The complexity of sphingolipid biosynthesis in the endoplasmic reticulum.

Unlike the synthesis of other membrane lipids, sphingolipid synthesis is compartmentalized between the endoplasmic reticulum and the Golgi apparatus. The initial steps of sphingolipid synthesis, from the activity of serine palmitoyltransferase through to dihydroceramide desaturase, take place in the endoplasmic reticulum, but the further metabolism of ceramide to sphingomyelin and complex glycosphingolipids takes place mostly in the Golgi apparatus. Studies over the last decade or so have revealed unexpected levels of complexity in the sphingolipid biosynthetic pathway, mainly due to either the promiscuity of some enzymes towards their substrates, or the tight selectivity of others towards specific substrates. We now discuss two enzymes in this pathway, namely serine palmitoyltransferase (SPT) and ceramide synthase (CerS), and one lipid transport protein, CERT. For SPT and CERT, significant structural information is available, and for CerS, significant information has recently been obtained that sheds light of the roles of the specific ceramide species that are produced by each of the CerS. We consider the mechanisms by which specificity is generated and speculate on the reasons that sphingolipid biosynthesis is so complex. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.