Sphingosine-1-phosphate
- (2S, 3R, 4E )-2- amino-4- octadecene -1 ,3 -diol 1-phosphate
- D -erythro- Sphingosine 1-phosphate
Fixed
Attention
Template: Infobox chemical / molecular formula search available
Sphingosine -1-phosphate, as well S1P, is occurring in vertebrates, insects, and plants, chemical compound from the group of sphingolipids and lysophosphatides. The phosphoric acid esters of sphingosine is a tissue hormone ( second messengers ) with impact on cell growth, change of location of the active cell ( cell migration ), and cell differentiation. Sphingosine -1 -phosphate, inhibits the apoptosis (programmed cell death).
- Fingolimod 4.1
- 4.2 Oncology
- 4.3 Cardiovascular System
Biosynthesis and metabolism
The biosynthesis of the sphingosine-1- phosphate is carried out of the sphingolipid is sphingomyelin. This is hydrolyzed by sphingomyelinase to cleave a Phosphocholinrestes to ceramide and further by ceramidase to sphingosine. To the latter, a phosphate residue is transferred to the hydroxyl group and sphingosine -1-phosphate released by the sphingosine kinase ( EC 2.7.1.91 ) with the consumption of one molecule ATP.
The reduction takes place in two ways: on the one hand, in the reverse of the last synthesis step S1P hydrolyzed to sphingosine and phosphate, on the other hand, by the sphinganine -1 - phosphate aldolase ( EC 4.1.2.27, also sphingosine -1-phosphate lyase ) a split in 2- hexadecenal and phosphoethanolamine are catalyzed. But also play a role in tackling several phosphatidate phosphatases.
Function
Sphingosine -1-phosphate as a signaling molecule has a variety of intra-and extracellular functions. Particularly noteworthy is its meaning for:
- Cell proliferation: S1P enhances cell proliferation and protection factor in the case of toxic events. For the purposes of the sphingolipid rheostat leads an increased formation of S1P to reduce of sphingosine and ceramide, which are the endogenous cell death, apoptosis, conducive.
- Cell migration: S1P causes tissue hormone as a reinforcement of the directed migratory behavior of individual cells (keyword chemotaxis) by increasing the activity of cytoskeletal movement functions ( activation of the S1P1 receptor ) and innergeweblicher anchors ( activation of the S1P2 receptor, keyword stress fiber). The recirculation of lymphocytes is inhibited.
- Vascular permeability: junction by activating the VE-Cadherin-Systems/adherens and unknown effects on the vesicular transcytosis, the permeability of the endothelium to large molecules and possibly cells is significantly reduced. The effect of VEGF is inhibited.
- Angiogenesis: Many processes of angiogenesis are supported: induction of endothelial NO synthase ( eNOS), proliferation and migration of endothelial cells, tube formation ( tube formation ), vascular smooth muscle cells and pericytes maturation.
- The function of platelets: S1P is formed in platelets, stored and secreted upon activation. It is found in the platelets no degrading pathway.
- Stimulation of cyclooxygenase 2 to the production of PGE2. Synergistic induction of cytosolic phospholipase A2 ( cPLA2 ) ceramide -1-phosphate.
Regulation
Receptors and signal transduction
S1P receptors are typically coupled to G proteins and by ligand binding and autophosphorylation or by ligand-independent phosphorylation by other kinases (eg akt/PI3K, keyword transactivation ) enabled. The receptors were first edg *, * s1p named later. 2nd messenger are all branches of the MAP kinases, PI3K, PLC/IP3/Calcium, rho kinase.
Positive regulation
S1P is formed by sphingosine kinases by phosphorylation of sphingosine. A regulation mechanism, the intracellular concentration of this enzyme in the ' migratory corner ' of the migrating cells, the plasma membrane is detected by their phosphatidylserine. SPHK1/SK1 induced by various growth factors and hormones.
Negative regulation of
Section through S1P lyase (coenzyme: pyridoxal phosphate ) to hexadecanal and phosphoethanolamine. Various Lipidphosphatasen which, inter alia, Dephosphorylate S1P to sphingosine.
System error
At S1P1 receptor knockout mice late events of angiogenesis larger vessels are defective, in which the behavior of the smooth muscle cells and pericytes is altered so that they do not form the necessary extent. S1P1 - / - Doppelknockout - Embyros die before birth from due to faulty vascularization.
Clinical Perspective
Fingolimod
Fingolimod is a sphingosine analogue and is used in phosphorylation by sphingosine kinase 2 (SK2 ) to FTY720 - phosphate to an agonist at several S1P receptors ( S1P1, S1P3, S1P4, S1P5 ). It is used to treat multiple sclerosis. The main effect of the substance based on an internalization and thus elimination of the S1P1 receptor. By shutting modulation of S1P1 receptors on lymphocytes remain the lymphocytes, which would leave the lymph nodes, there are subendothelial. Observing a sequestration of lymphocytes in the primary and secondary lymphoid organs with consequent reduced recirculation thereof.
( The basic anatomic structure of the marginal zone of the spleen is S1P - dependent, since the structural integrity of the inner Marginalsinusendothels the S1P3 receptor is dependent. Without anatomical barrier the particular marginal zone B enter cells event independently in the lymphoid follicles of the spleen, which autoimmune reactions are to be expected. Through functional antagonism ( failure of the S1P1 receptor ) migrate the MZ B cells in the lymphoid follicles. Usually this happens only if systemically a foreign antigen or bioactive agent material (eg LPS) this, the bloodstream exposed anatomically located, first activates B cells, whereupon reduce this their S1P receptor expression. )
Oncology
Modulation and cytotoxic oncology therapies. Neoangiogenesis.
Cardiovascular System
S1P3 receptor: vasoconstriction, hypertension, bradycardia. S1P1 Receptor: Endothelial permeability is reduced. Angiogenesis. PC1: is translosziert to the plasma membrane in the physiological state of the ischemic preconditionings and acts as cardioprotective. Unknown: negative inotropic (heart punch ).