Sphingosine kinase (SphK) is a conserved

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

that catalyzes formation

sphingosine-1-phosphate 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 aminoalcoho ...

(S1P) from the precursor

sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because o ...

sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phos ...

. Sphingolipid metabolites, such as

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make ...

and

, are lipid second messengers involved in diverse cellular processes. There are two forms of SphK, SphK1 and SphK2. SphK1 is found in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

of eukaryotic cells, and migrates to the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

upon activation. SphK2 is localized to the nucleus.

Function

S1P has been shown to regulate diverse cellular processes. It has been characterized as a

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 ...

molecule with dual function. On one hand, it exerts its actions extracellularly by binding to the five different S1P

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

that couple to a variety of

G-proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ac ...

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 Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first m ...

, 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 In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

, have therefore received considerable interest.

Sphingolipid metabolism

Sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because o ...

s 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

(Cer).

Ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make ...

s 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 Palmitoyl-CoA is an acyl-CoA thioester. It is an "activated" form of palmitic acid and can be transported into the mitochondrial matrix by the carnitine shuttle system (which transports fatty acyl-CoA molecules into the mitochondria), and once in ...

with

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...

, 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 In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

chain is then added in an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

linkage with the 2-amino group, forming dihydroceramide (dihydro-Cer). A head group, such as phosphocholine or a

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...

, can now be added to the 1-OH, forming a

, although most sphingolipids of higher eukaryotes contain further modifications of the LCB. Sphk1 diag b

Popular culture

During "100,000 Airplanes", a third season episode of ''

The West Wing ''The West Wing'' is an American serial political drama television series created by Aaron Sorkin that was originally broadcast on NBC from September 22, 1999, to May 14, 2006. The series is set primarily in the West Wing of the White Hous ...

'', 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 Josiah Edward "Jed" Bartlet is a fictional character from the American television serial drama ''The West Wing'' created by Aaron Sorkin and portrayed by actor Martin Sheen. The role earned Sheen a Golden Globe Award for Best Actor – Televi ...

, to consider launching an Apollo program to cure cancer.

References

External links

* {{DEFAULTSORT:Sphingosine Kinase EC 2.7.1 Lipids

Function

Sphingolipid metabolism

Popular culture

References

Further reading

External links