An overview of sphingolipid metabolism: from synthesis to breakdown.

Sphingolipids constitute a class of lipids defined by their eighteen carbon amino-alcohol backbones which are synthesized in the ER from nonsphingolipid precursors. Modification of this basic structure is what gives rise to the vast family of sphingolipids that play significant roles in membrane biology and provide many bioactive metabolites that regulate cell function. Despite the diversity of structure and function of sphingolipids, their creation and destruction are governed by common synthetic and catabolic pathways. In this regard, sphingolipid metabolism can be imagined as an array of interconnected networks that diverge from a single common entry point and converge into a single common breakdown pathway. In their simplest forms, sphingosine, phytosphingosine and dihydrosphingosine serve as the backbones upon which further complexity is achieved. For example, phosphorylation of the C1 hydroxyl group yields the final breakdown products and/or the important signaling molecules sphingosine-1-phosphate, phytosphingosine-1-phosphate and dihydrosphingosine-1-phosphate, respectively. On the other hand, acylation of sphingosine, phytosphingosine, or dihydrosphingosine with one of several possible acyl CoA molecules through the action of distinct ceramide synthases produces the molecules defined as ceramide, phytoceramide, or dihydroceramide. Ceramide, due to the differing acyl CoAs that can be used to produce it, is technically a class of molecules rather than a single molecule and therefore may have different biological functions depending on the acyl chain it is composed of. At the apex of complexity is the group of lipids known as glycosphingolipids (GSL) which contain dozens of different sphingolipid species differing by both the order and type of sugar residues attached to their headgroups. Since these molecules are produced from ceramide precursors, they too may have differences in their acyl chain composition, revealing an additional layer of variation. The glycosphingolipids are divided broadly into two categories: glucosphingolipids and galactosphingolipids. The glucosphingolipids depend initially on the enzyme glucosylceramide synthase (GCS) which attaches glucose as the first residue to the C1 hydroxyl position. Galactosphingolipids, on the other hand, are generated from galactosylceramide synthase (GalCerS), an evolutionarily dissimilar enzyme from GCS. Glycosphingolipids are further divided based upon further modification by various glycosyltransferases which increases the potential variation in lipid species by several fold. Far more abundant are the sphingomyelin species which are produced in parallel with glycosphingolipids, however they are defined by a phosphocholine headgroup rather than the addition of sugar residues. Although sphingomyelin species all share a common headgroup, they too are produced from a variety of ceramide species and therefore can have differing acyl chains attached to their C-2 amino groups. Whether or not the differing acyl chain lengths in SMs dictate unique functions or important biophysical distinctions has not yet been established. Understanding the function of all the existing glycosphingolipids and sphingomyelin species will be a major undertaking in the future since the tools to study and measure these species are only beginning to be developed (see Fig 1 for an illustrated depiction of the various sphingolipid structures). The simple sphingolipids serve both as the precursors and the breakdown products of the more complex ones. Importantly, in recent decades, these simple sphingolipids have gained attention for having significant signaling and regulatory roles within cells. In addition, many tools have emerged to measure the levels of simple sphingolipids and therefore have become the focus of even more intense study in recent years. With this thought in mind, this chapter will pay tribute to the complex sphingolipids, but focus on the regulation of simple sphingolipid metabolism.