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Structure paper

TitleStructural basis of the mechanism and inhibition of a human ceramide synthase.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 3, Page 431-440, Year 2025
Publish dateNov 11, 2024
AuthorsTomas 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 /
PubMed AbstractCeramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for ...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.
External linksNat Struct Mol Biol / PubMed:39528795 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.2 Å
Structure data

18770

8qz6

EMDB-18770, PDB-8qz6:
Structure of human ceramide synthase 6 (CerS6) bound to C16:0
Method: EM (single particle) / Resolution: 3.2 Å

18771

8qz7

EMDB-18771, PDB-8qz7:
Structure of human ceramide synthase 6 (CerS6) in complex with N-palmitoyl fumonisin B1
Method: EM (single particle) / Resolution: 3.0 Å

19869

9eot

EMDB-19869, PDB-9eot:
Structure of human ceramide synthase 6 (CerS6) bound to C16:0 (nanobody Nb02)
Method: EM (single particle) / Resolution: 3.02 Å

Chemicals

ChemComp-PLM:
PALMITIC ACID

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


ChemComp, No image

ChemComp-XBX:
Unknown entry

Source
  • homo sapiens (human)
  • vicugna pacos (alpaca)
KeywordsMEMBRANE PROTEIN / CERAMIDE / SPHINGOLIPID / COVALENT INTERMEDIATE / MYCOTOXIN / FUMONISIN B1 / INHIBITORY PRODUCT

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