SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
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 termin...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/73913 |
| _version_ | 1811203640486002688 |
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| author | Pascal Demange Etienne Joly Julien Marcoux 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 |
| author_facet | Pascal Demange Etienne Joly Julien Marcoux 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 |
| author_sort | Pascal Demange |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:58:37Z |
| format | Article |
| id | doaj.art-793efaee61f44925b2fa3f2f6920aeac |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:58:37Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-793efaee61f44925b2fa3f2f6920aeac2022-12-22T03:50:44ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.73913SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive speciesPascal Demange0Etienne Joly1Julien Marcoux2Patrick RA Zanon3https://orcid.org/0000-0002-8883-8275Dymytrii Listunov4Pauline Rullière5Cécile Barthes6Céline Noirot7Jean-Baptiste Izquierdo8Alexandrine Rozié9Karen Pradines10Romain Hee11Maria Vieira de Brito12Marlène Marcellin13Remy-Felix Serre14Olivier Bouchez15Odile Burlet-Schiltz16Maria Conceição Ferreira Oliveira17Stéphanie Ballereau18https://orcid.org/0000-0002-7250-6188Vania Bernardes-Génisson19Valérie Maraval20Patrick Calsou21Stephan M Hacker22Yves Génisson23https://orcid.org/0000-0002-3647-4617Remi Chauvin24https://orcid.org/0000-0002-4491-6390Sébastien Britton25https://orcid.org/0000-0002-7008-5316Institut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceLeiden Institute of Chemistry, Leiden University, Leiden, Netherlands; Department of Chemistry, Technical University of Munich, Garching, GermanySPCMIB, UMR5068, CNRS, Université de Toulouse, UPS, Toulouse, France; LCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, FranceSPCMIB, UMR5068, CNRS, Université de Toulouse, UPS, Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, FranceINRAE, UR 875 Unité de Mathématique et Informatique Appliquées, Genotoul Bioinfo Auzeville, Castanet-Tolosan, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, France; Equipe labellisée la Ligue contre le Cancer 2018, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, France; Equipe labellisée la Ligue contre le Cancer 2018, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, France; Equipe labellisée la Ligue contre le Cancer 2018, Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France; Department of Organic and Inorganic Chemistry, Science Center, Federal University of Ceará, Fortaleza, BrazilInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceINRAE, US 1426 GeT-PlaGe, F-31326, Castanet-Tolosan, FranceINRAE, US 1426 GeT-PlaGe, F-31326, Castanet-Tolosan, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, FranceDepartment of Organic and Inorganic Chemistry, Science Center, Federal University of Ceará, Fortaleza, BrazilSPCMIB, UMR5068, CNRS, Université de Toulouse, UPS, Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, France; Equipe labellisée la Ligue contre le Cancer 2018, Toulouse, FranceLeiden Institute of Chemistry, Leiden University, Leiden, Netherlands; Department of Chemistry, Technical University of Munich, Garching, GermanySPCMIB, UMR5068, CNRS, Université de Toulouse, UPS, Toulouse, FranceLCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, IPBS, CNRS, Université de Toulouse, Toulouse, France; Equipe labellisée la Ligue contre le Cancer 2018, Toulouse, FranceHundreds 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.https://elifesciences.org/articles/73913prodrugsshort-chain dehydrogenase/reductasechiral cytototoxic lipidendoplasmic reticulum stressunfolded protein responseubiquitin-proteasome system |
| spellingShingle | Pascal Demange Etienne Joly Julien Marcoux 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 SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species eLife prodrugs short-chain dehydrogenase/reductase chiral cytototoxic lipid endoplasmic reticulum stress unfolded protein response ubiquitin-proteasome system |
| title | SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species |
| title_full | SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species |
| title_fullStr | SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species |
| title_full_unstemmed | SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species |
| title_short | SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species |
| title_sort | sdr enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein reactive species |
| topic | prodrugs short-chain dehydrogenase/reductase chiral cytototoxic lipid endoplasmic reticulum stress unfolded protein response ubiquitin-proteasome system |
| url | https://elifesciences.org/articles/73913 |
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