Ceramidsyntasen

Ceramidsyntasen, or ceramide synthases (CerS), are a family of endoplasmic reticulum–resident enzymes that catalyze the acylation of sphingoid bases with fatty acyl-CoA to form ceramides, the core molecules of sphingolipid biosynthesis. They play a central role in de novo ceramide production and in shaping the cellular sphingolipid profile, which influences membrane properties and signaling pathways.

In mammals, the CerS family comprises six isoforms, CerS1–CerS6, each with distinct fatty acyl chain-length specificities that contribute to tissue- and context-dependent ceramide compositions. For example, CerS2 preferentially uses very long-chain acyl-CoAs (C22–C24), CerS5 and CerS6 favor C16 chains, CerS1 is associated with C18 acyl chains, CerS3 participates in very long-chain synthesis important in skin, and CerS4 shows intermediate specificities. The expression patterns of CerS isoforms vary across tissues, contributing to diverse biological roles of ceramides.

Biochemically, ceramide synthases are integral membrane proteins containing conserved motifs within the TLC (TRAM-LAG1-CLN8) domain and often function as part of larger multi-enzyme complexes. The canonical reaction is sphinganine (or other sphingoid base) plus a fatty acyl-CoA to yield dihydroceramide, which is subsequently desaturated to ceramide. The different CerS isoforms determine the acyl-chain length of the resulting ceramide, influencing the physical properties of membranes and the outcome of signaling pathways.

Genetically, ceramide synthases are encoded by CERS1–CERS6 in humans, with functional homologs in yeast (Lag1p and Lac1p). Dysregulation of CerS activity or expression has been linked to altered sphingolipid balance and is associated with metabolic disorders, neurodegenerative diseases, and cancer. Inhibitors such as fumonisin B1 target CerS activity, underscoring their importance in cellular lipid homeostasis.