Ceramidases in the regulation of ceramide levels and function.

Abstract

Ceramide (Cer) occupies a central role in sphingolipid metabolism (Hannun and Luberto, 2000; Merrill and Wang, 1992). Ceramide metabolism commences in the de novo pathway with the condensation of serine and palmitoyl CoA, resulting in the formation of 3ketodihydrosphingosine (Merrill and Wang, 1992), which in turn serves as a precursor to dihydrosphingosine (Figure 1). Dihydrosphingosine is then acylated at the 2-amino position to cause the formation of dihydroceramide. It is accepted that the sphingolipid 4-5 double bond is inserted at this point, causing the formation of Cer. In turn, Cer is the precursor of mammalian complex sphingolipids, which are distinguished by substitutions at the 1hydroxyl position of ceramide. For example, sphingomyelin contains a choline phosphate head group, whereas cerebroside contains a glucosyl or galactosyl subunit. Other complex neutral and acidic glycolipids are based on the cerebrosides through sequential additions of glycose units at the 1hydroxyl position (Hannun and Luberto, 2000). Reciprocally, the catabolism of complex sphingolipids proceeds in a stepwise fashion through the action of several hydrolytic enzymes that result in the eventual formation of Cer.