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, Makani Dollinger, Esteban Figueroa, Sarah R. McShane, Rachel D. Cohen, Jian Jin, Stephen V. Frye, William C. Zamboni, Charles Pepe-Ranney, Sridhar Mani, Libusha KellyMatthew R. Redinbo

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)1238-1249
Number of pages12
JournalChemistry and Biology
Volume22
Issue number9
DOIs
StatePublished - Sep 17 2015

Keywords

  • NSAIDs
  • chemotherapy-induced diarrhea
  • irinotecan
  • microbiota

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Wallace, B. D., Roberts, A. B., Pollet, R. M., Ingle, J. D., Biernat, K. A., Pellock, S. J., Venkatesh, M. K., Guthrie, L., O'Neal, S. K., Robinson, S. J., Dollinger, M., Figueroa, E., McShane, S. R., Cohen, R. D., Jin, J., Frye, S. V., Zamboni, W. C., Pepe-Ranney, C., Mani, S., ... Redinbo, M. R. (2015). Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity. Chemistry and Biology, 22(9), 1238-1249. https://doi.org/10.1016/j.chembiol.2015.08.005