The lysosomal β-glucosidase named glucocerebrosidase (GCase) is a retaining β-glucosidase that hydrolyzes the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose at acid pH.... Show moreThe lysosomal β-glucosidase named glucocerebrosidase (GCase) is a retaining β-glucosidase that hydrolyzes the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose at acid pH. Inherited deficiency of GCase causes Gaucher disease (GD), a relatively common lysosomal storage disorder. GCase fulfills another crucial function beyond lysosomes. The enzyme generates ceramides from GlcCer molecules in the outer part of the skin, the stratum corneum. This is essential for skin barrier properties compatible with terrestrial life. GCase is catalytically versatile and can hydrolyze as well as catalyze transglycosylation.In this thesis a novel sensitive in situ method for the detection of active GCase in skin sections is described. Followed by a study of skin sections of patiens with atopic dermatitis revealing that the localization and activity of GCase and acid sphingomyelinase (ASM) was abnormal in skin of AD patients, particularly at lesional skin sites.It is demonstrated that GCase not only cleaves 4-methylumbelliferyl-β-D-glucose, but also 4-methylumbelliferyl-β-D-xylose. It is reported for the first time that GCase is able to transxylosylate cholesterol to render xylosyl-β-cholesterol (XylChol). The formed XylChol can act as a subsequent acceptor for further transxylosylation, rendering di-xylosyl-cholesterol. And finally the discovery of of GlcChol as novel component of human epidermis is reported. Show less
Aerts, J.M.F.G.; Kuo, C.L.; Lelieveld, L.T.; Boer, D.E.C.; Lienden, M.J.C. van der; Overkleeft, H.S.; Artola, M. 2019
Glycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited... Show moreGlycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited defects in degradation cause lysosomal glycosphingolipid storage disorders. The relatively common glycosphingolipidosis Gaucher disease is highlighted here to discuss new insights in the molecular basis and pathophysiology of glycosphingolipidoses reached by fundamental research increasingly using chemical biology tools. We discuss improvements in the detection of glycosphingolipid metabolites by mass spectrometry and review new developments in laboratory diagnosis and disease monitoring as well as therapeutic interventions. Show less
