Phospholipids and sphingolipids are the major structural lipids of membranes, and their synthesis, degradation, and remodeling are tightly regulated. Beyond their structural roles, these lipids also function as signaling molecules and precursors for second messengers.
Glycerophospholipid Synthesis
Glycerophospholipid synthesis occurs primarily in the endoplasmic reticulum. The pathway begins with the formation of phosphatidic acid from glycerol-3-phosphate and two fatty acyl-CoA molecules. Phosphatidic acid is converted to diacylglycerol by phosphatidate phosphatase, and diacylglycerol is then activated by CDP-diacylglycerol or reacted with CDP-choline or CDP-ethanolamine to form the major phospholipid classes.
Phosphatidylcholine, the most abundant phospholipid, is synthesized via the CDP-choline pathway. Choline is phosphorylated by choline kinase, then activated by CTP-phosphocholine cytidylyltransferase, and finally transferred to diacylglycerol by choline phosphotransferase. Phosphatidylethanolamine is synthesized analogously via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine.
Phosphatidylserine is formed by a base-exchange reaction that replaces the head group of phosphatidylcholine or phosphatidylethanolamine with serine. Phosphatidylinositol is synthesized from CDP-diacylglycerol and inositol.
Sphingolipid Synthesis
Sphingolipid synthesis begins in the ER with the condensation of palmitoyl-CoA and serine to form 3-ketosphinganine, catalyzed by serine palmitoyltransferase. This is the rate-limiting step. 3-Ketosphinganine is reduced to sphinganine, which is then acylated with a fatty acyl-CoA to form dihydroceramide. Introduction of a double bond produces ceramide.
Ceramide is the central hub of sphingolipid metabolism. It is converted to sphingomyelin by the addition of phosphocholine from phosphatidylcholine, catalyzed by sphingomyelin synthase in the Golgi. Glycosphingolipids are formed by the addition of sugar residues to ceramide. Glucosylceramide is the simplest glycosphingolipid, and further glycosylation produces complex gangliosides.
Phospholipid Degradation
Phospholipases are a diverse family of enzymes that hydrolyze phospholipids at specific ester bonds. Phospholipase A1 cleaves the sn-1 fatty acid, while phospholipase A2 cleaves the sn-2 fatty acid, releasing a free fatty acid and lysophospholipid. Arachidonic acid released by phospholipase A2 serves as the precursor for eicosanoids. Both products are themselves bioactive or can be further metabolized. Phospholipase C cleaves the phosphodiester bond, generating diacylglycerol and a phosphorylated head group. Phospholipase D hydrolyzes the terminal phosphate ester, producing phosphatidic acid and the free head group.
Sphingolipid Degradation
Sphingolipid degradation occurs in lysosomes through the sequential action of specific hydrolases. Sphingomyelin is cleaved by sphingomyelinase to produce ceramide and phosphocholine. Ceramide is further broken down by ceramidase to sphingosine and a free fatty acid.
Defects in sphingolipid degradation cause lysosomal storage diseases. Niemann-Pick disease results from sphingomyelinase deficiency, causing accumulation of sphingomyelin. Gaucher disease, the most common lysosomal storage disease, is caused by glucocerebrosidase deficiency. Tay-Sachs disease results from hexosaminidase A deficiency, leading to accumulation of GM2 ganglioside. Fabry disease involves alpha-galactosidase A deficiency, and Krabbe disease results from galactocerebrosidase deficiency.
Signaling Roles
Phosphatidylinositol is phosphorylated at specific positions on the inositol ring to generate phosphoinositides. Phosphatidylinositol 4,5-bisphosphate is cleaved by phospholipase C to produce the second messengers inositol trisphosphate and diacylglycerol. Phosphatidylinositol 3,4,5-trisphosphate, generated by PI3-kinase, recruits signaling proteins to the plasma membrane.
Sphingolipid metabolites are also potent signaling molecules. Ceramide promotes apoptosis and cell cycle arrest. Sphingosine-1-phosphate stimulates cell proliferation, survival, and migration through specific G protein-coupled receptors. The balance between ceramide and sphingosine-1-phosphate is thought to determine cell fate decisions.
