Nitrene generation and transfer for unnatural biosynthesis in living cells
10 affiliations
- 1Department of Chemistry, University of California, Berkeley, Berkeley, CA USA
- 2Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA USA
- 3Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA USA
- 4College of Natural Resources, University of California, Berkeley, Berkeley, CA USA
- 5Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA
- 6Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA USA
- 7Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA USA
- 8Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA USA
- 9Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA USA
- 10Department of Bioengineering, University of California, Berkeley, Berkeley, CA USA
Abstract
Synthetic biology has enabled the production of natural and unnatural products from inexpensive sustainable feedstocks. Yet, the scope of available products has been limited largely to compounds accessible from nature’s chemical reactions. Evolved enzymes can catalyse reactions of unnatural substrates or reactions not found in nature but often require the addition of synthetic reagents to purified enzymes or to resting cells containing those enzymes. Here we show that chemical reactions of metabolic intermediates produced intracellularly in living cells can include intermolecular nitrene transfers. The biosynthesis of N-acetoxyanilines, in combination with the generation and transfer of N-aryl nitrene intermediates from them catalysed by a cytochrome P450, generates amino alcohols, diamines, diarylamines and aminoalkyl arenes from simple carbon feedstocks. These products—common substructures of pharmaceuticals and agrochemicals—are challenging to synthesize by standard organic chemistry and were produced from inexpensive, renewable feedstocks. Evolution of the enzymes in this pathway showed that titres can be increased by engineering and that the products can be synthesized with high enantioselectivity.
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BibTeX
@article{donnell2026nitrene,
title = {{Nitrene generation and transfer for unnatural biosynthesis in living cells}},
author = {Isaac Donnell and Andrew Quest and Jeremy Tang and Maodun Zhang and Brandon Bloomer and Douglas S. Clark and Aindrila Mukhopadhyay and John Hartwig and Jay D. Keasling},
journal = {Nature Chemistry},
year = {2026},
month = aug,
doi = {10.1038/s41557-026-02224-4},
url = {https://doi.org/10.1038/s41557-026-02224-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nitrene generation and transfer for unnatural biosynthesis in living cells
AU - Isaac Donnell
AU - Andrew Quest
AU - Jeremy Tang
AU - Maodun Zhang
AU - Brandon Bloomer
AU - Douglas S. Clark
AU - Aindrila Mukhopadhyay
AU - John Hartwig
AU - Jay D. Keasling
PY - 2026
DA - 2026/08/18
JO - Nature Chemistry
DO - 10.1038/s41557-026-02224-4
UR - https://doi.org/10.1038/s41557-026-02224-4
AB - Synthetic biology has enabled the production of natural and unnatural products from inexpensive sustainable feedstocks. Yet, the scope of available products has been limited largely to compounds accessible from nature’s chemical reactions. Evolved enzymes can catalyse reactions of unnatural substrates or reactions not found in nature but often require the addition of synthetic reagents to purified enzymes or to resting cells containing those enzymes. Here we show that chemical reactions of metabolic intermediates produced intracellularly in living cells can include intermolecular nitrene transfers. The biosynthesis of N-acetoxyanilines, in combination with the generation and transfer of N-aryl nitrene intermediates from them catalysed by a cytochrome P450, generates amino alcohols, diamines, diarylamines and aminoalkyl arenes from simple carbon feedstocks. These products—common substructures of pharmaceuticals and agrochemicals—are challenging to synthesize by standard organic chemistry and were produced from inexpensive, renewable feedstocks. Evolution of the enzymes in this pathway showed that titres can be increased by engineering and that the products can be synthesized with high enantioselectivity.
SN - 1755-4330
SN - 1755-4349
ER -