Heparan Sulfate Microarray Reveals That Heparan Sulfate-Protein Binding Exhibits Different Ligand Requirements.
Heparan Sulfate Microarray Reveals That Heparan Sulfate-Protein Binding Exhibits Different Ligand Requirements.
复制标题
DOI：
10.1021/jacs.7b01399
复制
发表时间：
2017-07-19
影响因子：
15
通讯作者：
Boons GJ
中科院分区：
文献类型：
--
作者：
Zong C;Venot A;Li X;Lu W;Xiao W;Wilkes JL;Salanga CL;Handel TM;Wang L;Wolfert MA;Boons GJ
硫酸乙酰肝素（HS）是一种线性硫酸多糖，可调节广泛的生理和疾病过程。HS差向异构化和硫酸化的变化提供了巨大的结构多样性，这被认为是蛋白质结合和调节特性的基础。然而，HS结合蛋白的配体要求仅在少数情况下被定义。我们在这里描述了一种合成方法，可以快速提供一个明确的HS寡糖库。它是基于使用模块二糖组装几个选择性保护的四糖，进行选择性的化学修饰，如区域选择性O-和N-硫酸化和选择性双磷酸化。通过3-O-磺基转移酶-1（3-OST 1）对许多所得化合物进行酶促修饰，以提供3-O-硫酸化衍生物。多样化的各种方法允许一个四糖转化为12个不同的硫酸化衍生物。通过使用具有不同骨架组成的四糖，制备了47种HS-寡糖的文库，并将所得化合物用于构建HS微阵列。使用阵列检查了许多HS结合蛋白的配体需求，包括成纤维细胞生长因子2（FGF-2）和趋化因子CCL 2、CCL 5、CCL 7、CCL 13、CXCL 8和CXCL 10。虽然所有的蛋白质识别多种化合物，但它们在结构结合特征上表现出明显的差异。HS微阵列数据指导了可能干扰细胞增殖等生物过程的化合物的选择。虽然该库没有覆盖HS-四糖的整个化学空间，但结合数据支持细胞表面HS组成的变化可以调节蛋白质功能的观点。
Heparan sulfates (HS) are linear sulfated polysaccharides that modulate a wide range of physiological and disease-processes. Variations in HS epimerization and sulfation provide enormous structural diversity, which is believed to underpin protein binding and regulatory properties. The ligand requirements of HS-binding proteins have, however, been defined in only a few cases. We describe here a synthetic methodology that can rapidly provide a library of well-defined HS oligosaccharides. It is based on the use of modular disaccharides to assemble several selectively protected tetrasaccharides that were subjected to selective chemical modifications such as regioselective O- and N-sulfation and selective desulfation. A number of the resulting compounds were subjected to enzymatic modifications by 3-O-sulfotransferases-1 (3-OST1) to provide 3-O-sulfated derivatives. The various approaches for diversification allowed one tetrasaccharide to be converted into 12 differently sulfated derivatives. By employing tetrasaccharides with different backbone compositions, a library of 47 HS-oligosaccharides was prepared and the resulting compounds were used to construct a HS microarray. The ligand requirements of a number of HS-binding proteins including fibroblast growth factor 2 (FGF-2), and the chemokines CCL2, CCL5, CCL7, CCL13, CXCL8, and CXCL10 were examined using the array. Although all proteins recognized multiple compounds, they exhibited clear differences in structure–binding characteristics. The HS microarray data guided the selection of compounds that could interfere in biological processes such as cell proliferation. Although the library does not cover the entire chemical space of HS-tetrasaccharides, the binding data support a notion that changes in cell surface HS composition can modulate protein function.
登录
查看更多内容
DOI：
10.1074/jbc.m800688200
发表时间：
2008-06-06
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Fukuhara N;Howitt JA;Hussain SA;Hohenester E
通讯作者：
Hohenester E
影响因子：
3.2
作者：
Dhamale OP;Zong C;Al-Mafraji K;Boons GJ
通讯作者：
Boons GJ
DOI：
10.1021/acs.joc.5b02172
发表时间：
2015-12-18
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Dulaney SB;Xu Y;Wang P;Tiruchinapally G;Wang Z;Kathawa J;El-Dakdouki MH;Yang B;Liu J;Huang X
通讯作者：
Huang X
影响因子：
3.7
作者：
Campanella GS;Colvin RA;Luster AD
通讯作者：
Luster AD
影响因子：
4
作者：
de Paz, Lose L.;Moseman, E. Ashley;Seeberger, Peter H.
通讯作者：
Seeberger, Peter H.