Sphingoid bases (SP01)

From LipidomicsWiki

Jump to: navigation, search


LIPID MAPS Subclasses


The bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P) is an important lipid mediator that has been implicated in many biological processes. S1P has been detected in organisms as diverse as plants, yeast, worms, flies, and mammals. More than a decade has elapsed since it was first suggested that S1P can regulate cell growth.



Natural sources



Biophysical properties

Biochemical pathways

Biochemical synthesis

S1P is produced upon phosphorylation of sphingosine by sphingosine kinase during the breakdown of sphingomyelin. Sphingosine kinase is a highly conserved enzyme, which is activated by several stimuli. S1P can be further degraded to phosphoethanolamine and hexadecanal by sphingosine-1-phosphate lyase. It can be also converted back to sphingosine via the action of sphingosine-1-phosphate phosphatase thus increasing the level of sphingosine in the cytosol and cell membranes. Elevated concentration of sphingosine is potentially toxic for the cells as sphingosine modulates critical molecules such as protein kinase C and ion-channels and disturbs cell membranes (Hannun et al. 2001). Sphingosine is also a substrate for sphingosine kinase to produce sphingosine-1-phosphate.

Extracellular S1P can be generated through two pathways: phosphorylation of extracellular sphingosine by sphingosine kinase released from endothelial cells or release of intracellular S1P from various cell types.

Sphingosine kinase

Sphingosine kinase is the enzyme that catalyses the phosphorylation of sphingosine and its two isoforms SPHK1 and SPHK2 have been identified as separate genes (Kohama et al. 1998, Liu et al. 2000). These kinases have homology to the diacylglycerol kinase catalytic site and to calmodulin-binding motifs (Kohama et al 1998). SPHK1 is localized in the cytosol, however some growth factors can induce its translocation to the plasma membrane (Spiegel and Milstien, 2003 and lipid-protein interactions may play a major role in the regulation of membrane translocation and activation of SPHK1 (Stahelin at al, 2005). Growth and survival factors regulate the activity of SPHK1 and S1P synthesised in the presence of this isoform has been found to exert mitogenic and anti-apoptotic effects (Olivera et al, 1999). In contrast, little is known about SPHK2. Whereas SPHK1 is stimulated by several simuli, SPHK2 is activated specifically in the response to EGF (Olivera et al, 2005). Although, these both isoforms have similar amino acid sequence, they differ in their kinetic properties, developmental and tissue expression suggesting that they may have distinct physiological properties. Interestingly, SPHK2 contains a 9-amino acid motif that is similar to that present in BH3-only proteins, what would partially explain why SPKH2 supresses growth and induces apoptosis (Liu at al, 2003). Similarly to other BH3-only proteins, SPHK2 has been localized to the endoplasmic reticulum. Additionally, recently, it has been documented that this isoform is present in nuclei and due to its localization, is able to inhibit DNA synthesis (Igarashi et al. 2003). Interestingly, S1P activity is dependent on the isoform of the sphingosine kinase, which takes part in S1P biosynthesis. S1P is now recognized as a potent bioactive lipid with multiple functions and it is suggested to be involved in the regulation of cell shape changes, platelet aggregation, neurite retraction and smooth muscle cell chemotaxis (Spiegel, 1999). Various stimuli increase the intracellular concentration of S1P by activating sphingosine kinase. The list includes growth and survival factors, such as PDGF, serum, NGF as well as muscarinic acetylcholine agonists and TNF-alpha. Free plasma levels of S1P are tightly regulated by protein binding to albumin and HDL.


S1P is present both in plasma and serum. Its concentration is regulated by the balance between synthesis through sphingosine kinase and degradation by phosphohydrolase or lyase. However, the concentration of S1P is relatively low, possibly reflecting the low expression of sphingosine kinase. Blood platelets are an exception as they release substantial amounts of S1P from α-granules where it is stored by platelet activation and have a robust sphingosine kinase activity and lack of S1P-lyse (Olivera and Spiegel, 2001). S1P export from mammalian cells is not yet well documented. It has been shown that mammalian cells of haematopoietic origin actively export/secrete S1P (Yatomi et al. 2001), the precise mechanism of this transport, however, is not known.


S1P is considered as a unique lipid mediator acting both internally and externally. As a second messenger is S1P implicated in the regulation of Ca+2 mobilization, in cellular growth and proliferation and survival induced by platelet-derived growth factor, nerve growth factor and serum. Through its high affinity G protein-coupled receptors, S1P acts as an extracellular physiological mediator regulating heart rate (Sugiyama et al. 2000), coronary artery blood flow (Ohmori et al. 2003), blood pressure (Karliner 2002), endothelial integrity in the lung (English et al. 2002, Garcia et al. 2001) and most recently it has been shown to regulate the recirculation of lymphocytes (Rosen et al. 2003, Xie et al. 2003).

Similarities with lysophosphatidic acid

The structure of S1P is similar to that of the glycerophospholipid, lysophosphatidic acid (LPA), a platelet-derived mediator that acts through its G protein-coupled receptor to influence target cells. Lysophosphatidic acid is one of the simplest natural phospholipids (Moolenaar 1995). Its important role as a precursor of phospholipid synthesis in both eukaryotic and prokaryotic cells has been known since a long time, and recently it has emerged as an intracellular signalling molecule. The appearance and functional properties of both LPA and S1P suggest similar roles in development, wound healing and tissue regeneration. LPA and S1P also evoke cellular effector functions, which are dependent on cytoskeletal responses such as contraction, secretion, adhesion and chemotaxis. The list of biological responses to both molecules (Fig. 34) includes also cell aggregation and proliferation, hypertrophy, differentiation, migration, in neuroblastoma cells: cell rounding, neurite retraction and inhibition of melanoma and breast cancer cell motility (An et al. 1998).

Figure 34. S1P and LPA receptor-mediated pathways (An et al. 1998)
Figure 34. S1P and LPA receptor-mediated pathways (An et al. 1998)



Biological processes associated

Link to Lipids as constituents of biological processes


Link to Lipidomics technologies

Analysis methods

Chemical synthesis

Personal tools
Create a book