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Structure paper

TitleMechanism of ceramide synthase inhibition by fumonisin B.
Journal, issue, pagesStructure, Vol. 32, Issue 9, Page 1419-11428.e4, Year 2024
Publish dateSep 5, 2024
AuthorsZike Zhang / Qi Fang / Tian Xie / Xin Gong /
PubMed AbstractCeramide 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 ...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 B (FB) has been extensively studied as a potent inhibitor of eukaryotic CerSs. In this study, we characterize the inhibition mechanism of FB on yeast CerS (yCerS) and determine the structures of both FB-bound and N-acyl-FB-bound yCerS. Through our structural analysis and the observation of N-acylation of FB by yCerS, we propose a potential ping-pong catalytic mechanism for FB N-acylation by yCerS. Lastly, we demonstrate that FB exhibits lower binding affinity for yCerS compared to the C26- coenzyme A (CoA) substrate, suggesting that the potent inhibitory effect of FB on yCerS may primarily result from the N-acyl-FB catalyzed by yCerS, rather than through direct binding of FB.
External linksStructure / PubMed:38964337
MethodsEM (single particle)
Resolution2.86 - 3.19 Å
Structure data

38857

8y2m

EMDB-38857, PDB-8y2m:
Cryo-EM structure of the FB1-bound Lac1-Lip1 complex
Method: EM (single particle) / Resolution: 3.07 Å

38858

8y2n

EMDB-38858, PDB-8y2n:
Cryo-EM structure of the apo Lac1-Lip1 complex
Method: EM (single particle) / Resolution: 3.19 Å

39894

8zb1

EMDB-39894, PDB-8zb1:
Cryo-EM structure of the C26-FB1-bound Lac1-Lip1 complex
Method: EM (single particle) / Resolution: 2.86 Å

Chemicals

ChemComp-6PL:
(4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE / phospholipid*YM

PDB-1d5v:
SOLUTION STRUCTURE OF THE FORKHEAD DOMAIN OF THE ADIPOCYTE-TRANSCRIPTION FACTOR FREAC-11 (S12)

ChemComp-7PO:
hexacosanoic acid

PDB-1d74:
Unknown entry

Source
  • saccharomyces cerevisiae (strain atcc 204508 / s288c) (yeast)
  • saccharomyces cerevisiae s288c (yeast)
  • Saccharomyces cerevisiae (strain YJM789) (yeast)
KeywordsTRANSFERASE / Inhibitor / Complex

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