Figure 1. The sphingolipid metabolic pathway.
The de novo biosynthesis of sphingolipids initiates in the endoplasmic reticulum (ER) where serine palmitoyltransferase condenses L-serine and palmitoyl-CoA, generating 3-ketodihydrosphingosine (3-keto-DHS), which is rapidly reduced to form dihydrosphingosine (DHS). DHS is N-acylated to form dihydroceramide, which is further converted into ceramide by the introduction of a double bond in the DHS base. Newly synthesized ceramide is transported to the Golgi apparatus where it is converted to sphingomyelin (SM) and glucosylceramide (GluCer). Ceramide transport to the Golgi is facilitated by CERT as well as vesicular transport 99. Transfer of GluCer from the cytoplasmic to the luminal side of the Golgi for the synthesis of complex glycosphingolipids (GSL) is facilitated by FAPP2 99. SM and GSL are transported via vesicles from the Golgi to the plasma membrane. The recycling/degradation of higher order sphingolipids in the plasma membrane or lysosomal compartment also gives rise to ceramide, which can be further deacylated to yield sphingosine 100. Sphingosine and ceramide can be phosphorylated and de-phosphorylated by kinase and phosphatase activities, which exist in multiple compartments (see text for details). Sphingosine-1-phosphate (S1P) can be irreversibly degraded by S1P lyase located at the cytoplasmic side of the ER. Alternatively, S1P can be de-phosphorylated by specific phosphatases at the luminal side and converted back to ceramide for recycling (salvage pathway). The salvage pathway may also utilize sphingosine exiting directly from the lysosome. SM synthase activity resulting in ceramide-phosphoethanolamine (CPE) formation is found in the plasma membrane and ER.