CHAPTER 15: Tipping the Balance of Sphingosine 1-Phosphate Production: Sphingosine Kinases and Sphingosine 1-Phosphate Lyase as Immune Therapeutic Targets

Sphingolipid metabolism involves the synthesis and degradation of a number of structurally similar molecules that function as building blocks of cell membranes as well as signalling molecules. Sphingosine, derived from the breakdown of ceramide, is phosphorylated by two sphingosine kinases (SK), SK1 and SK2, producing Sphingosine-1-Phosphate (S1P). S1P is an important signalling agent present in all mammalian cells as well as in the circulation. It can serve both as a chemotactic ligand of G-protein coupled receptors and as a second messenger in signal transduction pathways, which control cell differentiation, proliferation and apoptosis. S1P levels are regulated by two other catalytic processes in addition to the kinase activities. Sphingosine 1-phosphate lyase (S1PL) irreversibly degrades S1P through a retro-aldol reaction, and two classes of phosphatases, acting on lipids, dephosphorylate S1P to regenerate sphingosine. It has become evident that tipping the balance of S1P production can augment as well as inhibit inflammation in a context-dependent manner. This dual function places S1P in the company of other secreted factors that display a Yin-Yang role in the inflammatory process, such as INF-γ, TGF-β and members of the IL-17 family of cytokines. Therefore, enzymes of sphingolipid metabolism have become important new drug targets for the control of inflammation, autoimmune disorders and cancer. This chapter covers the immunology of S1PL, SK1 and SK2, and summarizes the drug-discovery efforts aimed at exploiting the potential of these enzymes as novel anti-inflammatory drug targets.