Divergent Synthesis of Heparan Sulfate Oligosaccharides.
Divergent Synthesis of Heparan Sulfate Oligosaccharides.
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DOI：
10.1021/acs.joc.5b02172
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发表时间：
2015-12-18
期刊：
影响因子：
--
通讯作者：
Huang X
中科院分区：
文献类型：
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作者：
Dulaney SB;Xu Y;Wang P;Tiruchinapally G;Wang Z;Kathawa J;El-Dakdouki MH;Yang B;Liu J;Huang X
硫酸乙酰肝素与多种生物过程有关。破译其结构和活性关系的一个主要挑战是获得具有明确硫酸化模式的各种硫酸乙酰肝素寡糖的合成困难。为了加速合成，开发了不同的合成策略。通过整合化学合成和两种类型的O-磺基转移酶，从单一六糖前体中获得了七种不同的六糖。这种方法结合了化学合成的灵活性和酶催化硫酸化的选择性，从而简化了整个合成操作。为了建立硫酸乙酰肝素与其受体结合的结构活性关系，将合成的寡糖整合到聚糖微阵列上，并检查它们与生长因子 FGF-2 的结合。化学和酶方法的独特组合扩大了寡糖合成的能力。此外，明确的硫酸乙酰肝素结构有助于揭示生物合成酶的精细底物特异性，并确认生物合成中酶促反应的潜在序列。
Heparan sulfates are implicated in a wide range of biological processes. A major challenge in deciphering their structure and activity relationship is the synthetic difficulties to access diverse heparan sulfate oligosaccharides with well-defined sulfation patterns. In order to expedite the synthesis, a divergent synthetic strategy was developed. By integrating chemical synthesis and two types of O-sulfo transferases, seven different hexasaccharides were obtained from a single hexasaccharide precursor. This approach combined the flexibility of chemical synthesis with the selectivity of enzyme-catalyzed sulfations, thus simplifying the overall synthetic operations. In an attempt to establish structure activity relationships of heparan sulfate binding with its receptor, the synthesized oligosaccharides were incorporated onto a glycan microarray, and their bindings with a growth factor FGF-2 were examined. The unique combination of chemical and enzymatic approaches expanded the capability of oligosaccharide synthesis. In addition, the well-defined heparan sulfate structures helped shine light on the fine substrate specificities of biosynthetic enzymes and confirm the potential sequence of enzymatic reactions in biosynthesis.