Sphingolipids

Sphingolipids are a class of lipids that use a sphingoid base, typically sphingosine, as their foundational backbone. The defining feature is an amide-linked fatty acid, forming ceramide, which serves as a central hub for complex sphingolipids. Depending on the head group attached to ceramide, sphingolipids are classified into several major groups, including sphingomyelins and glycosphingolipids.

Ceramide is the core molecule from which other sphingolipids are derived. Sphingomyelin contains a phosphocholine head group, produced by a transfer from phosphatidylcholine via sphingomyelin synthase. Glycosphingolipids carry carbohydrate moieties; glucosylceramide and galactosylceramide are simple examples, while more elaborate forms give rise to cerebrosides and gangliosides. Glycosphingolipids, particularly gangliosides, are enriched in the nervous system and contribute to cell recognition and signaling.

Biosynthesis of sphingolipids begins in the endoplasmic reticulum with de novo synthesis: serine palmitoyltransferase condenses serine with palmitoyl-CoA to form 3-ketosphinganine, which is reduced to sphinganine and subsequently acylated by (dihydro)ceramide synthases to dihydroceramide. Desaturation yields ceramide, the central metabolite. Ceramide can be further modified to form sphingomyelin or glycosphingolipids through specific transferases and glycosyltransferases.

Functions extend beyond membrane structure to bioactive signaling. Ceramide, sphingosine, and its phosphorylated form sphingosine-1-phosphate regulate processes such as apoptosis, cell growth, differentiation, and inflammation. Degradation in lysosomes yields ceramide and sphingosine, which can be recycled or phosphorylated.

Clinical relevance includes lysosomal storage disorders such as Gaucher disease, Niemann-Pick disease, and Tay-Sachs disease, all involving altered sphingolipid metabolism. Dysregulation is also linked to metabolic and neurodegenerative diseases.