Complete integration of carbene-transfer chemistry into biosynthesis
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
Biosynthesis is an environmentally benign and renewable approach that can be used to produce a broad range of natural and, in some cases, new-to-nature products. However, biology lacks many of the reactions that are available to synthetic chemists, resulting in a narrower scope of accessible products when using biosynthesis rather than synthetic chemistry. A prime example of such chemistry is carbene-transfer reactions1. Although it was recently shown that carbene-transfer reactions can be performed in a cell and used for biosynthesis2,3, carbene donors and unnatural cofactors needed to be added exogenously and transported into cells to effect the desired reactions, precluding cost-effective scale-up of the biosynthesis process with these reactions. Here we report the access to a diazo ester carbene precursor by cellular metabolism and a microbial platform for introducing unnatural carbene-transfer reactions into biosynthesis. The α-diazoester azaserine was produced by expressing a biosynthetic gene cluster in Streptomyces albus. The intracellularly produced azaserine was used as a carbene donor to cyclopropanate another intracellularly produced molecule-styrene. The reaction was catalysed by engineered P450 mutants containing a native cofactor with excellent diastereoselectivity and a moderate yield. Our study establishes a scalable, microbial platform for conducting intracellular abiological carbene-transfer reactions to functionalize a range of natural and new-to-nature products and expands the scope of organic products that can be produced by cellular metabolism.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:617 |
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| Enthalten in: |
Nature - 617(2023), 7960 vom: 21. Mai, Seite 403-408 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huang, Jing [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 15.05.2023 Date Revised 26.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41586-023-06027-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Date Revised 26.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. | ||
| 520 | |a Biosynthesis is an environmentally benign and renewable approach that can be used to produce a broad range of natural and, in some cases, new-to-nature products. However, biology lacks many of the reactions that are available to synthetic chemists, resulting in a narrower scope of accessible products when using biosynthesis rather than synthetic chemistry. A prime example of such chemistry is carbene-transfer reactions1. Although it was recently shown that carbene-transfer reactions can be performed in a cell and used for biosynthesis2,3, carbene donors and unnatural cofactors needed to be added exogenously and transported into cells to effect the desired reactions, precluding cost-effective scale-up of the biosynthesis process with these reactions. Here we report the access to a diazo ester carbene precursor by cellular metabolism and a microbial platform for introducing unnatural carbene-transfer reactions into biosynthesis. The α-diazoester azaserine was produced by expressing a biosynthetic gene cluster in Streptomyces albus. The intracellularly produced azaserine was used as a carbene donor to cyclopropanate another intracellularly produced molecule-styrene. The reaction was catalysed by engineered P450 mutants containing a native cofactor with excellent diastereoselectivity and a moderate yield. Our study establishes a scalable, microbial platform for conducting intracellular abiological carbene-transfer reactions to functionalize a range of natural and new-to-nature products and expands the scope of organic products that can be produced by cellular metabolism | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Cruz-Morales, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Deng, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Jose Henrique |e verfasserin |4 aut | |
| 700 | 1 | |a Van Cura, Devon |e verfasserin |4 aut | |
| 700 | 1 | |a Kakumanu, Ramu |e verfasserin |4 aut | |
| 700 | 1 | |a Baidoo, Edward E K |e verfasserin |4 aut | |
| 700 | 1 | |a Dan, Qingyun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Petzold, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Northen, Trent R |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Paul D |e verfasserin |4 aut | |
| 700 | 1 | |a Clark, Douglas S |e verfasserin |4 aut | |
| 700 | 1 | |a Balskus, Emily P |e verfasserin |4 aut | |
| 700 | 1 | |a Hartwig, John F |e verfasserin |4 aut | |
| 700 | 1 | |a Mukhopadhyay, Aindrila |e verfasserin |4 aut | |
| 700 | 1 | |a Keasling, Jay D |e verfasserin |4 aut | |
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