Lyso-glycosphingolipids: presence and consequences

Lyso-glycosphingolipids are generated in excess in glycosphingolipid storage disorders. In the course of these pathologies glycosylated sphingolipid species accumulate within lysosomes due to flaws in the respective lipid degrading machinery. Deacylation of accumulating glycosphingolipids drives the formation of lyso-glycosphingolipids. In lysosomal storage diseases such as Gaucher Disease, Fabry Disease, Krabbe disease, GM1 -and GM2 gangliosidosis, Niemann Pick type C and Metachromatic leukodystrophy massive intra-lysosomal glycosphingolipid accumulation occurs. The lysosomal enzyme acid ceramidase generates the deacylated lyso-glycosphingolipid species. This review discusses how the various lyso-glycosphingolipids are synthesized, how they may contribute to abnormal immunity in glycosphingolipid storing lysosomal diseases and what therapeutic opportunities exist.Medical Biochemistr

Fabry disease: molecular basis, pathophysiology, diagnostics and potential therapeutic directions

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of alpha-galactosidase A (alpha-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.Medical BiochemistryBio-organic Synthesi

Marked differences in tissue-specific expression of chitinases in mouse and man

FWN – Publicaties zonder aanstelling Universiteit Leide

Structure of human chitotriosidase - Implications for specific inhibitor design and function of mammalian chitinase-like lectins

FWN – Publicaties zonder aanstelling Universiteit Leide

Xylose-configured cyclophellitols as selective inhibitors for glucocerebrosidase

Glucocerebrosidase (GBA), a lysosomal retaining beta-d-glucosidase, has recently been shown to hydrolyze beta-d-xylosides and to transxylosylate cholesterol. Genetic defects in GBA cause the lysosomal storage disorder Gaucher disease (GD), and also constitute a risk factor for developing Parkinson's disease. GBA and other retaining glycosidases can be selectively visualized by activity-based protein profiling (ABPP) using fluorescent probes composed of a cyclophellitol scaffold having a configuration tailored to the targeted glycosidase family. GBA processes beta-d-xylosides in addition to beta-d-glucosides, this in contrast to the other two mammalian cellular retaining beta-d-glucosidases, GBA2 and GBA3. Here we show that the xylopyranose preference also holds up for covalent inhibitors: xylose-configured cyclophellitol and cyclophellitol aziridines selectively react with GBA over GBA2 and GBA3 in vitro and in vivo, and that the xylose-configured cyclophellitol is more potent and more selective for GBA than the classical GBA inhibitor, conduritol B-epoxide (CBE). Both xylose-configured cyclophellitol and cyclophellitol aziridine cause accumulation of glucosylsphingosine in zebrafish embryo, a characteristic hallmark of GD, and we conclude that these compounds are well suited for creating such chemically induced GD models.NWO737.016.002Bio-organic SynthesisMedical Biochemistr

A Sensitive Gel-Based Method Combining Distinct Cyclophellitol-Based Probes for the Identification of Acid/Base Residues in Human Retaining Beta-Glucosidases

Medical Biochemistr

N-Azidoacetylmannosamine-mediated chemical tagging of gangliosides

Bio-organic Synthesi