MIT chemists discover unexpected enzyme structure

MIT researchers have shown that some of the atoms in an enzyme called carbon monoxide dehydrogenase can reorganize when oxygen levels are low. A nickel atom (green) leaves the cube-shaped structure, displacing an iron atom (orange). A sulfur atom (yellow) also comes out of the cube. Image: Elizabeth Wittenborn

Many microbes have an enzyme that can convert carbon dioxide into carbon monoxide. This reaction is essential for the construction of carbon compounds and the production of energy, especially for bacteria that live in oxygen-free environments.

This enzyme is also of great interest to researchers who want to find new ways to remove greenhouse gases from the atmosphere and turn them into useful carbon compounds. Current industrial processes for converting carbon dioxide are very energy intensive.

“There are industrial processes that perform these reactions at high temperature and high pressure, and then there is this enzyme which can do the same thing at room temperature,” explains Catherine Drennan, a MIT professor of chemistry and biology and researcher at Howard Hughes Medical Institute. “For a long time, people have been interested in understanding how nature does this difficult chemistry with this assemblage of metals.”

Drennan and his colleagues at MIT, Brandeis University and Aix-Marseille University in France have now discovered a unique aspect of the “C-cluster” structure – the collection of metal atoms and sulfur which forms the heart of the enzyme carbon monoxide dehydrogenase (CODH). Instead of forming a rigid scaffold, as expected, the cluster can actually change configuration.

“It wasn’t what we expected to see,” says Elizabeth Wittenborn, recent MIT PhD holder and lead author of the study, who appears in the October 2 issue of eLife magazine.

A molecular wheel

Clusters containing metals such as cluster C perform many other critical reactions in microbes, including the splitting of nitrogen gas, which are difficult to reproduce industrially.

Drennan began studying the structure of carbon monoxide dehydrogenase and cluster C about 20 years ago, shortly after starting his lab at MIT. She and another research group each proposed a structure for the enzyme using x-ray crystallography, but the structures weren’t quite the same. The differences were eventually resolved and the structure of CODH was considered well established.

Wittenborn took over the project a few years ago, hoping to understand why the enzyme is so sensitive to oxygen inactivation and how cluster C is formed.

To the researchers’ surprise, their analysis revealed two distinct structures for cluster C. The first was an arrangement they expected to see – a cube made up of four atoms of sulfur, three atoms of iron, and one nickel. atom, with a fourth iron atom connected to the cube.

In the second structure, however, the nickel atom is removed from the cube-shaped structure and takes the place of the fourth iron atom. The displaced iron atom binds to a nearby amine acid, cysteine, which keeps it in its new location. One of the sulfur atoms also comes out of the cube. All of these movements seem to occur in unison, in a movement that researchers describe as a “molecular wheel.”

“Sulfur, iron and nickel are all moving to new locations,” Drennan explains. “We were really shocked. We thought we figured out this enzyme, but found it to perform this incredibly dramatic movement that we never expected. Then we found more evidence that this is in fact something relevant and important – it’s not just fluke, but part of the design of this cluster. “

Researchers believe that this movement, which occurs on exposure to oxygen, helps protect the cluster from complete and irreversible disintegration in response to oxygen.

“It appears to be a safety net, allowing metals to be moved to places where they are more secure on the protein,” Drennan explains.

Douglas Rees, professor of chemistry at Caltech, described the article as “a beautiful study of a fascinating cluster conversion process”.

“These clusters have mineral characteristics and you would think they would be ‘as stable as a rock’,” says Rees, who was not involved in the research. “Instead, clusters can be dynamic, giving them properties essential to their function in a biological setting.”

Not a rigid scaffolding

This is the largest metal displacement ever observed in an enzyme cluster, but smaller scale rearrangements have been observed in others, including a metal cluster found in the enzyme nitrogenase, which converts nitrogen gas in ammonia.

“In the past, people thought these clusters were really rigid scaffolding, but over the last few years, there’s more and more evidence that they’re not really rigid,” says Drennan.

Researchers are now trying to understand how cells put these clusters together. Learning more about how these clusters work, how they fit together, and how they impact oxygen could help scientists trying to copy their action for industrial purposes, Drennan says. There is great interest in finding ways to combat the build-up of greenhouse gases, for example by converting carbon dioxide to carbon monoxide and then to acetate, which can be used as a building block for many. useful types of carbon-containing compounds. .

“It’s more complicated than people think. If we understand that, then we have a much better chance of really mimicking the biological system, ”Drennan says.

The research was funded by the National Institutes of Health and the French National Research Agency.

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