PXD014864

PXD014864 is an original dataset announced via ProteomeXchange.

Title	Deciphering Differential Gut Bacterial Drug Metabolism with Activity-Based Protein Profiling
Description	Gut bacterial β-glucuronidases (GUS) promote the toxic side effects of therapeutics by reactivating drugs from their inactive glucuronide conjugates. It is increasingly clear that the interindividual variability of bacterial GUS-producing species in the gut microbiota contributes to differential drug responses. Indeed, the anticancer drug irinotecan exhibits variable clinical toxicity outcomes that have been linked to interindividual differences in the composition of the gut microbiota. However, identification of the specific GUS enzymes responsible for drug metabolism in the context of the complexity of the human fecal microbiota has not been achieved. Here we pinpoint the specific bacterial GUS enzymes that reactivate SN-38, the active metabolite of irinotecan, from complex human fecal microbiota samples with activity-based protein profiling (ABPP). We identify and quantify gut bacterial GUS enzymes from human feces with ABPP-enabled proteomics and then integrate this information with ex vivo kinetics to reveal the specific GUS enzymes responsible for the reactivation of SN-38. The same ABPP approach also reveals the molecular basis for differential gut bacterial GUS inhibition between human fecal samples. Taken together, this work provides an unprecedented pipeline to identify the specific bacterial GUS enzymes responsible for drug-induced GI toxicity from the complexity of human feces, which may serve as highly precise biomarkers of clinical outcomes for irinotecan and other therapeutics.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:57:40.755.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Goldfarb
SpeciesList	scientific name: human gut metagenome; NCBI TaxID: 408170;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-01 01:23:13	ID requested
1	2019-12-03 00:33:51	announced
⏵ 2	2024-10-22 04:57:48	announced	2024-10-22: Updated project metadata.

10.1021/acschembio.9b00788;

Jariwala PB, Pellock SJ, Goldfarb D, Cloer EW, Artola M, Simpson JB, Bhatt AP, Walton WG, Roberts LR, Major MB, Davies GJ, Overkleeft HS, Redinbo MR, Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling. ACS Chem Biol, 15(1):217-225(2020) [pubmed]

submitter keyword: Drug metabolism,Gut Microbiome, Activity-based Protein Profiling

Matthew Redinbo
contact affiliation	Department of Chemistry Center for Gastrointestinal Biology and Disease Integrated Program for Biological and Genome Sciences University of North Carolina at Chapel Hill
contact email	redinbo@unc.edu
lab head
Dennis Goldfarb
contact affiliation	Cell Biology and Physiology Institute for Informatics
contact email	d.goldfarb@wustl.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/2019/12/PXD014864

PRIDE project URI

• PRIDE
  1. PXD014864
     1. Label: PRIDE project
     2. Name: Deciphering Differential Gut Bacterial Drug Metabolism with Activity-Based Protein Profiling