Researchers at the University of Illinois Urbana-Champaign have discovered important new clues in the mystery of how an ancient enzyme can turn atmospheric carbon into biomolecules, a natural process that could be helpful in developing new methods for converting greenhouse gases like carbon dioxide into useful chemicals.
As deforestation and the use of fossil fuels cause atmospheric gases, like carbon dioxide (CO2), to rise to unprecedented levels, many scientists have turned to ancient biology searching for solutions to combat the imbalance of these gases in the atmosphere. From the beginning of life on Earth microscopic organisms have found ways to convert atmospheric carbon dioxide (CO2) and carbon monoxide (CO) into useful biomolecules.
These organisms use specialized biological catalysts, or enzymes, to “fix” these gases into molecular building blocks. Scientists have been particularly interested in understanding how one special Ni-containing ancient enzyme –acetyl-CoA synthase (ACS) – takes in carbon dioxide and carbon monoxide and converts them into acetyl-CoA — a key biomolecule that metabolizes sugars, lipids, and proteins inside cells.
This happens in a process called the Wood-Ljungdahl Pathway (WLP), and ACS catalyzes the final step of this set of biochemical reactions. But exactly how this enzyme operates remains a mystery to scientists despite decades of studying the enzyme. There have been conflicting hypotheses put forward regarding some fundamental aspects of the enzyme mechanism. Each step of the chemical reaction happens quickly, and the intermediate species in the reaction pathway are so short lived, oxygen-sensitive, and unstable that characterizing each step and understanding the entire mechanism remains enigmatic.
In a study led by Illinois chemistry professor Liviu Mirica, William H. and Janet G. Lycan Professor of Chemistry, and graduate student Shounak Nath, researchers created a synthetic functional model that mimics ACS and enables an in-depth exploration of the enzyme’s mechanism, a feat unachieved by any previous synthetic models, according to the researchers. Their investigation unveiled four key mechanistic insights – detailed in their recently published paper in Nature Communications – that are directly relevant to the mechanism of ACS.
They studied in detail most of the organometallic intermediates, including a very rare nickel intermediate, Ni(methyl)(CO).
Mirica and Nath explained that a key to the success of their synthetic model is a special ligand called iPr3tacn (1,4,7-triisopropyl-1,4,7-triazacyclononane) that forms a cage around the nickel atom and slows the reaction rate just enough that the labile intermediates can be observed directly. It also allows for some of the reactions to occur in both forward and backward directions, which enabled the researchers to characterize the kinetic and thermodynamic parameters associated with the molecular transformations.
Researchers said that the bulky tridentate iPr3tacn ligand has the right steric and electronic balance to allow for a suitable binding site for substrates and at the same time allows for the stabilization of both high- and low-valent Ni intermediates. This enables this system to access all proposed steps in the enzyme mechanism — something that was not achieved in other synthetic small-molecule models. Importantly, other models have failed to observe the key Ni(methyl)(CO) intermediate species that Nath and Mirica have identified.
According to the researchers, this work can be the key to scientists designing new and improved catalysts to sequester carbon dioxide and carbon monoxide gases out of the air into useful molecules. By having a full understanding of ACS’s steps and intermediates, Mirica said scientists can engineer synthetic catalysts that perform the same transformations as ACS using nickel, which is an earth-abundant metal.
Nath conducted this study over the course of three years and presented their work at the 6th Symposium on Advanced Biological Inorganic Chemistry (SABIC-2024) in Kolkata, India. Nath said he received positive feedback from biochemists who have been searching for decades for answers to the mechanism of ACS.
Nath said there were a lot of people from the bioinorganic community at the poster session, including Steve Ragsdale, one of the scientists who pioneered the study of this enzyme.
“I presented this work to him, and he was very excited about this,” Nath said. “He was excited about the fact that we could actually see the Ni(methyl)(CO) intermediate which he has been after for a very long time in the native enzyme.”
Mirica said this research is also impactful because the catalytic steps in natural ACS catalysis that are modeled in their synthetic system are fundamentally the same as the steps in the industrial production of chemicals like Monsanto’s acetic acid process. The catalyst in that industrial process is rhodium, a rare and expensive precious metal, and Mirica hopes that this work can serve as inspiration for designs of new industrial catalysts based on more economical nickel catalysts.
“There is a big interest in the chemical industry to develop catalytic processes employing more abundant and less expensive transition metal catalysts. For example, there's a push to potentially develop a nickel-based, Monsanto acetic acid-type transformation,” Mirica said.
“This is a very interesting enzyme from a fundamental, organometallic point of view, which is somewhat of a surprise that we talk about organometallic chemistry in the context of a biological system. If you look at the fundamental steps of the reaction catalyzed by this enzyme, it actually mimics classical steps involved in nickel-mediated organometallic transformations,” Mirica said.
The synthetic ACS model that the researchers designed is a simple one containing only one nickel atom that mimics the proximal nickel center (Np) of the active site where the substrates bind. Having this monometallic 3-coordinate nickel center with all steps characterized enables further study where scientists can speculate on the importance of the distal nickel atom (Nd) and other metal atoms near the active site in the natural ACS mechanism.
Nath said the greatest challenge was working with such sensitive compounds and learning how to work with carbon monoxide safely.
“A lot of these intermediates are very air sensitive and each of them have very different thermal stability windows. So, figuring out the exactly the right conditions at which each intermediate is stable enough for full characterization and at the same time competent to react further was the most challenging and intriguing part,” Nath said.
Editor's notes:
This work was supported by the National Science Foundation (CHE 2155160).
To contact Liviu Mirica: mirica@illinois.edu
To contact Shounak Nath: shounak2@illinois.edu
The paper “The mechanism of acetyl-CoA synthase through the lens of a nickel model system” was authored by Shounak Nath, Leonel Griego, and Liviu Mirica and published in Nature Communications on June 4, 2025, and is available online.