Ceramide synthase 5 (CERS5)

Ceramide synthase 5 (CERS5) is an integral membrane enzyme of the TLC domain family that specifically catalyzes the N-acylation of sphinganine and sphingosine with palmitoyl-CoA to synthesize C16-ceramide, a bioactive sphingolipid involved in cell signaling. CerS5 operates via a ping-pong mechanism that involves covalent acyl–enzyme intermediates using a conserved histidine nucleophile. Its activity regulates apoptosis, autophagy, and metabolic adaptation, especially in cancer cells (where it sensitizes to chemotherapy), lung and brain tissue, and cardiomyocytes. Altered CerS5 function has implications in cancer, metabolic disease, and hereditary neuropathies. Clinical relevance is further supported by its role as a drug target and by associations with altered ceramide pools in disease contexts.

Other names

CerS5LASS5TRH4Ceramide synthase 5LAG1 longevity assurance homolog 5Sphingoid base N-palmitoyltransferase CERS5Sphingosine N-acyltransferase CERS5LAG1 homologTRAM homolog 4

Most drugs act by modulating ceramide production, either by directly inhibiting CerS5 (e.g., fumonisin B1 acts as an inhibitor through covalent modification), or by potentiating its pro-apoptotic actions (doxorubicin/vincristine sensitize cells via increased C16-ceramide generation). Enzyme inhibition (fumonisin B1 binds CerS family enzymes, blocking ceramide synthesis). Mitogenic/adjuvant effect (chemo-sensitization attributed to increased C16-ceramide following CerS5 upregulation).