Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases**

Autor: Thorsten Hornemann, Cedric Leyrat, Christoph Arenz, Shibom Basu, Damien Maurel, Marion Drapeau, Julie Saint Paul, Essa M. Saied, Gergely Karsai, Elise Del Nero, Sébastien Granier, Xiaojing Cong, Ludovic Gabellier, Guillaume Bossis, Jérôme Golebiowski, Cherine Bechara, Robert D. Healey, Sylvain Jeannot, Simon Fontanel
Přispěvatelé: Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Humboldt-Universität zu Berlin, University hospital of Zurich [Zurich], Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), European Molecular Biology Laboratory (EMBL), Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Humboldt University Of Berlin, Guerineau, Nathalie C., University of Zurich, Granier, Sebastien
Rok vydání: 2021
Předmět:
Ceramide
1503 Catalysis
[SDV]Life Sciences [q-bio]
Ceramidases
610 Medicine & health
1600 General Chemistry
Alkaline Ceramidase
Catalysis
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
540 Chemistry
[CHIM] Chemical Sciences
FRET screening assay
lipid metabolism
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
intramembrane enzyme inhibition
[CHIM]Chemical Sciences
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
ceramidase
10038 Institute of Clinical Chemistry
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Drug discovery
General Medicine
General Chemistry
structural dynamics
Ceramidase
Small molecule
3. Good health
[SDV] Life Sciences [q-bio]
Enzyme
Biochemistry
chemistry
Drug development
030220 oncology & carcinogenesis
Zdroj: Angewandte Chemie International Edition
Angewandte Chemie International Edition, Wiley-VCH Verlag, 2021, ⟨10.1002/anie.202109967⟩
Angewandte Chemie International Edition, 2022, 61 (2), pp.e202109967. ⟨10.1002/anie.202109967⟩
Angewandte Chemie International Edition, Wiley-VCH Verlag, 2022, 61 (2), pp.e202109967. ⟨10.1002/anie.202109967⟩
ISSN: 1521-3773
1433-7851
DOI: 10.1002/anie.202109967
Popis: International audience; Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. Here, we present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to reveal a new paradigm for inhibition of lipid metabolising enzymes with nonlipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.
Databáze: OpenAIRE
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