Evidence map›Paper›PMID 26364932›Full record

ArticleChemistry & biology2015

Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity.

Bret D Wallace, Adam B Roberts, Rebecca M Pollet, James D Ingle, Kristen A Biernat, Samuel J Pellock, Madhu Kumar Venkatesh, Leah Guthrie, Sara K O'Neal, Sara J Robinson and 11 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Chemistry & biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 148 papers.

0numbers the graph read from it
0cells of the map it votes in
148citing papers in PubMed
8.3field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

148 citing papers in PubMed, 270 citations in OpenAlex.

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  10. The Gut-Vagina Axis.Microorganisms · 2026
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88 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 3 institutions in 1 country.

Bret D WallaceDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Adam B RobertsDepartment of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Rebecca M PolletDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
James D IngleDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Kristen A BiernatDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Samuel J PellockDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Madhu Kumar VenkateshDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Leah GuthrieDepartment of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Sara K O'NealDepartment of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Sara J RobinsonDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Makani DollingerDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Esteban FigueroaDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Sarah R McShaneDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Rachel D CohenDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Jian JinDepartment of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Stephen V FryeDepartment of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
William C ZamboniDepartment of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, NC 27599-3290, USA.
Charles Pepe-RanneyDepartment of Soil and Crop Sciences, Cornell University, Ithaca, NY 14853, USA.
Sridhar ManiDepartment of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Libusha KellyDepartment of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Matthew R RedinboDepartment of Chemistry, University of North Carolina at Chapel Hill, NC 27599-3290, USA; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, NC 27599-3290, USA. Electronic address: redinbo@unc.edu.
University of North Carolina at Chapel Hill · USAlbert Einstein College of Medicine · USCornell University · US

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5M
WORD PROCESSORP30CA013330 · NCI · YESHIVA UNIVERSITY · PI THOMAS E ROHAN · 1985 to 2026
$111.2M
TRAINING PROGRAM IN CELLULAR &MOLEC. BIOLOGY &GENETICST32GM007491 · NIGMS · YESHIVA UNIVERSITY · PI QUERY, CHARLES C · 1985 to 2021
$17.0M
MOLECULAR AND CELLULAR BIOPHYSICS TRAINING PROGRAMT32GM008570 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI KUHLMAN, BRIAN A, SLEP, KEVIN C · 1995 to 2022
$5.1M
Improving CPT-11 Efficacy Using Structural BiologyR01CA098468 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI REDINBO, MATTHEW R · 2003 to 2018
$3.9M
Microbial Metabolite Mimics, PXR and Colitis-Induced Colorectal CancerR01CA222469 · NCI · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI MANI, SRIDHAR · 2018 to 2022
$2.3M
Development of Novel Drugs to Alleviate CPT-11 ToxicityR01CA161879 · NCI · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI MANI, SRIDHAR, REDINBO, MATTHEW R · 2012 to 2016
$1.6M
NCI NIH HHS CA161879NCI NIH HHS CA98468NCI NIH HHS P30 CA013330NCI NIH HHS R01 CA098468NCI NIH HHS R01 CA161879NIGMS NIH HHS T32 GM007491NIGMS NIH HHS T32 GM008570
6 · The paper itself

Abstract

The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan. Here, we report crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli, and the characterization of a β-glucuronidase from the Bacteroidetes Bacteroides fragilis. While largely similar in structure, these enzymes exhibit marked differences in catalytic properties and propensities for inhibition, indicating that the microbiome maintains functional diversity in orthologous enzymes. Small changes in the structure of designed inhibitors can induce significant conformational changes in the β-glucuronidase active site. Finally, we establish that β-glucuronidase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice. Together, the data presented advance our in vitro and in vivo understanding of the microbial β-glucuronidases, a promising new set of targets for controlling drug-induced gastrointestinal toxicity.

Indexed as

Amino Acid SequenceAnimalsAntineoplastic AgentsBacterial ProteinsBacteroides fragilisCamptothecinClostridium perfringensDrug Screening Assays, AntitumorEnzyme InhibitorsEscherichia coliGlucuronidaseIrinotecanMiceMice, Inbred BALB CMicrobiotaModels, MolecularAntineoplastic AgentsBacterial ProteinsCamptothecinEnzyme InhibitorsGlucuronidaseIrinotecanchemotherapy-induced diarrheairinotecanmicrobiotaNSAIDs

Identifiers

PMID26364932
PMCPMC4575908
OpenAlexW1872238436

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.