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,[1] although the relevant molecular target(s) to which it binds within cells remains to be discovered. The 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.[2]
Sphingolipid metabolism
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
palmitoyl-CoA with
serine, forming 3-ketosphinganine (Fig. 1). This product is then reduced to
sphinganine, also known as dihydrosphingosine (dihydro-Sph; 2-amino-1,3-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.[3]
De novo synthesis
Popular culture
During "100,000 Airplanes", a
third season episode of The West Wing, sphingosine kinase is fictitiously described as "the enzyme believed to control all signal pathways to cancer growth." Learning of it inspires the protagonist of the series, President
Josiah Bartlet, to consider launching an Apollo program to cure cancer.
References
^Olivera A, Spiegel S (April 2001). "Sphingosine kinase: a mediator of vital cellular functions". Prostaglandins Other Lipid Mediat. 64 (1–4): 123–34.
doi:
10.1016/S0090-6980(01)00108-3.
PMID11324702.
^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.
^Maceyka M, Milstien S, Spiegel S (September 2005). "Sphingosine kinases, sphingosine-1-phosphate and sphingolipidomics". Prostaglandins Other Lipid Mediat. 77 (1–4): 15–22.
doi:
10.1016/j.prostaglandins.2004.09.010.
PMID16099387.
Further reading
Stoffel W, Bauer E, Stahl J (1974). "The metabolism of sphingosine bases in Tetrahymena pyriformis Sphingosine kinase and sphingosine-1-phosphate lyase". Hoppe-Seyler's Z. Physiol. Chem. 355 (1): 61–74.
doi:
10.1515/bchm2.1974.355.1.61.
PMID4373374.
S2CID22342605.
Stoffel W, Heimann G, Hellenbroich B (1973). "Sphingosine kinase in blood platelets". Hoppe-Seyler's Z. Physiol. Chem. 354 (5): 562–6.
doi:
10.1515/bchm2.1973.354.1.562.
PMID4372149.
