CERAMIDE-1-PHOSPHATE

STRUCTURE, BIOSYNTHESIS AND FUNCTION

Ceramide-1-phosphate, a sphingoid analogue of phosphatidic acid, is one of the metabolites in the 'sphingomyelin cycle'. It is formed from ceramide by the action of a specific ceramide kinase, which is related to but distinct from the sphingosine kinases that synthesise sphingosine-1-phosphate. There is evidence that the ceramide precursor is derived from sphingomyelin but not from glucosylceramide in animal tissues.

Formula of ceramide-1-phosphate

The enzyme ceramide kinase (CERK) is associated exclusively with membranes; it is stimulated by calcium and is optimally active at neutral pH. It was first detected in brain synaptic vesicles and in human leukaemia (HL 60) cells, but it has since been found in many other tissues, and especially brain, heart, skeletal muscle, kidney, and liver. It is specific for natural ceramides with the erythro configuration in the base component and esterified to long-chain fatty acids. An interesting relationship to glycerophospholipid metabolism is evident in that a molecule of phosphatidylinositol 4,5-bisphosphate is bound to ceramide kinase and is essential for its activity. This may also direct the enzyme to particular membranes within the cell. The activity of the enzyme is also promoted by cardiolipin.

Catabolism to ceramide is accomplished by a specific ceramide-1-phosphate phosphatase, suggesting that ceramide and ceramide-1-phosphate are readily interconvertible in cells. A recent study suggest that ceramide-1-phosphate may be much more abundant in some tissues than has been supposed, perhaps several fold higher than ceramide and 25% of the level of sphingomyelin.

It is now known that ceramide-1-phosphate possesses a number of biological functions, some of which are confined to specific cell types and are very different from those of other sphingolipid metabolites. For example, it reportedly stimulates DNA synthesis and cell division in rat fibroblasts by mechanisms that are as yet unclear, and it has affects upon the immune system.

In particular, it is an important mediator of the inflammatory response, by stimulating the release of arachidonic acid by activating the specific phospholipase A₂ that is the initial rate-limiting step of eicosanoid biosynthesis. This last important discovery arose from the finding that an important component of the venom from the spider Loxosceles reclusus is the enzyme sphingomyelinase D, which hydrolyses sphingomyelin to ceramide-1-phosphate, and causes a severe inflammatory response mediated by prostaglandins. It appears that ceramide-1-phosphate activates phospholipase A₂ by binding with it directly as opposed to indirectly via a receptor mechanism. Indeed, there is evidence that ceramide kinase and phospholipase A₂ activities are closely linked within the same membranes (the trans-Golgi network), following recruitment of the latter enzyme from the cytosol. A specific pool of ceramide, containing 16:0 and 18:0 fatty acid components, is transported to the site of synthesis by the ceramide transport protein (CERT) for the purpose.

Also, ceramide-1-phosphate is a potent inhibitor of apoptosis and is an inducer of cell survival. Thus, ceramide and ceramide-1-phosphate have antagonistic functions, and a correct balance between the concentrations of the two metabolites is essential for cell and tissue homeostasis. The relative concentrations of sphingosine-1-phosphate and long-chain bases must also be considered, as all are mutually convertible. As a consequence of distortion of this balance in any direction may be metabolic dysfunction or disease, the activities of the enzymes involved in synthesis and catabolism must be coordinated efficiently to ensure that cells function normally.

Interestingly, a ceramide kinase has been detected in plants such as Arabidopsis thaliana, where its function may be to remove excess ceramide and make the plant more resistant to environmental stress. Similarly, the balance between ceramide and ceramide-1-phosphate may be crucial in modulating the process of apoptosis in plants. Ceramide kinase is not present in yeast.

Whereas sphingosine-1-phosphate functions mainly via G-protein-coupled receptors, ceramide-1-phosphate appears to bind directly to its target molecules, for example phospholipase A₂ (see above). Although exogenously added ceramide-1-phosphate induces a number of several cellular responses in vitro, it is believed that these effects are a result of ceramide generated on the plasma membrane via hydrolysis of ceramide-1-phosphate, rather through than a direct interaction with a receptor at the cell surface.

Analysis of the various components of the sphingomyelin cycle, including ceramide-1-phosphate, can now be carried out in a comprehensive manner by high-performance liquid chromatography in conjunction with tandem mass spectrometry.

The Lipid Library

CERAMIDE-1-PHOSPHATE

STRUCTURE, BIOSYNTHESIS AND FUNCTION

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