Labeled chemical biology tools for investigating sphingolipid metabolism, trafficking and interaction with lipids and proteins

•Fluorescent sphingolipids are perfect for FRET studies in lipid–protein interaction.•Biotin-GM1 discloses intracellular localization by immuno-electron microscopy.•Photoactivatable GM2 labels the binding site of GM2 activator protein.•Non-degradable glycosphingolipids for metabolic and traffic studies•Synthetic inhibitors of acid sphingomyelinase

The unraveling of sphingolipid metabolism and function in the last 40 years relied on the extensive study of inherited human disease and specifically-tailored mouse models. However, only few of the achievements made so far would have been possible without chemical biology tools, such as fluorescent and/or radio-labeled and other artificial substrates, (mechanism-based) enzyme inhibitors, cross-linking probes or artificial membrane models. In this review we provide an overview over chemical biology tools that have been used to gain more insight into the molecular basis of sphingolipid-related biology. Many of these tools are still of high relevance for the investigation of current sphingolipid-related questions, others may stimulate the tailoring of novel probes suitable to address recent and future issues in the field. This article is part of a Special Issue entitled Tools to study lipid functions.