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

• Published in: Cell chemical biology Vol. 24; no. 12; pp. 1467 - 1478.e5
• Main Authors: Kizuka, Yasuhiko, Nakano, Miyako, Yamaguchi, Yoshiki, Nakajima, Kazuki, Oka, Ritsuko, Sato, Keiko, Ren, Chien-Tai, Hsu, Tsui-Ling, Wong, Chi-Huey, Taniguchi, Naoyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 21.12.2017
• Subjects: Alkynes - chemistry; Alkynes - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carbohydrate Epimerases - antagonists & inhibitors; Carbohydrate Epimerases - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement - drug effects; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; fucose; Fucose - chemistry; Fucose - pharmacology; fucosylation inhibitor; FX (TSTA3); glycosylation; Guanosine Diphosphate Fucose - biosynthesis; HEK293 Cells; HeLa Cells; Humans; Ketone Oxidoreductases - antagonists & inhibitors; Ketone Oxidoreductases - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; sugar analog; fucose; glycosylation; FX (TSTA3); sugar analog; fucosylation inhibitor
• DOI: 10.1016/j.chembiol.2017.08.023
• ISSN: 2451-9456

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. [Display omitted] •6-Alkynyl-fucose, a widely used fucosylation probe, strongly inhibits fucosylation•6-Alkynyl-fucose competitively inhibits GDP-fucose synthetase FX•6-Alkynyl-fucose halts hepatoma invasion•6-Alkynyl-fucose is a powerful tool for modulating cellular fucosylation Fucose sugar is involved in cancer and inflammation. Kizuka et al. found that a fucose alkyne strongly inhibits cellular fucosylation. The compound selectively inhibits GDP-fucose synthetase FX and can be applied to glycan-related diseases.