：
4.6
作者：
Guimond SE
通讯作者：
Guimond SE
十二种系统修饰的肝素衍生物的主要序列的 1H 和 13C NMR 谱归属。
影响因子：
3.1
作者：
E. Yates;F. Santini;M. Guerrini;A. Naggi;G. Torri;B. Casu*
通讯作者：
B. Casu*
肝素衍生物中取代模式对 1H、13C NMR 化学位移和 1J(CH) 偶联常数的影响。
影响因子：
3.1
作者：
E. Yates;F. Santini;Barbara De Cristofano;N. Payre;C. Cosentino;M. Guerrini;A. Naggi;G. Torri;M. Hricovíni
通讯作者：
M. Hricovíni
同步光源用于测定肝素真空紫外圆二色性
影响因子：
15
作者：
E. S. Stevens;E. Morris;D. Rees;J. Sutherland
通讯作者：
J. Sutherland