Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases
The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Esc...
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| Format: | Article |
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Elsevier BV
2018
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| Online Access: | http://hdl.handle.net/1721.1/117726 https://orcid.org/0000-0002-3783-0433 https://orcid.org/0000-0003-0844-4776 |
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| author | Guo, Chun-Jun Chang, Fang-Yuan Wyche, Thomas P. Backus, Keriann M. Acker, Timothy M. Funabashi, Masanori Taketani, Mao Donia, Mohamed S. Nayfach, Stephen Pollard, Katherine S. Craik, Charles S. Cravatt, Benjamin F. Clardy, Jon Voigt, Christopher A. Fischbach, Michael A. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Guo, Chun-Jun Chang, Fang-Yuan Wyche, Thomas P. Backus, Keriann M. Acker, Timothy M. Funabashi, Masanori Taketani, Mao Donia, Mohamed S. Nayfach, Stephen Pollard, Katherine S. Craik, Charles S. Cravatt, Benjamin F. Clardy, Jon Voigt, Christopher A. Fischbach, Michael A. |
| author_sort | Guo, Chun-Jun |
| collection | MIT |
| description | The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals. Keywords: microbiome; natural products; synthetic biology; metagenomics; biosynthetic gene cluster; peptide aldehyde; protease inhibitor |
| first_indexed | 2024-09-23T13:13:24Z |
| format | Article |
| id | mit-1721.1/117726 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T13:13:24Z |
| publishDate | 2018 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1177262022-09-28T12:46:42Z Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases Guo, Chun-Jun Chang, Fang-Yuan Wyche, Thomas P. Backus, Keriann M. Acker, Timothy M. Funabashi, Masanori Taketani, Mao Donia, Mohamed S. Nayfach, Stephen Pollard, Katherine S. Craik, Charles S. Cravatt, Benjamin F. Clardy, Jon Voigt, Christopher A. Fischbach, Michael A. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Synthetic Biology Center Chang, Fang-Yuan Voigt, Christopher A. The gut microbiota modulate host biology in numerous ways, but little is known about the molecular mediators of these interactions. Previously, we found a widely distributed family of nonribosomal peptide synthetase gene clusters in gut bacteria. Here, by expressing a subset of these clusters in Escherichia coli or Bacillus subtilis, we show that they encode pyrazinones and dihydropyrazinones. At least one of the 47 clusters is present in 88% of the National Institutes of Health Human Microbiome Project (NIH HMP) stool samples, and they are transcribed under conditions of host colonization. We present evidence that the active form of these molecules is the initially released peptide aldehyde, which bears potent protease inhibitory activity and selectively targets a subset of cathepsins in human cell proteomes. Our findings show that an approach combining bioinformatics, synthetic biology, and heterologous gene cluster expression can rapidly expand our knowledge of the metabolic potential of the microbiota while avoiding the challenges of cultivating fastidious commensals. Keywords: microbiome; natural products; synthetic biology; metagenomics; biosynthetic gene cluster; peptide aldehyde; protease inhibitor 2018-09-12T17:52:03Z 2018-09-12T17:52:03Z 2017-01 2016-10 2018-09-12T13:11:59Z Article http://purl.org/eprint/type/JournalArticle 0092-8674 1097-4172 http://hdl.handle.net/1721.1/117726 Guo, Chun-Jun et al. “Discovery of Reactive Microbiota-Derived Metabolites That Inhibit Host Proteases.” Cell 168, 3 (January 2017): 517–526 © 2017 Elsevier Inc https://orcid.org/0000-0002-3783-0433 https://orcid.org/0000-0003-0844-4776 http://dx.doi.org/10.1016/J.CELL.2016.12.021 Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Guo, Chun-Jun Chang, Fang-Yuan Wyche, Thomas P. Backus, Keriann M. Acker, Timothy M. Funabashi, Masanori Taketani, Mao Donia, Mohamed S. Nayfach, Stephen Pollard, Katherine S. Craik, Charles S. Cravatt, Benjamin F. Clardy, Jon Voigt, Christopher A. Fischbach, Michael A. Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title | Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title_full | Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title_fullStr | Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title_full_unstemmed | Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title_short | Discovery of Reactive Microbiota-Derived Metabolites that Inhibit Host Proteases |
| title_sort | discovery of reactive microbiota derived metabolites that inhibit host proteases |
| url | http://hdl.handle.net/1721.1/117726 https://orcid.org/0000-0002-3783-0433 https://orcid.org/0000-0003-0844-4776 |
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