Researchers at Northwestern University have made significant strides in understanding Acetyl-CoA Synthase (ACS), an ancient enzyme that plays a crucial role in converting carbon dioxide and carbon monoxide into acetyl-CoA. This new finding sheds light on the very basic biochemical pathways inside cells. It opens a path toward creating low-cost industrial catalysts to accelerate carbon capture and draw down more carbon. The study, led by Liviu Mirica and Shounak Nath, provides essential insights into ACS’s mechanisms, which could influence future chemical production methods.
The research team created a synthetic functional model of ACS that more closely resembles the movement and action of the enzyme. This new innovation allows them to look more deeply into its innovative catalytic mechanism. This simple model uses just one nickel atom, which mirrors the ncMBP’s proximal nickel center in the active site—the place where substrates stick. To surround the nickel atom with a cage, researchers relied on a new ligand called iPr 3 tacn. This configuration reduced the reaction rate, giving them time to see labile intermediates. Taken together these findings uncover four major mechanistic insights that are broadly applicable to ACS’s mode of action.
Understanding Acetyl-CoA Synthase
Acetyl-CoA Synthase, Left : Another essential biomolecule that metabolizes sugars, lipids and proteins inside of cells. Its ability to convert gaseous substrates like carbon dioxide and carbon monoxide into acetyl-CoA makes it a valuable target for research focused on sustainable energy and industrial processes.
Mirica and Nath’s study breaks a 60-plus year mystery surrounding the phenomenon known as ACS. They developed a test tube model that allows a detailed investigation of the enzyme’s catalytic process. Importantly, our model emphasizes the crucial role of the nickel atom at the active site. Without this atom, the enzyme would be unable to perform its function.
“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,” – Liviu Mirica
This attention to organometallic chemistry provides an insight into how ACS can be at the forefront of showing the marriage between biology and chemistry. ACS-catalyzed transformations often replicate classical nickel-mediated classics. This intuitive connection provides the link between nature-inspired and synthetic techniques in the production of complex chemicals.
Insights from the Study
Our research unlocked some important mechanistic discoveries, such as the discovery of a key Ni(methyl)(CO) intermediate species. This specific intermediate had slipped under the radar in past models, so observing it was a major coup in furthering our comprehension of how ACS works.
The team’s efforts helped lead to four key realizations that promise to change the way scientists approach and interpret enzyme mechanisms. Findings like these have captivated the biochemistry community, who have been trying for decades to understand ACS’s catalytic mechanism.
“A lot of these intermediates are very air-sensitive and each of them has very different thermal stability windows. So, figuring out 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.”
The ramifications of this research go beyond fundamental science and into practical applications in eco-friendly manufacturing of chemicals. The catalytic steps in nature’s ACS catalysis are very similar to those utilized in industry. One striking case in point is the process developed by Monsanto for acetic acid. This similarity indicates that lessons learned from the biology of ACS could inform novel approaches to engineering more sustainable catalysts.
Implications for Industry
This study uses a relatively cheaper nickel catalysts. It would help develop new carbon capture technologies and generate more efficiency in the production of chemicals and materials.
These discoveries were recently reported at the 6th Symposium on Advanced Biological Inorganic Chemistry (SABIC-2024) hosted in Kolkata, India. The novel approach of the presentation immediately captured the attention of widespread experts in this quickly-accelerating field. Included within was Steve Ragsdale, a leader in ACS research.
“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.”
He further elaborated on Ragsdale’s reaction to their discovery of the Ni(methyl)(CO) intermediate:
Presentation and Recognition
The enthusiastic response from luminaries in the field of biochemistry shows that these studies might have a profound impact on the scientific community.
Nath noted Ragsdale’s enthusiasm about their work:
“I presented this work to him, and he was very excited about this.”
He further elaborated on Ragsdale’s reaction to their discovery of the Ni(methyl)(CO) intermediate:
“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.”
The positive feedback from established figures in biochemistry reflects the potential significance of this research within the scientific community.