Sweeter Enzyme Inhibitor

A glycosyltransferase (GT) inhibitor with a novel mechanism of action could aid glycobiology research and drug discovery, according to a report in Nature Chemical Biology (DOI: 10.1038/nchembio.343). GTs are enzymes that extend oligosaccharides or add sugars to proteins and lipids. They play many roles in cell signaling, adhesion, and recognition. Researchers would like to design potent GT inhibitors to intercede in those processes, but the inhibitors developed to date are primarily substrate mimics with lackluster activity. Now, a small molecule that acts in a different way to inhibit one type of GT—galactosyltransferase (GalT)—has been developed by Gerd K. Wagner of the University of East Anglia, in England; Monica M. Palcic of Carlsberg Laboratory, in Copenhagen; and coworkers. For GalT to work, it must adopt a closed conformation stabilized by a tryptophan-arginine interaction. Instead of just sitting passively in the active site, the new inhibitor has a 5-formylthien-2-yl substituent that blocks formation of the closed conformation. It is thus twice as potent as earlier GT inhibitors and could be further optimized, the researchers note. The new inhibitor is effective against five different GalTs, and the researchers believe other inhibitors that function the same way will work against other types of GTs.