There are three major pathways of ceramide generation.
First, the sphingomyelinase pathway uses an enzyme to break down sphingomyelin in the cell membrane
and release ceramide.
Second, the de novo pathway creates ceramide from less complex molecules.
Third, in the "salvage" pathway, sphingolipids that are broken down into sphingosine are reused by reacylation to form ceramide.
1) Sphingomyelin hydrolysis
Hydrolysis of sphingomyelin is catalyzed by the enzyme sphingomyelinase. Because sphingomyelin is one of the four common phospholipids found in the plasma membrane of cells, the implications of this method of generating ceramide is that the cellular membrane is the target of extracellular signals leading to programmed cell death. There has been research suggesting that when ionizing radiation causes apoptosis in some cells, the radiation leads to the activation of sphingomyelinase in the cell membrane and ultimately, to ceramide generation.[2]
2) De novo
De novo synthesis of ceramide begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine. This reaction is catalyzed by the enzyme serine palmitoyl transferase and is the rate-limiting step of the pathway. In turn, 3-keto-dihydrosphingosine is reduced to dihydrosphingosine, which is then followed by acylation by the enzyme (dihydro)ceramide synthase to produce dihydroceramide. The final reaction to produce ceramide is catalyzed by dihydroceramide desaturase. De novo synthesis of ceramide occurs in the endoplasmic reticulum. Ceramide is subsequently transported to the Golgi apparatus by either vesicular trafficking or the ceramide transfer protein CERT.
Once in the Golgi apparatus,
ceramide can be further metabolized
to other sphingolipids,
such as sphingomyelin and the complex glycosphingolipids.[3]
3) Salvage pathway
Constitutive degradation of sphingolipids and glycosphingolipids takes place in the acidic subcellular compartments, the late endosomes and the lysosomes, with the end goal of producing sphingosine. In the case of glycosphingolipids, exohydrolases acting at acidic pH optima cause the stepwise release of monosaccharide units from the end of the oligosaccharide chains, leaving just the sphingosine portion of the molecule, which may then contribute to the generation of ceramides. Ceramide can be further hydrolyzed by acid ceramidase to form sphingosine and a free fatty acid, both of which are able to leave the lysosome, unlike ceramide. The long-chain sphingoid bases released from the lysosome may then re-enter pathways for synthesis of ceramide and/or sphingosine-1-phosphate. The salvage pathway re-utilizes long-chain sphingoid bases to form ceramide through the action of ceramide synthase. Thus, ceramide synthase family members probably
trap free sphingosine released
from the lysosome
at the surface of the endoplasmic reticulum or in endoplasmic reticulum-associated membranes.
The salvage pathway has been estimated to contribute from 50% to 90% of sphingolipid biosynthesis.[4]
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