Researchers built the Reductive Formate Pathway, called the ReForm pathway, to convert CO2 into acetyl-CoA outside living cells.
Acetyl-CoA is a small but essential molecule your cells use to turn food into energy. When your body breaks down carbohydrates, fats, and proteins, it often funnels the results into acetyl-CoA.
From there, acetyl-CoA carries a tiny chemical package called an acetyl group into the citric acid cycle, where your cells “burn” it.
That process releases energy, and your body captures it to help make ATP, the main energy currency that powers cellular work.
This study shows how engineered enzymes, electricity-derived carbon feedstocks, and cell-free systems can be combined to recycle CO2 into useful chemical building blocks, while avoiding the limits of living cells and pointing toward new ways to make materials with lower carbon footprints.
Converting CO2 into Acetyl-CoA
The work was led by Ashty Karim, Ph.D., at Northwestern University, and collaborators at Stanford University helped assemble the pathway.
Her research focuses on designing enzyme pathways for carbon recycling, and that focus makes the ReForm pathway easier to optimize.
“The unabated release of CO2 has caused many pressing social and economic challenges for humanity,” said Northwestern’s Ashty Karim.
“If we’re going to address this global challenge, we critically need new routes to carbon-negative manufacturing of goods.
A cell-free setup lets researchers control each ingredient directly. The feedstock starts as formate, which is a simple carbon compound that stays dissolved in water, and can be stored as a liquid.
Because formate already carries carbon and hydrogen, enzymes can build larger molecules by adding bonds one step at a time. This helps only if the later steps work efficiently, which is where the ReForm pathway aims to help.
Turning electricity into feedstock
Using electricity to add electrons and change molecules, which is called an electrochemical reduction, can turn CO2 into formate enzymes that can be used as feedstock.
Enzymes do the selective building, because proteins prefer specific shapes and bonds. Hybrid systems could turn intermittent power into stored liquids and solids, but engineers must balance efficiency, cost, and durability.
Living cells can convert many foods into energy and parts, yet most struggle to use formate as their main carbon.
A cell must keep itself alive while processing formate, and that balancing act limits how much carbon reaches product molecules.
“ReForm can readily use diverse carbon sources, including formate, formaldehyde and methanol,” said Stanford’s Michael Jewett, who co-led the study with Karim.
“This is the first demonstration of a synthetic metabolic pathway architecture that can do so. By combining electrochemistry and synthetic biology, the ReForm pathway also expands possible solutions for generalizable CO2-fixation strategies.
Fast screening finds working enzymes
Finding the right enzyme variants, slightly different protein versions made by changing amino acids, took fast testing outside cells.
Using cell-free extracts, the team tested 66 candidate enzymes drawn from many species, then kept only the best performers.
Bench-top control can speed prototyping, but each recipe still needs tuning of enzyme levels and helper molecules for output.
The pathway required nonnatural reactions, chemical steps not found in any organism, to build carbon upward from formate.
Researchers redesigned five enzymes so each one grabs a carbon fragment or reduces it, then passes it to the next.
“Typically, people will test a handful of enzymes, and that takes months or more,” said Karim.
Acetyl-CoA and the ReForm pathway
Why sketch a metabolic pathway, a chain of enzyme reactions that changes molecules stepwise, before any enzyme touches a tube?
In the ReForm pathway, six steps turn formate into acetyl-CoA by adding carbon and moving electrons through helper molecules.
Acetyl-CoA feeds many growth and storage reactions, so reaching it creates a flexible starting point for making many other chemicals.
Many enzymes depend on a cofactor, a helper molecule enzyme needed for chemical steps, to pass electrons and stay active.
By adjusting cofactor amounts and enzyme loadings, the researchers raised reaction rates, which matters when many steps share the same pool.
Those knobs are simple in a test tube, but they become harder to control in large reactors with heat and mixing limits.
Desperate for carbon solutions
Human activities have warmed Earth about 2.0°F since 1850-1900, and that heat makes CO2 recycling urgent.
Scientists consider a process to be carbon-negative – removing more CO2 than it emits – only when its energy use stays low across capture and production.
Life-cycle checks add up emissions from power and equipment, then show whether ReForm-based manufacturing truly cuts warming gases.
Next steps for carbon reuse
More efficient carbon fixation, turning CO2 into organic molecules, depends on finding fast reactions that waste little energy.
Karim’s team plans to refine enzyme performance and explore alternate routes, because small gains in each step can add up.
“From here, we can imagine this work going in a couple of different directions,” said Karim.
Together, the ReForm pathway shows how engineered enzymes can turn captured carbon into common building blocks without living organisms.
Future success will hinge on clean electricity, durable enzymes, and careful accounting that proves the whole process removes more carbon.
The study is published in Nature.
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