PXD033546

PXD033546 is an original dataset announced via ProteomeXchange.

Title	Conditional covalent lethality driven by oncometabolite accumulation
Description	Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of synthetic lethal interactions using genetic screens. Inspired by recent advances in chemoproteomic target identification, here we test the hypothesis that the electrophilicity of the HLRCC metabolome may produce unique susceptibilities to covalent small molecules, a phenomenon we term conditional covalent lethality. Screening a panel of chemically diverse electrophiles we identified a covalent ligand, MP-1, that exhibits FH-dependent cytotoxicity. Synthesis and structure-activity profiling identified key molecular determinants underlying the molecule’s effects. Chemoproteomic profiling of cysteine reactivity together with clickable probes validated the ability of MP-1 to engage an array of functional cysteines, including one lying in the Zn-finger domain of the tRNA methyltransferase enzyme TRMT1. TRMT1 overexpression rescues tRNA methylation from inhibition by MP-1 and partially attenuates the covalent ligand’s cytotoxicity. Our studies highlight the potential for covalent metabolites and small molecules to synergistically produce novel synthetic lethal interactions and raise the possibility of applying phenotypic screening with chemoproteomic target identification to identify new functional oncometabolite targets.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:25:33.034.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daniel Bak
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-28 02:28:59	ID requested
1	2024-01-26 06:40:42	announced
⏵ 2	2024-10-22 06:25:36	announced	2024-10-22: Updated project metadata.

10.1021/acschembio.2c00384;

Perez M, Nance KD, Bak DW, Thalalla Gamage S, Najera SS, Conte AN, Linehan WM, Weerapana E, Meier JL, Conditional Covalent Lethality Driven by Oncometabolite Accumulation. ACS Chem Biol, 17(10):2789-2800(2022) [pubmed]

submitter keyword: oncometabalite,HLRCC, Fumarate, chemoproteomics, fumarate hydratase, TRMT1

Eranthie Weerapana
contact affiliation	Chemistry Department, Boston College, USA
contact email	eranthie@bc.edu
lab head
Daniel Bak
contact affiliation	Boston College
contact email	bakd@bc.edu
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/2024/01/PXD033546

PRIDE project URI

• PRIDE
  1. PXD033546
     1. Label: PRIDE project
     2. Name: Conditional covalent lethality driven by oncometabolite accumulation