Novel mannosidase inhibitors probe glycoprotein degradation pathways in cells |
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Authors: | Terry D Butters Dominic S Alonzi Nikolay V Kukushkin Yuan Ren Yves Blériot |
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Institution: | 1.Oxford Glycobiology Institute, Department of Biochemistry,University of Oxford,Oxford,UK;2.Glycochemistry group, Institut Parisien de Chimie Moléculaire (IPCM) UMR-CNRS 7201,Université Pierre et Marie Curie—Paris 06,Paris,France |
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Abstract: | Multiple isoforms of mammalian α-mannosidases are active in the pathways of N-linked glycoprotein synthesis and catabolism.
They differ in specificity, function and location within the cell and can be selectively inhibited by imino sugar monosaccharide
mimics. Previously, a series of structurally related novel 7-membered iminocyclitols were synthesised and found to be inhibitors
of α-mannosidase using in vitro assays. The present study aimed to delineate α-mannosidases hydrolytic pathways in azepane inhibitor treated cells by the
analysis of free oligosaccharides (FOS) as markers of endoplasmic reticulum (ER), Golgi, lysosomal and cytosolic α-mannosidase
activities. Two compounds were identified as potent and selective cytosolic α-mannosidase inhibitors. Two related compounds
were shown to be potent inhibitors of lysosomal α-mannosidase with different potencies towards α1,6 mannosidase. The specificities
of these novel 7-membered imino sugars are related to differences in their structure and d-mannose-like stereochemistry. Specific ER-mannosidase inhibition by kifunensine also reveals significant non-proteasomal
degradation following FOS analysis and appears to be cell line dependent. The availability of more selective inhibitors allows
the pathways of N-linked oligosaccharide metabolism to be dissected. |
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