1. Structure and Biosynthesis
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 primarily from sphingomyelin and only at trace levels from other sphingolipids in animal tissues.
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 conversion to ceramide-1-phosphate. The enzyme ceramide kinase (CERK) is associated mainly with membranes, especially the Golgi; it utilizes ATP as the phosphate donor, and it is stimulated by calcium and is optimally active at neutral pH, though a second isoform is cytosolic. 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 and a 4,5-trans double bond 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 appears to bind selectively to CERK via a Pleckstrin homology domain. This lipid may also direct the enzyme to particular membranes within the cell. In addition, ceramide kinase has a calmodulin-binding motif.
Other biosynthetic routes to ceramide-1-phosphate must exist, but have yet to be demonstrated experimentally, as mice in which the CERK enzyme has been deleted have normal levels of the metabolite. Certainly, sphingosine-1-phosphate is not acylated in mammalian cells, nor does there appear to be an enzyme equivalent to phospholipase D (sphingomyelinase D).
A recent study suggests that ceramide-1-phosphate is present in animal tissues at a level comparable to that of sphingosine-1-phosphate. It is presumed to be located at the cytosolic leaflet of cellular membranes. Catabolism to ceramide is accomplished by a phosphatase, suggesting that ceramide and ceramide-1-phosphate are readily interconvertible in cells.
Phytoceramide-1-phosphate has recently been detected in plant tissues, where it is generated by a sphingolipid-specific phospholipase D, presumably from glycosylinositol phosphoceramide.
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. Some of these may be a result of its physical properties in that it is fusogenic, increasing the fusibility of vesicle membranes. It is not believed to participate in raft formation in membranes.
It is a key regulator of cell growth and survival and stimulates DNA synthesis and cell division in rat fibroblasts by mechanisms that are as yet unclear, but probably involve stimulation of various protein kinases and phosphatidylinositol 3-kinase. It is a potent inhibitor of apoptosis and is an inducer of cell survival. For example in macrophages, ceramide-1-phosphate blocks apoptosis through inhibition of the enzyme acid sphingomyelinase, which generates the pro-apoptotic molecule ceramide. It also inhibits serine palmitoyltransferase, the key regulatory enzyme in the biosynthesis of long-chain bases and thence of ceramides.
Ceramide-1-phosphate is an important mediator of inflammation by stimulating the release of arachidonic acid by activating the specific phospholipase A2, which is the initial rate-limiting enzyme in the production of the inflammatory prostaglandins and leukotrienes via the release of arachidonic acid. The discovery of the role of ceramide-1-phosphate 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. Ceramide-1-phosphate activates phospholipase A2 by binding with it directly via a Ca2+-dependent phospholipid binding domain, as opposed to indirectly via a receptor mechanism; the effect is to translocate the enzyme to the membrane. 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 lipid transport protein has been identified that transfers ceramide-1-phosphate between membranes and so contributes to the regulation of eicosanoid production.
Also, in relation to inflammation, ceramide-1-phosphate stimulates the migration of macrophages, and it inhibits the formation of tumour necrosis factor α, which if produced to excess can be a contributor to the deleterious effects of septic shock.
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. A consequence of distortion of this balance in any direction may be metabolic dysfunction or disease, as 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 higher 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.
There may be synergy with the activity of sphingosine-1-phosphate, which induces up-regulation of the enzyme cyclooxygenase-2 (COX-2). However, there is now evidence that ceramide-1-phosphate binds to and activates a plasma membrane receptor that is different from the receptors for sphingosine-1-phosphate. Sphingosine-1-phosphate functions mainly via G-protein-coupled receptors, and this may be true for certain functions of ceramide-1-phosphate, for example by stimulating cell migration. However, the latter also acts by binding directly to its target molecules, for example phospholipase A2 (see above). Although ceramide-1-phosphate added exogenously induces a number of 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 than through a direct interaction with a receptor at the cell surface.
In addition, there is increasing evidence that ceramide-1-phosphate has a negative role in cancer, and that it has functions in the nervous and immune systems.
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 and electrospray ionization. However, a popular method in which a strong alkaline treatment is used to cleave interfering glycerolipids must be followed by a neutralization step, otherwise there can be a gross overestimation of ceramide-1-phosphate levels.
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Updated March 31, 2014