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Chemoproteomic identification of a dipeptidyl peptidase 4 (DPP4) homolog in Bacteroides thetaiotaomicron important for envelope integrity and fitness
Open accessPreprint — published as 10.1038/s41589-023-01357-8 · Paper page
Abstract
Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Keller, L., Nguyen, T., Liu, L., Lakemeyer, M., Gelsinger, D., Chanin, R., Ngo, N., Lum, K., Faucher, F., Ipock, P., Niphakis, M., Bhatt, A., O'Donoghue, A., Huang, K., & Bogyo, M.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- University of California San Diego (US)
- Stanford University
- Lundbeck La Jolla Research Center
- Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego
- Chan Zuckerberg Biohub San Francisco (US)
- Corresponding author
- Bogyo, Matthew
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2022-08-11
- Volume
- 19
- Issue
- 12
- Pages
- 1469-1479
- ISSN
- 1552-4450 (ISSN-L)
- OpenAlex
- W4381612678
- Cited by
- 25
- References
- 1
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 2
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Chemical Biology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (DGE-165651 8, 1656518, 2125383)
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (DGE-1656518, AI147023, HG000044)
- Chemistry, Engineering and Medicine for Human Health, Stanford University
- National Human Genome Research Institute (K22HG000044, T32HG000044)
- National Institute of General Medical Sciences (T32GM120007, T32GM007752, RM1GM135102, T32GM113854)
- National Institute of Allergy and Infectious Diseases (R01AI148623, R01AI147023, R01AI143757, R01AI158612)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK131005)
- National Institute of Biomedical Imaging and Bioengineering (R01EB026285, R01EB026332)
- Division of Graduate Education (1656518, DGE1656518)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Keywords
- Bacteroides thetaiotaomicron, serine hydrolases, chemoproteomics, gut commensal bacteria, Bacteroidetes, insulin signaling
- MeSH terms
- Bacteroides thetaiotaomicron, Diabetes Mellitus, Type 2, Humans, Serine, Dipeptidyl Peptidase 4
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