Molecular requirements of imino sugars for the selective control of N-linked glycosylation and glycosphingolipid biosynthesis |
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| Affiliation: | 1. Glycobiology Institute, Department of Biochemistry, Oxford University, South Parks Road, Oxford, OX1 3QU, UK;2. N. V. Organon, PO Box 20, 5340 BH Oss, The Netherlands;3. Dyson Perrins Laboratory, Oxford University, South Parks Road, Oxford, OX1 3QQ, UK;1. State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China;2. School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, China;3. Wuhan Borenpharm Co., Ltd., Wuhan 430073, China;1. Department of Biomolecular Science, Section of Organic Chemistry and Organic Natural Compounds, Università degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy;2. Department of Chemistry, Università degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy;1. Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Republic of Korea;2. Department of Chemistry and Nano Science, Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Republic of Korea;1. Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada;2. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India;3. Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada |
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| Abstract: | 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 (Ki=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. |
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