Synergistic Inhibition of Human α-1,3-Fucosyltransferase V

Abstract

Human α-1,3-fucosyltransferase V (FucT V), which catalyzes the transfer of l-fucose moiety from guanosine diphosphate β-l-fucose (GDP-Fuc) to an acceptor sugar to form sialyl Lewis x (sLex), was shown to proceed through an ordered, sequential mechanism by product inhibition studies. The designed azatrisaccharide propyl 2-acetamido-2-deoxy-4-O-(β-d-galactopyranosyl)-3-O-(2-(N-(β-l-homofuconojirimycinyl))ethyl)-α-d-glucopyranoside (2), prepared by covalently linking the N-group of β-l-homofuconojirimycin (1) to the 3-OH of LacNAc through an ethylene unit, in the presence of GDP was found to be an effective inhibitor of FucT V. In the presence of 30 μM GDP, the concentration of 2 necessary to cause 50% inhibition was reduced 77-fold to 31 μM. Presumably, the azatrisaccharide and GDP form a complex which mimics the transition state of the enzymatic reaction. Given the low affinity of FucT V for its substrate LacNAc (Km = 35 mM), the designed azatrisaccharide in the presence of GDP represents the most potent synergistic inhibitor complex reported so far.