Abstract
Ceramide synthases (CerSs) play crucial roles in sphingolipid metabolism and have emerged as promising drug targets for metabolic diseases, cancers, and antifungal therapy. However, the therapeutic targeting of CerSs has been hindered by a limited understanding of their inhibition mechanisms by small molecules. Fumonisin B1 (FB1) has been extensively studied as a potent inhibitor of eukaryotic CerSs. In this study, we characterize the inhibition mechanism of FB1 on yeast CerS (yCerS) and determine the structures of both FB1-bound and N-acyl-FB1-bound yCerS. Through our structural analysis and the observation of N-acylation of FB1 by yCerS, we propose a potential ping-pong catalytic mechanism for FB1 N-acylation by yCerS. Lastly, we demonstrate that FB1 exhibits lower binding affinity for yCerS compared to the C26- coenzyme A (CoA) substrate, suggesting that the potent inhibitory effect of FB1 on yCerS may primarily result from the N-acyl-FB1 catalyzed by yCerS, rather than through direct binding of FB1.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
