Sphingosine-1-Phosphate Lyase

Summary

Sphingosine-1-phosphate lyase is responsible for the ultimate step in sphingolipid degradation. Sphingosine-1-phosphate and other phosphorylated long chain bases generated through the actions of sphingosine kinase may be dephosphorylated by lipid phosphatases or cleaved at the C_2–3 carbon-carbon bond by the pyridoxal 5’-phosphate-dependent enzyme, sphingosine-1-phosphate lyase. By regulating intracellular levels of phosphorylated long chain bases, sphingosine-1-phosphate lyase may control intracellular and extracellular signaling events mediated by these bioactive molecules. Through additional effects mediated by its substrate and products on the biosynthesis of sphingolipids, their conversion into phospholipids, and the synthesis of sterols and fatty acids, sphingosine-1-phosphate lyase may regulate the flow of lipid intermediates through several metabolic pathways. Subsequent to the cloning of the first sphingosine-1-phosphate lyase gene from Saccharomyces cerevisiae, putative homologs have been identified in various plant and animal species, indicating that the enzyme is highly conserved. Sphingosine-1-phosphate lyase mutant phenotypes in fungi, simple metazoans, and mammalian cells suggest that the enzyme plays a role in the regulation of apoptosis, stress responses, reproduction, development, and tissue integrity and repair. Analysis of sphingosine-1-phosphate lyase gene expression has shed light on how the enzyme may be regulated under physiological conditions. Identification of specific inhibitors and generation of constitutive and conditional mouse knockout models should facilitate the dissection of sphingosine-1-phosphate lyase’s role within the context of mammalian development, physiology and the pathophysiology of various disease states.