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Cell Chem Biol. 2017 Dec 21;24(12):1467-1478.e5. doi: 10.1016/j.chembiol.2017.08.023. Epub 2017 Oct 12.

An Alkynyl-Fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose-Synthesizing Enzyme FX, TSTA3.

Author information

1
Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan.
2
Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashihiroshima, Hiroshima 739-8530, Japan.
3
Structural Glycobiology Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan.
4
Division of Clinical Research Promotion and Support, Center for Research Promotion, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
5
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.
6
Disease Glycomics Team, Global Research Cluster, RIKEN, Wako, Saitama 351-0198, Japan. Electronic address: dglycotani@riken.jp.

Abstract

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-Alk-Fuc 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 GDP-Fuc, 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.

KEYWORDS:

FX (TSTA3); fucose; fucosylation inhibitor; glycosylation; sugar analog

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