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 (sLe x ), 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 ( K m = 35 mM), the designed azatrisaccharide in the presence of GDP represents the most potent synergistic inhibitor complex reported so far.