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  • SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species.

SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species.

eLife (2022-05-11)
Pascal Demange, Etienne Joly, Julien Marcoux, Patrick R A 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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
IRE1 Inhibitor I, STF-083010, The IRE1 Inhibitor I, STF-083010 controls the biological activity of IRE1. This small molecule/inhibitor is primarily used for Biochemicals applications.
Sigma-Aldrich
Cycloheximide, from microbial, ≥94% (TLC)
Sigma-Aldrich
MG-132, A cell-permeable, potent, reversible proteasome inhibitor (Ki = 4 nM).
Sigma-Aldrich
PERK Inhibitor I, GSK2606414, GSK2606414 is a cell-permeable, highly potent inhibitor of EIF2AK3/PERK (IC₅₀ = 0.4 nM; [ATP] = 5 µM). Targets PERK in its inactive DFG conformation at the ATP-binding region.