An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3
An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3
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DOI：
10.1016/j.chembiol.2017.08.023
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发表时间：
2017-12-21
影响因子：
8.6
通讯作者：
Taniguchi, Naoyuki
中科院分区：
文献类型：
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作者：
Kizuka, Yasuhiko;Nakano, Miyako;Taniguchi, Naoyuki
岩藻糖基化是一种糖链修饰，与癌症和炎症密切相关。虽然有效的岩藻糖基化抑制剂在基础和临床研究中很有用，但目前只开发了几种抑制剂。在这里，我们重点介绍了一种带有炔基的岩藻糖类似物，6-烷基-岩藻糖(6-ALK-Fuc)，它被广泛用作岩藻糖化多糖的检测探针，但也被建议用作岩藻糖基化抑制剂。我们的凝集素和质谱学分析表明，6-AlkFuc是一种有效和通用的细胞岩藻糖基化抑制剂，其效力远远高于现有的2-氟岩藻糖(2-F-Fuc)。其作用机制是消耗细胞内的GDPFuc，而6-ALK-Fuc的直接靶点是由TSTA3编码的双功能GDP-Fuc合成酶Fx。我们还发现6-ALK-Fuc可以抑制肝癌的侵袭。这些结果突出了6-ALK-Fuc作为岩藻糖化抑制剂的未被评价的作用及其在基础和临床科学中的潜在用途。
Fucosylation is a glycan modification critically involved in cancer and inflammation. Although potent fucosylation inhibitors are useful for basic and clinical research, only a few inhibitors have been developed. Here, we focus on a fucose analog with an alkyne group, 6-alkynyl-fucose (6-Alk-Fuc), which is used widely as a detection probe for fucosylated glycans, but is also suggested for use as a fucosylation inhibitor. Our glycan analysis using lectin and mass spectrometry demonstrated that 6-AlkFuc is a potent and general inhibitor of cellular fucosylation, with much higher potency than the existing inhibitor, 2-fluoro-fucose (2-F-Fuc). The action mechanism was shown to deplete cellular GDPFuc, and the direct target of 6-Alk-Fuc is FX (encoded by TSTA3), the bifunctional GDP-Fuc synthase. We also show that 6-Alk-Fuc halts hepatoma invasion. These results highlight the unappreciated role of 6-Alk-Fuc as a fucosylation inhibitor and its potential use for basic and clinical science.