PXD033059-1

PXD033059 is an original dataset announced via ProteomeXchange.

Title	SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species
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.
HostingRepository	PRIDE
AnnounceDate	2022-05-10
AnnouncementXML	Submission_2022-05-10_02:41:00.441.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Julien Marcoux
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos; Q Exactive; Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-07 03:20:25	ID requested
⏵ 1	2022-05-10 02:41:00	announced

Dataset with its publication pending

submitter keyword: SDR enzymes, cancer, alkynylcarbinol, isoDTB

Julien Marcoux
contact affiliation	Institute of Pharmacology and Structural Biology (IPBS), CNRS, Toulouse
contact email	julien.marcoux@ipbs.fr
lab head
Julien Marcoux
contact affiliation	IPBS
contact email	julien.marcoux@ipbs.fr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/05/PXD033059

PRIDE project URI

• PRIDE
  1. PXD033059
     1. Label: PRIDE project
     2. Name: SDR enzymes oxidize specific lipidic alkynylcarbinols into cytotoxic protein-reactive species