Abstract |
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.
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Authors | F M Platt, G R Neises, G B Karlsson, R A Dwek, T D Butters |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 269
Issue 43
Pg. 27108-14
(Oct 28 1994)
ISSN: 0021-9258 [Print] United States |
PMID | 7929454
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glycolipids
- Oligosaccharides
- 1-Deoxynojirimycin
- miglustat
- migalastat
- Glucosyltransferases
- ceramide glucosyltransferase
- alpha-Glucosidases
- Glucosylceramidase
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Topics |
- 1-Deoxynojirimycin
(analogs & derivatives, pharmacology)
- Animals
- Cells, Cultured
- Disease Models, Animal
- Gaucher Disease
(metabolism)
- Glucosylceramidase
(drug effects)
- Glucosyltransferases
(antagonists & inhibitors)
- Glycolipids
(biosynthesis)
- Humans
- Mice
- Oligosaccharides
(biosynthesis)
- Structure-Activity Relationship
- alpha-Glucosidases
(drug effects)
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