Tomas C. Pascoa, Ashley C. W. Pike, Christofer S. Tautermann, Gamma Chi, Michael Traub, Andrew Quigley, Rod Chalk, Saša Štefanić, Sven Thamm, Alexander Pautsch, Elisabeth P. Carpenter, Gisela Schnapp, David B. Sauer
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引用次数: 0
Abstract
Ceramides 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. Pascoa et al. reveal structures of the human ceramide synthase 6 and elucidate the enzyme’s mechanism. Furthermore, the work uncovers the basis of inhibition by the mycotoxin fumonisin B1.
期刊介绍:
Nature Structural & Molecular Biology is a comprehensive platform that combines structural and molecular research. Our journal focuses on exploring the functional and mechanistic aspects of biological processes, emphasizing how molecular components collaborate to achieve a particular function. While structural data can shed light on these insights, our publication does not require them as a prerequisite.