Some sphingolipid fundamentals. (A) Depictions of sphingomyelin and ceramide. The bonds cleaved by SMase C and SMase D are indicated. (B) De novo synthesis of sphingomyelin. The first four enzymatic steps of the de novo pathway take place at the cytoplasmic face of the ER, the last step at the cytoplasmic face of the Golgi complex. Breakdown of cellular sphingomyelin and resynthesis of sphingomyelin from ceramide also occur at other locations in the cell. Separate branches of the de novo synthetic pathway (not depicted) lead from ceramide to the two major classes of glycosphingolipids. (C) Sphingomyelin metabolism. Mammalian cellular enzymes are able to catalyze all the steps indicated, except the conversion of sphingomyelin to ceramide-1-phosphate. Specific SMase D enzymes that catalyze this step have been isolated from C. pseudotuberculosis and from spider venoms. The spider SMase D product is ceramide 1,3-cyclic phosphate rather than ceramide-1-phosphate (Lajoie et al., 2013), adding a further nuance, since it is not clear whether the cyclic phosphate is readily metabolized by mammalian cellular enzymes. Although the mapped metabolic pathways provide guidance, it is still necessary to determine the actual extent and pattern of sphingomyelin metabolism for any specific cell type, localization in the cell, and experimental condition. CERK, ceramide kinase; LPP, lipid phosphate phosphatase; S1P phosphatase, sphingosine-1-phosphate phosphatase; S1P lyase, sphingosine-1-phosphate lyase. See Gault et al. (2010) for a complete discussion of sphingolipid synthesis and degradation.