N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis.
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.
Platt
F M
FM
Department of Biochemistry, University of Oxford, United Kingdom.
Neises
G R
GR
Dwek
R A
RA
Butters
T D
TD
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D005776:Gaucher Disease; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006017:Glycolipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008954:Models, Biological; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D006017:Glycolipids; D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases