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Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.


Production

S1P is formed from ceramide, which is composed of a sphingosine and a fatty acid. Ceramidase, an enzyme primarily present in plasma membrane, will convert ceramide to sphingosine. sphingosine is then phosphorylated by sphingosine kinase (SK) isoenzymes. There are two identified isoenzymes, SK1 and SK2. These two enzymes have different tissue distribution. SK1 is highly expressed in spleen, lung and leukocytes, while SK2 is highly expressed in liver and kidney. SK2 is located mainly in the mitochondria, nucleus and the endoplasmic reticulum whereas SK1 is mainly located in cytoplasm and the cell membrane.


Metabolism and degradation

S1P can be dephosphorylated to sphingosine by sphingosine phosphatases and can be irreversibly degraded by an enzyme, sphingosine phosphate lyase.


Function

S1P is a blood borne lipid mediator, in particular in association with lipoproteins such as high density lipoprotein (HDL). It is less abundant in tissue fluids. This is referred to as the S1P gradient, which seems to have biological significance in immune cell trafficking. Originally thought as an intracellular second messenger, it was discovered to be an extracellular ligand for G protein-coupled receptor S1PR1 in 1998. It is now known that
sphingosine-1-phosphate receptor The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5. Discov ...
s (S1P receptors) are members of the
lysophospholipid receptor The lysophospholipid receptor (LPL-R) group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eight LPL receptors, each encoded by a separate gene. T ...
family. There are five described to date. Most of the biological effects of S1P are mediated by signaling through the cell surface receptors. Although S1P is of importance in the entire human body, it is a major regulator of vascular and immune systems. In addition, it might be relevant in the
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...
. In the vascular system, S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. Inhibition of S1P receptors was shown to be critical for immunomodulation. S1P has also been shown to directly suppress TLR mediated immune response from T cells. A research team, led by a scientist at Weill Cornell Medical College, has discovered that red blood cells perform a second vital function: angiogenesis. Given its role in creating new blood vessels, scientists recognize S1P as vital to human health — and a player in some diseases, such as
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. And although S1P is known to be blood borne, no one realized until this study that S1P is supplied by red blood cells to control blood vessel growth.


Clinical significance

The levels of S1P (in a range of 5–40 μmol/L) are 5 to 10 times up-regulated in ovarian cancer patients' ascites. S1P at this physiological concentration stimulates migration and invasion of epithelial ovarian cancer cells but inhibits migration of normal ovarian surface epithelial cells. Most (more than 90%) ovarian cancers arise from the epithelium of the ovary. Therefore, extracellular S1P could have an important role in cancer progression by promoting migration of epithelial ovarian cancer cells. Ozonization of human blood is associated with increased concentrations of S1P in the plasma. In addition, S1P modulates the proliferation of skin cells. This in particular applies to keratinocytes while
fibroblast A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
s are not addressed in this way, apart from cell growth and differentiation While S1P suppresses epidermal proliferation as the glucocorticoids do, it differs from them in so far, as proliferation of dermal fibroblasts is not reduced. In fact, S1P even activates fibroblast-derived
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide s ...
protein production.


As a drug

Administration of S1P has been shown to protect oocytes from chemotherapeutic agents ''in vitro'', as well as ''in vivo'' from chemotherapeutic and radiation therapies. which otherwise induce
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
of the cells. S1P has protected ovarian tissue xenografts in SCID mouse models from radiation induced
atresia Atresia is a condition in which an orifice or passage in the body is (usually abnormally) closed or absent. Examples of atresia include: *Aural atresia, a congenital deformity where the ear canal is underdeveloped. * Biliary atresia, a condition i ...
. In animal models these protected oocytes have been used to produce healthy live young. Radiotherapies and chemotherapies can cause apoptosis of
ovarian follicles An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with ...
, causing premature ovarian failure, and so S1P is of great interest in fertility preservation. However, its mechanism of inhibiting the sphingomyelin apoptotic pathway may also interfere with the
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
action of chemotherapy drugs. Due to the hyperproliferative action against epidermal cells, S1P has been considered as an active pharmaceutical ingredient for hyperproliferative skin diseases, in particular, psoriasis vulgaris and acne vulgaris. Although S1P is active at very low concentrations, bioavailability of the compound in human skin is a concern. Therefore, a topical formulation based on specific drug carriers has been considered inevitable.


As a drug target

Lpath Inc has produced and optimized a monoclonal anti-S1P antibody ( Sphingomab). Sphingomab can absorb S1P from the extracellular fluid, thereby lowering the effective concentration of S1P. is an experimental anti-S1P monoclonal antibody that has had a phase II clinical trial for
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, re ...
. Sonepcizumab (LT1009) as ASONEP (for intravenous injection) has been studied for solid tumours. As iSONEP, a formulation for intravitreal injection, it has been studied for age-related macular degeneration.


S1P receptor(s) as a drug target

There are 5 types of
Sphingosine-1-phosphate receptor The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5. Discov ...
.


S1P receptor modulators

The drug fingolimod (FTY720), which agonizes the S1P receptor, prevents autoimmune lymphocytes from moving from the lymphoid organs into the central nervous system. It has been shown in phase III clinical trials to reduce relapses and improve other outcomes in multiple sclerosis. S1P, as well as FTY720, has been shown to have anti-inflammatory properties at low concentrations and prevent monocyte:endothelial interactions in aorta, possibly through the S1P1 receptor. ONO-4641 (a drug of Ono Pharmaceutical Co., Ltd.) is a sphingosine-1-phosphate (S1P) receptor agonist which keeps lymphocytes in lymph nodes and thereby inhibits the infiltration of lymphocytes into lesions. The compound is therefore expected to be a drug for the treatment of auto-immune diseases such as multiple sclerosis, which is regarded as an intractable disease. Ozanimod is an agonist of the S1P1 and S1P5 receptors. and has been studied for various forms of
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...
.New Frontiers in S1P Modulators. March 2017
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See also

*
Lipid signaling Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellula ...
*
Lysophosphatidic acid Lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule. Function LPA acts as a potent mitogen due to its activation of three high-affinity G-protein-coupled receptors called LPAR1, LPAR2, and LPAR3 (als ...


Notes


References

* * *
MS Drug ONO-4641 Slows Brain Legions By 92%


Further reading

* {{DEFAULTSORT:Sphingosine-1-Phosphate Lipids