Formate can be seen as the backbone of a carbon-neutral bioeconomy, produced from CO2 using (electro)chemical methods and converted to value-added products using enzymatic cascades or engineered microorganisms. An important step in expanding the assimilation of synthetic formate is its thermodynamically complex reduction of formaldehyde, which here appears as a yellow color change. Credit: Institute of Terrestrial Microbiology Max Planck/Geisel.
       Scientists at the Max Planck Institute have created a synthetic metabolic pathway that converts carbon dioxide into formaldehyde with the help of formic acid, offering a carbon-neutral way to produce valuable materials.
        New anabolic pathways for carbon dioxide fixation not only help to reduce carbon dioxide levels in the atmosphere, but can also replace the traditional chemical production of pharmaceuticals and active ingredients with carbon-neutral biological processes. New research demonstrates a process by which formic acid can be used to convert carbon dioxide into a material valuable to the biochemical industry.
        Given the rise in greenhouse gas emissions, carbon sequestration or carbon dioxide sequestration from large emission sources is a pressing issue. In nature, the assimilation of carbon dioxide has been going on for millions of years, but its power is far from sufficient to compensate for anthropogenic emissions.
        Researchers led by Tobias Erb of the Institute of Terrestrial Microbiology. Max Planck use natural tools to develop new methods for fixing carbon dioxide. They have now succeeded in developing an artificial metabolic pathway that produces highly reactive formaldehyde from formic acid, a possible intermediate in artificial photosynthesis. Formaldehyde can directly enter into several metabolic pathways to form other valuable substances without any toxic effects. As with a natural process, two main ingredients are required: energy and carbon. The first can be provided not only by direct sunlight, but also by electricity – for example, solar modules.
        In the value chain, carbon sources are variable. Carbon dioxide is not the only option here, we are talking about all the individual carbon compounds (C1 building blocks): carbon monoxide, formic acid, formaldehyde, methanol and methane. However, almost all of these substances are highly toxic, both for living organisms (carbon monoxide, formaldehyde, methanol) and for the planet (methane as a greenhouse gas). It is only after formic acid has been neutralized to its basic formate that many microorganisms tolerate high concentrations of it.
        “Formic acid is a very promising source of carbon,” emphasizes Maren Nattermann, first author of the study. “But converting it to formaldehyde in vitro is very energy intensive.” This is because formate, the salt of formate, is not easily converted to formaldehyde. “There is a serious chemical barrier between these two molecules, and before we can carry out a real reaction, we must overcome it with the help of biochemical energy – ATP.”
        The aim of the researchers was to find a more economical way. After all, the less energy required to feed carbon into metabolism, the more energy can be used to stimulate growth or production. But there is no such way in nature. “The discovery of so-called hybrid enzymes with multiple functions required some creativity,” says Tobias Erb. “However, the discovery of candidate enzymes is only the beginning. We’re talking about reactions that can be counted together because they’re very slow—in some cases, there’s less than one reaction per second per enzyme. Natural reactions can proceed at a rate that is a thousand times faster.” This is where synthetic biochemistry comes in, says Maren Nattermann: “If you know the structure and mechanism of an enzyme, you know where to intervene. It has been of great benefit.”
        Enzyme optimization involves several approaches: specialized building block exchange, random mutation generation, and capacity selection. “Both formate and formaldehyde are very suitable because they can penetrate cell walls. We can add formate to the cell culture medium, which produces an enzyme that turns the resulting formaldehyde into a non-toxic yellow dye after a few hours,” Maren said. Nattermann explained.
        Results in such a short period of time would not have been possible without the use of high-throughput methods. To do this, the researchers collaborated with industrial partner Festo in Esslingen, Germany. “After about 4,000 variations, we quadrupled our yield,” says Maren Nattermann. “Thus, we have created the basis for the growth of the model microorganism E. coli, the microbial workhorse of biotechnology, on formic acid. However, at the moment, our cells can only produce formaldehyde and cannot further transform.”
        In collaboration with his collaborator Sebastian Wink from the Institute of Plant Molecular Physiology. Max Planck researchers are currently developing a strain that can take up intermediates and introduce them into central metabolism. At the same time, the team is conducting research on the electrochemical conversion of carbon dioxide to formic acid with a working group at the Institute of Chemical Energy Conversion. Max Planck under the direction of Walter Leitner. The long-term goal is a “one-size-fits-all platform” from carbon dioxide produced by electrobiochemical processes to products such as insulin or biodiesel.
        Reference: Maren Nattermann, Sebastian Wenk, Pascal Pfister, Hai He, Seung Hwang Lee, Witold Szymanski, Nils Guntermann, Faiying Zhu “Development of a new cascade for the conversion of phosphate-dependent formate to formaldehyde in vitro and in vivo”, Lennart Nickel. , Charlotte Wallner, Jan Zarzycki, Nicole Pachia, Nina Gaisert, Giancarlo Francio, Walter Leitner, Ramon Gonzalez, and Tobias J. Erb, May 9, 2023, Nature Communications.DOI: 10.1038/s41467-023-38072-w
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