S1P has been shown to regulate diverse cellular processes. It has been characterized as a lipid signaling molecule with dual function. On one hand, it exerts its actions extracellularly by binding to the five different S1P receptors that couple to a variety of G-proteins to regulate diverse biological functions, ranging from cell growth and survival to effector functions, such as proinflammatory mediator synthesis. On the other hand, it appears to act as an intracellular second messenger, although the relevant molecular target(s) to which it binds within cells remains to be discovered. In any case, a role of S1P in various functions of cells and tissues is established, including regulation of cell survival and motility, angiogenesis, and inflammatory responses. Sphingosine kinases (SphKs) types 1 and 2, the two enzymes identified so far in mammals that produce S1P by ATP-dependent phosphorylation of sphingosine, have therefore received considerable interest.
Sphingolipids are ubiquitous membrane constituents of all eukaryotic cells. In general, the term sphingolipid (SL) refers to any of a number of lipids consisting of a head group attached to the 1-OH of ceramide (Cer). Ceramides consist of a sphingoid base, commonly referred to as a long-chain base (LCB), which is N-acylated. De novo synthesis of LCBs begins with the condensation of palmitoylCoA with serine, forming 3-ketosphinganine (Fig. 1). This product is then reduced to sphinganine, also known as dihydrosphingosine (dihydro-Sph; 2-amino-l,3-dihydroxy-octadecane). A 14– to 26-carbon fatty acid chain is then added in an amide linkage with the 2-amino group, forming dihydroceramide (dihydro-Cer). A head group, such as phosphocholine or a carbohydrate, can now be added to the 1-OH, forming a sphingolipid, although most sphingolipids of higher eukaryotes contain further modifications of the LCB.
At a White House residence dinner party in episode 55 (100,000 Airplanes) of The West Wing, sphingosine kinase was (fictitiously) described as "the enzyme believed to control all pathways to cancer growth." The revelation leads President Bartlet to briefly consider including a plan to develop a cure for cancer in his upcoming State of the Union address.
^Billich A, Bornancin F, Mechtcheriakova D, Natt F, Huesken D, Baumruker T (October 2005). "Basal and induced sphingosine kinase 1 activity in A549 carcinoma cells: function in cell survival and IL-1beta and TNF-alpha induced production of inflammatory mediators". Cell. Signal.17 (10): 1203–17. doi:10.1016/j.cellsig.2004.12.005. PMID16038795.
Stoffel W, Bauer E, Stahl J (1974). "The metabolism of sphingosine bases in Tetrahymena pyriformis Sphingosine kinase and sphingosine-1-phosphate lyase". Hoppe. Seylers. Z. Physiol. Chem.355 (1): 61–74. doi:10.1515/bchm2.1974.355.1.61. PMID4373374.