By the same authors

From the same journal

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

Research output: Contribution to journalArticle

Published copy (DOI)

Author(s)

  • Parth B. Jariwala
  • Samuel J. Pellock
  • Erica W. Cloer
  • Marta Artola
  • Joshua B. Simpson
  • Aadra P. Bhatt
  • William G. Walton
  • Lee R. Roberts
  • Gideon J. Davies
  • Herman S. Overkleeft
  • Matthew R. Redinbo

Department/unit(s)

Publication details

JournalACS Chemical Biology
DateAccepted/In press - 27 Nov 2019
DateE-pub ahead of print - 27 Nov 2019
DatePublished (current) - 17 Jan 2020
Volume15
Number of pages9
Pages (from-to)217-225
Early online date27/11/19
Original languageEnglish

Abstract

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 active drug, which damages the GI epithelium. Proteomics-based identification of the exact GUS enzymes responsible for drug reactivation from the complexity of the human microbiota has not been accomplished, however. Here, we discover the specific bacterial GUS enzymes that generate SN-38, the active and toxic metabolite of irinotecan, from human fecal samples using a unique activity-based protein profiling (ABPP) platform. We identify and quantify gut bacterial GUS enzymes from human feces with an ABPP-enabled proteomics pipeline and then integrate this information with ex vivo kinetics to pinpoint the specific GUS enzymes responsible for SN-38 reactivation. Furthermore, the same approach also reveals the molecular basis for differential gut bacterial GUS inhibition observed between human fecal samples. Taken together, this work provides an unprecedented technical and bioinformatics pipeline to discover the microbial enzymes responsible for specific reactions from the complexity of human feces. Identifying such microbial enzymes may lead to precision biomarkers and novel drug targets to advance the promise of personalized medicine.

Bibliographical note

© 2019 American Chemical Society. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

Discover related content

Find related publications, people, projects, datasets and more using interactive charts.

View graph of relations