SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
| Autor: | Julien Marcoux, Etienne Joly, Pascal Demange, Patrick RA Zanon, Dymytrii Listunov, Pauline Rullière, Cécile Barthes, Céline Noirot, Jean-Baptiste Izquierdo, Alexandrine Rozié, Karen Pradines, Romain Hee, Maria Vieira de Brito, Marlène Marcellin, Remy-Felix Serre, Olivier Bouchez, Odile Burlet-Schiltz, Maria Conceição Ferreira Oliveira, Stéphanie Ballereau, Vania Bernardes-Génisson, Valérie Maraval, Patrick Calsou, Stephan M Hacker, Yves Génisson, Remi Chauvin, Sébastien Britton |
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| Přispěvatelé: | Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Technische Universität München = Technical University of Munich (TUM), Leiden Institute of Chemistry, Universiteit Leiden, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade Federal do Ceará = Federal University of Ceará (UFC), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
chiral cytototoxic lipid
General Immunology and Microbiology General Neuroscience short-chain dehydrogenase/reductase chemical biology unfolded protein response Antineoplastic Agents General Medicine Endoplasmic Reticulum Stress Lipids General Biochemistry Genetics and Molecular Biology Short Chain Dehydrogenase-Reductases prodrugs Unfolded Protein Response biochemistry Humans human ubiquitin-proteasome system [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] |
| Zdroj: | eLife, 11:e73913 eLife eLife, 2022, 11, pp.e73913. ⟨10.7554/eLife.73913⟩ |
| ISSN: | 2050-084X |
| DOI: | 10.7554/eLife.73913⟩ |
| Popis: | © 2022, Demange et al.; International audience; Hundreds of cytotoxic natural or synthetic lipidic compounds contain chiral alkynylcarbinol motifs, but the mechanism of action of those potential therapeutic agents remains unknown. Using a genetic screen in haploid human cells, we discovered that the enantiospecific cytotoxicity of numerous terminal alkynylcarbinols, including the highly cytotoxic dialkynylcarbinols, involves a bioactivation by HSD17B11, a short-chain dehydrogenase/reductase (SDR) known to oxidize the C-17 carbinol center of androstan-3-alpha,17-beta-diol to the corresponding ketone. A similar oxidation of dialkynylcarbinols generates dialkynylketones, that we characterize as highly protein-reactive electrophiles. We established that, once bioactivated in cells, the dialkynylcarbinols covalently modify several proteins involved in protein-quality control mechanisms, resulting in their lipoxidation on cysteines and lysines through Michael addition. For some proteins, this triggers their association to cellular membranes and results in endoplasmic reticulum stress, unfolded protein response activation, ubiquitin-proteasome system inhibition and cell death by apoptosis. Finally, as a proof-of-concept, we show that generic lipidic alkynylcarbinols can be devised to be bioactivated by other SDRs, including human RDH11 and HPGD/15-PGDH. Given that the SDR superfamily is one of the largest and most ubiquitous, this unique cytotoxic mechanism-of-action could be widely exploited to treat diseases, in particular cancer, through the design of tailored prodrugs. |
| Databáze: | OpenAIRE |
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