The sphingolipid metabolism pathway depicted here describes the synthesis of sphingolipids which include sphingomyelins, ceramides, phosphoceramides, glucosylceramides, galactosylceramides, sulfagalactosylceramides, lactosylceramides, and various other ceramides. The core of a sphingolipid is the long-chain amino alcohol called sphingosine. Amino acylation, with a long-chain fatty acid, at the 2-carbon position of sphingosine yields a ceramide. Sphingolipids are a component of all membranes but are particularly abundant in the myelin sheath. De novo sphingolipid synthesis begins at the cytoplasmic side of the ER (endoplasmic reticulum) with the formation of 3-keto-dihydrosphingosine (also known as 3-ketosphinganine) by the enzyme known as serine palmitoyltransferase (SPT). The preferred substrates for this reaction are palmitoyl-CoA and serine. Next, 3-keto-dihydrosphingosine is reduced to form dihydrosphingosine (also known as sphinganine) via the enzyme 3-ketodihydrosphingosine reductase (KDHR), which is also known as 3-ketosphinganine reductase. Dihydrosphingosine (sphinganine) is acylated by the action of several dihydroceramide synthases (CerS) to form dihydroceramide. Dihydroceramide is then desaturated in the original palmitic portion of the lipid via dihydroceramide desaturase 1 (DES1) to form ceramide. Following the conversion to ceramide, sphingosine is released via the action of ceramidase. Sphingosine can be re-converted into a ceramide by condensation with an acyl-CoA catalyzed by the various CerS enzymes. Ceramide may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by glucosylceramide synthase (to form a glucosylceramide) or galactosylceramide synthase (to form a galactosylceramide). Additionally, it can be converted to sphingomyelin by the addition of a phosphorylcholine headgroup by sphingomyelin synthase (SMS). Sphingomyelins are the only sphingolipids that are phospholipids. Diacylglycerol is also generated via this process. Alternately, ceramide may be broken down by a ceramidase to form sphingosine. Sphingosine may be phosphorylated to form sphingosine-1-phosphate, which may, in turn, be dephosphorylated to regenerate sphingosine. Sphingolipid catabolism allows the reversion of these metabolites to ceramide. The complex glycosphingolipids are hydrolyzed to glucosylceramide and galactosylceramide. These lipids are then hydrolyzed by beta-glucosidases and beta-galactosidases to regenerate ceramide. Similarly, sphingomyelins may be broken down by sphingomyelinase to create ceramides and phosphocholine. The only route by which sphingolipids are converted into non-sphingolipids is through sphingosine-1-phosphate lyase. This forms ethanolamine phosphate and hexadecenal.

Sphingolipid Metabolism References