Figure 1: Diversity and Synthesis of Ceramides.

Synthesis of ceramide occurs via three main pathways, each of which utilizes enzymes with multiple isoforms, pathway-specific localization, and/or reactants with variable R-groups to yield a diverse array of Ceramide species with unique bioactivity. The De Novo Pathway occurs in the endoplasmic reticulum and begins with rate-limiting Serine Palmitoyltransferase-catalyzed condensation of Palmitoyl-CoA and L-Serine to form 3-keto-Sphinganine, which is then reduced to Sphinganine by 3-keto-Sphinganine Reductase. Ceramide Synthases 1-6 add a fatty acid chain (blue) of variable length (R) to form Dihydroceramide, which is then is converted to Ceramide by Dihydroceramide Desaturase and transported to the Golgi¹⁸². The Sphingomyelinase Pathway hydrolyzes Sphingomyelin to Ceramide via acid or neutral Sphingomyelinases 1-5, which are found in the plasma membrane, cytosol, mitochondria, endosomes, and lysosomes^{183, 184}. The Salvage Pathway breaks down complex sphingolipids such as gangliosides in endo-lysosomal compartments to Sphingosine, which may then be transported to the ER and reacylated to Ceramide by Ceramide Synthases 1-5. Alternatively, Sphingosine (R1 = H) may be phosphorylated at R1 to Sphingosine-1-Phosphate by Sphingosine Kinase^185–187. Ceramide may be phosphorylated at R1 by Ceramide Kinase to generate Ceramide-1-Phosphate, or it may be glycosylated to form Cerebrosides (Glucosylceramides and Galactosylceramides). Addition of a Galactose residue to a Glucosylceramide yields a Lactosylceramide, which may be further glycosylated or acquire sialic acid residues at various sites (Gn, Gn+1...) to form Gangliosides¹⁸⁸.