A type of ceramide, known as C16 ceramide, has been linked to obesity, insulin resistance and liver disease. Researchers hope that future drugs could target the C16 ceramide-synthesizing CerS6 to treat obesity-related diseases. However, the molecular mechanism underlying ceramide synthesis by CerS enzymes is poorly understood.
Ceramides are key nutritional signals, and abnormal build-up, especially of C16 ceramide, is associated with metabolic dysfunction. Elevated levels of ceramides have been observed in obesity-related metabolic disorders such as diabetes, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (also known as NASH).
The study provides structural snapshots of CerS6 at two stages of its reaction cycle. These reveal its ping-pong reaction mechanism, which requires transfer of a fatty acyl chain onto the enzyme, to form a stable acyl–imidazole intermediate. This then reacts with the sphingoid base to produce the final ceramide lipid reaction product. This CerS6-catalyzed reaction occurs for both the native substrate, sphinganine, and the drug FTY720 (fingolimod) used to treat relapsing-remitting multiple sclerosis. In addition to discovering CerS’s fundamental activity, the authors also revealed how a fungal toxin, Fumonisin B1 (FB1), often found in cereal crops inhibits the protein. Their results demonstrate that FB1 is a substrate of CerS6, and the resulting N-palmitoyl FB1 remains tightly bound to trap the protein in a product-bound state.
These results provide a framework for understanding CerS function, selectivity and inhibition. This opens new routes for future drug discovery, and shines a light on the role of the ceramide synthase proteins in the metabolism of currently used therapeutics.
Dr. David Sauer, Principal Investigator at the Centre for Medicines Discovery and co-lead author of the study, said: ‘This is a significant step forward in understanding how ceramide synthases work, bringing us closer to developing new treatments for conditions such as metabolic diseases. The collaboration with Boehringer Ingelheim was essential to our scientific discoveries, and ultimately will enable new therapies that make a real difference in patients' lives.’
Christofer Tautermann, Director and Global Head of Computational Chemistry at Boehringer Ingelheim, said: ‘Our collaboration with NDM's Centre for Medicines Discovery in Oxford via our SGC participation enabled us to gain a deeper understanding of ceramide synthase's structure and function. Working with the CMD accelerated the development of essential assays for compound screening and biophysical profiling. We were very impressed by the elucidation of the complex enzymatic mechanism and believe that the high-resolution structure will be highly useful to support future drug discovery projects.'
To find out more, read the full paper on the Nature Structural and Molecular Biology website: https://doi.org/10.1038/s41594-024-01414-3