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Researchers discover unique property of critical methane-producing enzyme

BY Emily Scott

An unexpected discovery has given scientists a greater understanding of an important methane-producing enzyme.

A team of IGB researchers published a paper in eLife that outlined their findings on an enzyme called methyl-coenzyme M reductase, or MCR.

Their findings overturn what was previously believed to be true in the field: that a set of unique modifications present in MCR were essential to how the enzyme functions.

They discovered that these modifications were in fact not essential, a finding that will bring scientists a step closer to fully understanding this enzyme, which plays an important role in methane production and the carbon cycle.

Researchers discover unique property of critical methane-producing enzyme
From left to right: G. William Arends Professor in Molecular and Cellular Biology William Metcalf, Associate Professor of Chemistry Douglas Mitchell, IGB Fellow Dipti Nayak, and postdoctoral researcher Nilkamal Mahanta.

Methane is an important greenhouse gas that contributes to approximately 20 percent of the greenhouse effect, which contributes to the warming of earth.

Methane comes from both geological sources and biological sources, including from a group of microorganisms called methanogens. These microscopic organisms, which are a member of the domain Archaea, produce methane as the byproduct of their metabolism. Gigatons of methane are produced by methanogens every year.

Methanogens have the enzyme MCR, which is the only enzyme that makes methane. It’s critical for both the production and consumption of methane.

“This is a hugely important enzyme,” said Professor of Molecular and Cellular Biology William Metcalf, co-author of the paper and leader of IGB’s Mining Microbial Genomes (MMG) theme. “I would argue it’s one of the most important enzymes on earth for the carbon cycle.”

MCR also has some unusual properties. Unlike most enzymes, MCR has a series of modifications that change the enzyme’s amino acids. These modifications were previously believed to have been essential to the enzyme’s functions.

Before now, it’s been impossible to do a genetic analysis of these enzymes — which would include taking away these modifications and looking at how the enzyme works without them.

“It was believed that if you did that, the enzyme wouldn’t work,” Metcalf said. “Because that enzyme is required for viability of the organism, it was thought to be an essential gene.”

But Douglas Mitchell, a professor of chemistry and faculty member of IGB’s MMG theme, thought otherwise. He and his research laboratory had been studying a class of molecules that had one of the modifications that is also present in MCR. They figured out how this modification was done and predicted that the same enzymatic machinery used to modify MCR in methanogens was the same machinery used to make antibiotics and bacteria.

However, their lab had a limitation, according to Nilkamal Mahanta, a postdoctoral researcher in Mitchell’s lab who was involved with the research. Their lab was limited in its ability to perform the kind of experiment needed to see if this was true. The organisms they wanted to study exist only in anaerobic environments, which do not contain oxygen.

Any research would have to be done in anaerobic chambers, and this is part of the reason why no experiments have been done to study these modifications.

The assumption that this modification was essential, therefore, was a hypothesis yet to be proven right or wrong by experimentation, according to Mahanta.

So Mitchell approached Metcalf to see if his lab could test it out. Metcalf was skeptical at first, believing the modification would be essential to MCR’s functions. Despite that, he decided to give it a try with the help of IGB fellow Dipti Nayak.  

Nayak had recently developed a novel genetic tool that could manipulate this type of organism. She used this tool to study the physical properties of MCR and understand how it works — and found that the modification was not essential to the enzyme’s function.

This came as a surprise to many in this field of research, and to Metcalf and Nayak as well.

“When I started this project, I didn’t quite know as much about the importance of these modifications,” Nayak said. “As the project moved along . . . I realized the impact of the discovery we made, that this modification we thought was important and involved in making methane or breaking down methane, suddenly was not playing as important a role as people in the literature had been talking about for the last 10 or 15 years — maybe even longer, actually.”

She remembers walking into Metcalf’s office, telling him the surprising result, and realizing they would have to form a new strategy for their research.

“But it’s always fun when the results are unexpected,” Nayak said. “I think it challenges you a little more.”

Their findings suggest there is more to be uncovered about this enzyme and the role it plays in producing and consuming methane.

“We have this important enzyme, but we really don’t understand why it’s made the way it is,” Metcalf said. “If we want to understand that enzyme, and how that enzyme fits in the organism, and how that organism fits into the global environment — we really have to be able to tease this puzzle apart piece by piece.”

There are other modifications of MCR yet to be studied, but Metcalf and Nayak hope to investigate these with the genetic tool Nayak created.

“We haven’t been able to do the detailed biochemistry that would allow us to really pinpoint how these modified amino acids function,” Metcalf said. “Now we have the tool to make the enzyme without the modifications . . . and this is really due to some very creative work that (Nayak) did on this project.”

The fact that this came from a “chance juxtaposition of researchers,” as Metcalf described it, shows what can happen when different disciplines cross paths.

“Without this collaboration and the technical know-how that (Metcalf’s lab) has and the enzymology that we have, this would not have been possible,” Mahanta said.

If the two labs hadn’t joined forces in this way and challenged each other’s point of view, this discovery may have never been made.

“This is not a project that would’ve happened had either lab started this on their own,” Metcalf said. “It really was a very nice synergy.”


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