N-butyldeoxygalactonojirimycin inhibits glycolipid biosynthesis but does not affect N-linked oligosaccharide processing.
We have previously reported that the imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits glycolipid biosynthesis, in addition to its known activity as an inhibitor of the N-linked oligosaccharide processing enzyme alpha-glucosidase I. In an attempt to dissociate these two activities and identify an inhibitor which was more selective for the glycolipid biosynthetic pathway, several imino sugars have been N-alkylated and tested for inhibitory activity. The galactose analogue N-butyldeoxygalactonojirimycin (NB-DGJ) was found to be a potent inhibitor of glycolipid biosynthesis but in contrast to NB-DNJ had no effect on the maturation of N-linked oligosaccharides or on lysosomal glucocerebrosidase. The effect of increasing N-alkyl chain length on glycolipid inhibition was investigated. Nonalkylated DGJ, the N-methyl and N-ethyl derivatives, were noninhibitory. However, N-propylation resulted in partial inhibition while the N-butyl and N-hexyl derivatives resulted in maximal inhibition. Increasing alkyl chain length also resulted in increased potency of glucosyltransferase inhibition. In an in vitro Gaucher's disease model NB-DGJ was as effective as NB-DNJ in preventing glycolipid storage and may represent a more selective potential therapeutic agent than NB-DNJ for the management of this and other glycosphingolipidoses.
Platt
F M
FM
Department of Biochemistry, University of Oxford, United Kingdom.
Neises
G R
GR
Karlsson
G B
GB
Dwek
R A
RA
Butters
T D
TD
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000378:metabolism; D005962:Glucosylceramidase / Q000187:drug effects; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D006017:Glycolipids / Q000096:biosynthesis*; D006801:Humans; D051379:Mice; D009844:Oligosaccharides / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000187:drug effects
D006017:Glycolipids; D009844:Oligosaccharides; D017485:1-Deoxynojirimycin; C059896:miglustat; C090092:migalastat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D000520:alpha-Glucosidases; D005962:Glucosylceramidase