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Structure of human ceramide synthase 6 (CerS6) bound to C16:0 (nanobody Nb02)
Structural highlights
FunctionCERS6_HUMAN Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward palmitoyl-CoA (hexadecanoyl-CoA; C16:0-CoA) (PubMed:17609214, PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). Can use other acyl donors, but with less efficiency (By similarity). N-acylates sphinganine and sphingosine bases to form dihydroceramides and ceramides in de novo synthesis and salvage pathways, respectively (PubMed:17977534, PubMed:23530041, PubMed:26887952, PubMed:31916624). Ceramides generated by CERS6 play a role in inflammatory response (By similarity). Acts as a regulator of metabolism and hepatic lipid accumulation (By similarity). Under high fat diet, palmitoyl- (C16:0-) ceramides generated by CERS6 specifically bind the mitochondrial fission factor MFF, thereby promoting mitochondrial fragmentation and contributing to the development of obesity (By similarity).[UniProtKB:Q8C172][1] [2] [3] [4] [5] Publication Abstract from PubMedCeramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl-enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery. Structural basis of the mechanism and inhibition of a human ceramide synthase.,Pascoa TC, Pike ACW, Tautermann CS, Chi G, Traub M, Quigley A, Chalk R, Stefanic S, Thamm S, Pautsch A, Carpenter EP, Schnapp G, Sauer DB Nat Struct Mol Biol. 2024 Nov 11. doi: 10.1038/s41594-024-01414-3. PMID:39528795[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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