Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis

Journal article

N-Butyl-deoxynojirimycin (NB-DNJ) has been approved for clinical trials as a potential therapy for Gaucher disease, a glycolipid lysosomal storage disorder. As this compound has both glycoprotein processing α-glucosidase and ceramide glucosyltransferase inhibitory activity, we have sought to determine the molecular basis for these two activities. NB-DNJ is known to resemble the positively charged oxocarbonium-like transition state for α-glucosidase I and the structure-function relationships we present now help to define the recognition epitope for the enzyme. Inhibition of ceramide glucosyltransferase by NB-DNJ was competitive for ceramide (K(i)=7.4 μM) and non-competitive for UDP-glucose, indicating inhibitory activity is by ceramide mimicry. The presence of an N-alkyl chain was obligatory for transferase inhibition and increases in alkyl chain length provided a modest increase in inhibitory potency.By contrast, α-glucosidase inhibition was independent of the N-alkyl chain and changes in chain length. The effects of ring substitutions identified the C3 hydroxyl group as being critical for both enzymes but C1 and C6 modifications led to a loss of transferase inhibition only. Attempts to rationalise these data for transferase inhibition using an energy minimised molecular model of NB-DNJ and ceramide predicted structural homology of three stereogenic centres and the N-alkyl chain of NB-DNJ, with the trans-alkenyl and N-acyl chain of ceramide. On the basis of these studies, modifications to imino sugar inhibitors can be suggested that allow a more selective approach for molecular inhibition of both ceramide glucosyltransferase and α-glucosidase I, leading to improved compounds for the potential treatment of lysosomal glycosphingolipid storage disorders and viral infections, respectively. Copyright (C) 2000.

Authors: Butters, T; van den Broek, L; Fleet, G; Krulle, T; Wormald, M

• Publication status: Published
• Journal: TETRAHEDRON-ASYMMETRY
• Volume: 11
• Issue: 1
• Pages: 113-124
• Publication date: 2000-01-28
• DOI: 10.1016/S0957-4166(99)00468-1
• ISSN: 0957-4166
• Language: English