N-BUTYLDEOXYNOJIRIMYCIN IS A NOVEL INHIBITOR OF GLYCOLIPID BIOSYNTHESIS

The imino sugar deoxynojirimycin and its alkylated derivatives are inh ibitors of the N-linked oligosaccharide processing enzymes alpha-gluco sidase I and II. These compounds are glucose analogues and have the po tential to inhibit both glucosidases and glucosyltransferases. However , to date there has been no report of deoxynojirimycin or similar anal ogues inhibiting a mammalian glucosyltransferase. We have investigated the effects of deoxynojirimycin and its alkylated derivatives on the biosynthesis of glycolipids in HL-60 cells. We have found that the N-b utyl and N-hexyl derivatives of deoxynojirimycin, but not deoxynojirim ycin itself, are novel inhibitors of the glucosyltransferase-catalyzed biosynthesis of glucosylceramide. This results in the inhibition of b iosynthesis of all glucosylceramide-based glycosphingolipids. We have investigated the ability of one of these compounds, N-butyldeoxynojiri mycin, to offset glucosylceramide accumulation in an in vitro Gaucher' s disease model. This compound prevents lysosomal glycolipid storage a nd offers a novel therapeutic approach for the management of this and other glycolipid storage disorders.