Chemical Biology Tools for the Sphingosine-1-phosphate (S1P) metabolism

Abstract

Generally, phospholipids were regarded as the major components of membrane and products of simple biosynthetic events. Beyond its passive role, metabolites of sphingolipids have recently been found to play key roles in cell signaling. For example, sphingosine-1-phosphate (S1P) is known to regulate various crucial physiological events such as angiogenesis, proliferation, and autophagy. As a result, phospholipid kinases have been regarded as promising drug targets for cancer, neurodegenerative diseases, and immune diseases. By the action of sphingosine kinase, S1P phosphatases and S1P lyase, the balance among S1P metabolites would be kept. However, it still remains elusive how the balance of these sphingolipids is dynamically regulated in vivo Despite its biological importance, current research tools for monitoring lipid metabolism are laborious and indirect. Most of the methods rely on radioactive labeling, extraction and chromatography for identification and quantification. Consequentially, real-time measurements S1P metabolism are essentially impossible.To address these points, we herein report our progress in the development of fluorogenic chemical probes to investigate the complex metabolism and interconversion of signaling sphingolipids. Our probe design should also be applicable to the phosphorylation probes for other signaling lipids such as ceramides and diacylglycerols. These tools will enable high-throughput screening of the activators/inhibitors of enzymes. Furthermore, monitoring of the enzyme reactivity in the living cell will provide invaluable biological insights for understanding the lipid signaling pathways.