Dataset Information

Deciphering Differential Gut Bacterial Drug Metabolism with Activity-Based Protein Profiling

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Human Gut Metagenome

TISSUE(S): Feces

SUBMITTER: Dennis Goldfarb

LAB HEAD: Matthew Redinbo

PROVIDER: PXD014864 | Pride | 2019-12-03

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	760MetaHit_139HMP_368PKU_511Bac.uniq.pep.sample_specific.fasta	Fasta
	RE010_human_poopernatant_F1_no_probe_Parth_EWC.raw	Raw
	RE011_human_poopernatant_F2_no_probe_Parth_EWC.raw	Raw
	RE012_human_poopernatant_F1_probe_Parth_EWC.raw	Raw
	RE013_human_poopernatant_F2_probe_Parth_EWC.raw	Raw

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Publications

Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling.

Jariwala Parth B PB Pellock Samuel J SJ Goldfarb Dennis D Cloer Erica W EW Artola Marta M Simpson Joshua B JB Bhatt Aadra P AP Walton William G WG Roberts Lee R LR Major Michael B MB Davies Gideon J GJ Overkleeft Herman S HS Redinbo Matthew R MR

ACS chemical biology 20191212 1

It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity is not observed in all patients treated with the anticancer drug irinotecan, and it has been suggested that this variability is a result of differences in the types and levels of gut bacterial β-glucuronidases (GUSs). GUS enzymes promote drug toxicity by hydrolyzing the inactive drug-glucuronide conjugate back to the ...[more]

PMID: 31774274

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