Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach.
Directing the biological activities of heparan sulfate oligosaccharides using a chemoenzymatic approach.
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使用化学酶方法指导硫酸乙酰肝素寡糖的生物活性。
DOI：
10.1093/glycob/cwr109
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发表时间：
2012
期刊：
影响因子：
4.3
通讯作者：
Liu,Jian
中科院分区：
文献类型：
--
作者：
Xu,Yongmei;Wang,Zhen;Liu,Renpeng;Bridges,ArleneS;Huang,Xuefei;Liu,Jian
硫酸乙酰肝素（HS）和肝素是高度硫酸化的多糖，具有重要的生理功能。硫酸化模式决定了HS和肝素的功能选择性。HS的化学合成，特别是那些大于六糖的HS，仍然具有挑战性。HS的酶促合成最近获得了动力。在这里，我们描述了不同的组装HS七糖和九糖从一个共同的六糖前体。通过化学方法合成六糖前体。随后的延伸、硫酸化和差向异构化由糖基转移酶、HS磺基转移酶和差向异构酶完成。使用合成的七糖，我们发现艾杜糖醛酸是关键的结合成纤维细胞生长因子-2。我们还设计了一种合成途径，以制备具有3 nM的抗凝血酶结合亲和力的九糖。我们的方法证明了结合化学和酶促合成来制备具有所需生物活性的结构确定的HS寡糖的可行性。
Heparan sulfate (HS) and heparin are highly sulfated polysaccharides exhibiting essential physiological functions. The sulfation patterns determine the functional selectivity for HS and heparin. Chemical synthesis of HS, especially those larger than a hexasaccharide, remains challenging. Enzymatic synthesis of HS has recently gained momentum. Here we describe the divergent assembly of HS heptasaccharides and nonasaccharides from a common hexasaccharide precursor. The hexasaccharide precursor was synthesized via a chemical method. The subsequent elongation, sulfation and epimerization were completed by glycosyltransferases, HS sulfotransferases and epimerase. Using the synthesized heptasaccharides, we discovered that the iduronic acid is critical for binding to fibroblast growth factor-2. We also designed a synthetic path to prepare a nonasaccharide with an antithrombin-binding affinity of 3 nM. Our method demonstrated the feasibility of combining chemical and enzymatic synthesis to prepare structurally defined HS oligosaccharides with desired biological activities.