Abstract
The imino sugar deoxynojirimycin and its alkylated derivatives are inhibitors of the N-linked oligosaccharide processing enzymes alpha-glucosidase I and II. These compounds are glucose analogues and have the potential to inhibit both glucosidases and glucosyltransferases. However, to date there has been no report of deoxynojirimycin or similar analogues 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-butyl and N-hexyl derivatives of deoxynojirimycin, but not deoxynojirimycin itself, are novel inhibitors of the glucosyltransferase-catalyzed biosynthesis of glucosylceramide. This results in the inhibition of biosynthesis of all glucosylceramide-based glycosphingolipids. We have investigated the ability of one of these compounds, N-butyldeoxynojirimycin, to offset glucosylceramide accumulation in an in vitro Gaucher's disease model. This compound prevents lysosomal glycolipid storage and offers a novel therapeutic approach for the management of this and other glycolipid storage disorders.
Highlights
The imino sugar deoxynojirimycin and its alkylated postulated to be involved in cellular recognition processes and derivatives are inhibitors of the N-linked oligosaccha- as modulators of transmembrane signaling(11)
The imino sugar N-butyldeoxynojirimycin (M3-DNJ)l is a n inhibitor of the N-linked oligosaccharide processing enzymes a-glucosidase I and I1 (1, 2) and isan inhibitor of HIV replication in vitro (5, 7)
The cells were ited by this glucose analoguewe wished to determine whether or not NB-DNJ can inhibit glucosyltransferases (3, 4) involved i n glycoconjugate biosynthesis
Summary
The imino sugar deoxynojirimycin and its alkylated postulated to be involved in cellular recognition processes and derivatives are inhibitors of the N-linked oligosaccha- as modulators of transmembrane signaling(11). This compound preventlsyso- tivity of M3-DNJ to manage glycolipid levels i n a n in vitro somal glycolipid storage and offers a novel therapeutic Gaucherâs disease model. Lipid Analysis-HL-60 cells were cultured (10 ml) as described previously (10) at a seeding density of 5 x lo[4] cells/ml in the presence or absence of 0.5 mM NB-DNJ (SC-48334, provided by SearleDfonsanto, St. Louis) for[24] h.
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