Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens
Open accessAbstract
Gut microbial β-glucuronidase (GUS) enzymes have been suggested to be involved in the estrobolome, the collection of microbial reactions involving estrogens. Furthermore, bacterial GUS enzymes within the gastrointestinal tract have been postulated to be a contributing factor in hormone-driven cancers. However, to date, there has been no experimental evidence to support these hypotheses. Here we provide the first in vitro analysis of the ability of 35 human gut microbial GUS enzymes to reactivate two distinct estrogen glucuronides, estrone-3-glucuronide and estradiol-17-glucuronide, to estrone and estradiol, respectively. We show that certain members within the Loop 1, mini-Loop 1, and FMN-binding classes of gut microbial GUS enzymes can reactivate estrogens from their inactive glucuronides. We provide molecular details of key interactions that facilitate these catalytic processes and present the structures of two novel human gut microbial GUS enzymes related to the estrobolome. Further, we demonstrate that estrogen reactivation by Loop 1 bacterial GUS enzymes can be inhibited both in purified enzymes and in fecal preparations of mixed murine fecal microbiota. Finally, however, despite these in vitro and ex vivo data, we show that a Loop 1 GUS-specific inhibitor is not capable of reducing the development of tumors in the PyMT mouse model of breast cancer. These findings validate that gut microbial GUS enzymes participate in the estrobolome but also suggest that the estrobolome is a multidimensional set of processes on-going within the mammalian gastrointestinal tract that likely involves many enzymes, including several distinct types of GUS proteins.
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Self-citation
- Authors
- Ervin, S. M., Li, H., Lim, L., Roberts, L. R., Liang, X., Mani, S., & Redinbo, M. R.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Albert Einstein College of Medicine (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Redinbo, Matthew R.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 294
- Issue
- 49
- Pages
- 18586-18599
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6901331
- OpenAlex
- W2982254388
- Cited by
- 397
- References
- 48
- Citations by year
- 2026: 99 · 2025: 73 · 2024: 71 · 2023: 66 · 2022: 50 · 2021: 29 · 2020: 9
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- HHS | National Institutes of Health (CA098468, CA207416)
- National Science Foundation (DGS-1650116)
- U.S. Department of Defense (W81XWH-17–1-0023)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- estrobolome, estrone-3-glucuronide, estrone, estradiol, enzyme inhibition, PyMT mouse model, breast cancer, gut microbiota
- MeSH terms
- Gastrointestinal Microbiome, Animals, Chromatography, High Pressure Liquid, Estrogens, Estrone, Female, Glucuronidase, Male, Mice, Inbred BALB C, Mutagenesis, Site-Directed, Mice
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