PXD045370

PXD045370 is an original dataset announced via ProteomeXchange.

Title	Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Lysine-Reactive Phloroglucinol Meroterpenoids
Description	Natural products have long been an enduring source of drug leads and chemical probes that have led to the development of numerous medicines. Despite their scarcity, the discovery of natural products that modulate protein function through covalent interactions with lysine residues holds immense potential to unlock new therapeutic interventions and advance our understanding of the intricate biological processes governed by these modifications. Phloroglucinol meroterpenoids comprise one of the largest classes of natural products displaying a vast array of biological activities. However, their mechanism of action and molecular targets have remained largely unexplored. In this study, we present an in-depth experimental and computational investigation into the synthesis, physicochemical and kinetic parameters, molecular mechanism of action, and functional cellular targets of selected phloroglucinol meroterpenoids. We leverage synthetic clickable analogues of natural products to observe disparate proteome-wide reactivity by in-gel fluorescence scanning and cell imaging. By implementing sample multiplexing and a redesigned desthiobiotin-based probe, we streamline a quantitative activity-based protein profiling protocol for mapping proteome-wide reactivity and ligandability of proteinaceous lysines directly in human cells. Using this platform, we identify numerous lysine-phloroglucinol meroterpenoid interactions in breast cancer cells that occur at functional sites on proteins from diverse structural and functional classes. Lastly, we demonstrate that phloroglucinol meroterpenoids perturb diverse biochemical functions through stereoselective and site-specific modification of lysines in proteins involved in glycolysis, lipid metabolism, and mitochondrial respiration. These findings underscore the broad potential of phloroglucinol meroterpenoids for targeting functional lysines in the human proteome.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:41:57.300.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mikail Abbasov
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-13 18:39:52	ID requested
1	2024-05-23 02:33:17	announced
⏵ 2	2024-10-22 06:42:03	announced	2024-10-22: Updated project metadata.

10.1021/jacs.3c10741;

Bracken AK, Gekko CE, Suss NO, Lueders EE, Cui Q, Fu Q, Lui ACW, Anderson ET, Zhang S, Abbasov ME, Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Phloroglucinol Meroterpenoids. J Am Chem Soc, 146(4):2524-2548(2024) [pubmed]

submitter keyword: mitochondrial respiration., lipid metabolism, lysine conjugation, activity-based protein profiling, natural products, glycolysis,Chemical proteomics, phloroglucinol meroterpenoids

Mikail E. Abbasov
contact affiliation	Department of Chemistry and Chemical Biology Cornell University United States of America
contact email	mikail.abbasov@cornell.edu
lab head
Mikail Abbasov
contact affiliation	Cornell University
contact email	abbasovgroupcornell@gmail.com
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/2024/05/PXD045370

PRIDE project URI

• PRIDE
  1. PXD045370
     1. Label: PRIDE project
     2. Name: Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Lysine-Reactive Phloroglucinol Meroterpenoids