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PXD033059 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleSDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
DescriptionHundreds 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJulien Marcoux
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentLTQ Orbitrap Velos; Q Exactive; Synapt MS
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-04-07 03:20:25ID requested
12022-05-10 02:41:00announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: SDR enzymes, cancer, alkynylcarbinol, isoDTB
Contact List
Julien Marcoux
contact affiliationInstitute of Pharmacology and Structural Biology (IPBS), CNRS, Toulouse
contact emailjulien.marcoux@ipbs.fr
lab head
Julien Marcoux
contact affiliationIPBS
contact emailjulien.marcoux@ipbs.fr
dataset submitter
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