Fast growth and high-titer bioproduction from renewable formate via metal-dependent formate dehydrogenase in Escherichia coli

Aidan E. Cowan (), Mason Hillers, Vittorio Rainaldi, Florent Collas, Hemant Choudhary, Basem S. Zakaria, Gregory G. Bieberach, David N. Carruthers, Maxwell Grabovac, Jennifer W. Gin, Bridgie Cawthon, Yan Chen, Emine Akyuz Turumtay, Edward E. K. Baidoo, Christopher J. Petzold, Adam M. Feist, Sara Tejedor-Sanz, Frank Kensy, Blake A. Simmons, Jay D. Keasling () and Nico J. Claassens ()
Additional contact information
Aidan E. Cowan: Joint BioEnergy Institute
Mason Hillers: Joint BioEnergy Institute
Vittorio Rainaldi: Wageningen University and Research
Florent Collas: b.fab GmbH
Hemant Choudhary: Joint BioEnergy Institute
Basem S. Zakaria: Advanced Biofuels and Bioproducts Process Development Unit
Gregory G. Bieberach: b.fab GmbH
David N. Carruthers: Joint BioEnergy Institute
Maxwell Grabovac: Joint BioEnergy Institute
Jennifer W. Gin: Joint BioEnergy Institute
Bridgie Cawthon: Joint BioEnergy Institute
Yan Chen: Joint BioEnergy Institute
Emine Akyuz Turumtay: Joint BioEnergy Institute
Edward E. K. Baidoo: Joint BioEnergy Institute
Christopher J. Petzold: Joint BioEnergy Institute
Adam M. Feist: Joint BioEnergy Institute
Sara Tejedor-Sanz: Advanced Biofuels and Bioproducts Process Development Unit
Frank Kensy: b.fab GmbH
Blake A. Simmons: Joint BioEnergy Institute
Jay D. Keasling: Joint BioEnergy Institute
Nico J. Claassens: Wageningen University and Research

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Microbial bioproduction using one-carbon (C1) feedstocks has the potential to decarbonize the manufacturing of materials, fuels, and chemicals. Formate is a promising C1 feedstock, and the realization of industrial, formatotrophic platform organisms is a key goal for C1-based bioproduction. So far, a major limitation for synthetic formatotrophy has been slow energy supply due to slow formate dehydrogenase activity. Here, we implement a fast, metal-dependent formate dehydrogenase complex in a synthetic formatotrophic Escherichia coli utilizing the reductive glycine pathway. After a short-term evolution, we demonstrate formatotrophic growth of E. coli with a doubling time of less than 4.5 h, comparable to the fastest natural formatotrophs. To further explore the potential of a formate-based bioeconomy, this strain is engineered to produce mevalonate, as well as the terpenoid and aviation fuel precursor isoprenol, using formate we generate directly from the electrochemical reduction of CO2. This work demonstrates an improvement in bioproduct titer from formate, achieving the production of 3.8 g/L of mevalonate. Additionally, the abundant and recalcitrant polymer lignin is chemically decomposed into a formate-rich mixture of small organic acids and subsequently bioconverted into mevalonate. Overall, the described fast-growing, formatotrophic bioproduction strain demonstrates that a sustainable formate bioeconomy is within reach.

Date: 2025
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DOI: 10.1038/s41467-025-61001-y

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