Complete integration of carbene-transfer chemistry into biosynthesis

Jing Huang, Andrew Quest, Pablo Cruz-Morales, Kai Deng, Jose Henrique Pereira, Devon Cura, Ramu Kakumanu, Edward E. K. Baidoo, Qingyun Dan, Yan Chen, Christopher J. Petzold, Trent R. Northen, Paul D. Adams, Douglas S. Clark (), Emily P. Balskus, John F. Hartwig (), Aindrila Mukhopadhyay () and Jay D. Keasling ()
Additional contact information
Jing Huang: Lawrence Berkeley National Laboratory
Andrew Quest: University of California
Pablo Cruz-Morales: Lawrence Berkeley National Laboratory
Kai Deng: Lawrence Berkeley National Laboratory
Jose Henrique Pereira: Lawrence Berkeley National Laboratory
Devon Cura: Harvard University
Ramu Kakumanu: Lawrence Berkeley National Laboratory
Edward E. K. Baidoo: Lawrence Berkeley National Laboratory
Qingyun Dan: Lawrence Berkeley National Laboratory
Yan Chen: Lawrence Berkeley National Laboratory
Christopher J. Petzold: Lawrence Berkeley National Laboratory
Trent R. Northen: Lawrence Berkeley National Laboratory
Paul D. Adams: Lawrence Berkeley National Laboratory
Douglas S. Clark: University of California
Emily P. Balskus: Harvard University
John F. Hartwig: University of California
Aindrila Mukhopadhyay: Lawrence Berkeley National Laboratory
Jay D. Keasling: Lawrence Berkeley National Laboratory

Nature, 2023, vol. 617, issue 7960, 403-408

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06027-2

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