Inhibitors of Glycosphingolipid Biosynthesis.

Abstract

Glycosphingolipids (GSLs) are ubiquitous components of eukaryotic cell surfaces and contribute to the glycocalyx, along with other cell surface glycoconjugates. They play a role in recognition events and are exploited as receptors by a number of infectious disease agents. Their expression changes with cell transformation and if they are incompletely catabolised pathology results, leading to the GSL lysosomal storage diseases. However, the role(s) played by the majority of GSL species remain obscure. One approach for probing their functions is to study the effects of GSL depletion using specific inhibitors of GSL biosynthesis. Two structurally distinct classes of GSL biosynthesis inhibitors have been characterised to date, ceramide analogues and N-alkylated imino sugars. Both types of compound inhibit the first step in GSL biosynthesis, namely the glucosyltransferase catalysed synthesis of glucosylceramide. This results in the failure to synthesise all glucosylceramide derived GSL species. GSL depletion using these inhibitors is well tolerated in vitro and in vivo and they offer a novel therapeutic strategy for the treatment of the glycosphingolipid storage diseases, and are invaluable reagents for studying GSL functions.