Using a lesser-known feature of microbiology, Michigan State University researchers have helped open a door that could lead to the manufacture of drugs, vitamins and more at lower cost and with improved efficiency.
The international research team, led by Henning Kirst and Cheryl Kerfeld repurposed so-called bacterial microcompartments and programmed them to produce valuable chemicals from inexpensive starting ingredients.
The team recently published their work in the journal Proceedings of the National Academy of Sciences.
“Microcompartments, they’re like nanoreactors or nanofactories,” said Kirst, senior research associate in Kerfeld’s laboratorywhich operates at both MSU and Lawrence Berkeley National Laboratory.
Kirst, Kerfeld and their teammates saw the microcompartments as an opportunity to take important chemical reactions to the next level. Over the past few decades, researchers have harnessed the power of enzymes found in bacteria to create valuable chemicals, including biofuels and medicines.
In these industrial applications, however, chemists often rely on the entire microorganism to produce the desired compound, which Kirst says can lead to complications and inefficiencies.
“The analogy we use is that it’s like a house. If you have reactions all over the place, it can get very complex,” Kirst said. “Imagine starting to shower in the basement, but then having to go to the second floor to get shampoo, then back to the basement to finish showering, then to the first floor to get your towel. It’s just very inefficient.
In the case of microorganisms, the bacterium can make an ingredient on one side of its cell, while the specific enzyme that uses that ingredient to make the final product is on the other side. Then, even though that ingredient might make the trip through the cell, there are other enzymes along the way that might catch it and use it for something else.
Enzymes, however, live in bacterial micro-compartments, which are like rooms inside the house of the cell. The Spartans and their colleagues showed that they could design microcompartments to optimize a specific reaction, bringing together the necessary enzymes and ingredients in the same smaller space, rather than scattering them.
“We put everything we need for a task in one room,” Kirst said. “Compartmentalization gives us a lot more control and improves efficiency.”
“It’s like working in an efficiency apartment compared to Spelling Manor [the Spelling Manor is a huge property in Los Angeles — it has over 100 rooms and more than 50,000 square feet]“said Hannah Professor Emeritus Kerfeld at MSU. Department of Biochemistry and Molecular Biology in the College of Natural Sciences and a faculty member of the MSU-DOE Plant Research Laboratorywhich is supported by the US Department of Energy.
As a proof of concept, the team designed a microcompartment system that could transform the simple and inexpensive compounds formate and acetate into pyruvate.
“Pyuvate is also a relatively simple precursor to virtually anything biology can make — for example, pharmaceuticals, vitamins, and flavorings,” Kirst said. “But we think the whole principle is very generalizable to many other metabolic pathways that would be interesting to explore.”
And they’re not the only ones to think so.
“The system described here can be used as a platform in ambitious engineering projects”, wrote Volker Müller in a comment on research. Müller is the head of the department of microbiology and bioenergetics at Goethe University Frankfurt and was not involved in the project.
“It’s exciting and paves the way for using the engineering strategy (bacterial microcompartments) for the production of various compounds from inexpensive substrates,” he said.
Bacterial microcompartments are similar to organelles or tiny “organs” found in cells of eukaryotes, which include plants, humans, and other animals. Although they are found in many types of bacteria, where they help perform a multitude of reactions, they are still relatively new to science. It took the advent of high-resolution electron microscopy and affordable gene sequencing for researchers to realize the extent and versatility of these compartments, Kerfeld explained.
In collaboration with researchers from the Max Planck Institute for Molecular Plant Physiology, Spartan researchers have reinforced this versatility. They showed how scientists can create versions of these compartments that are not found in nature.
“We can take the architecture of the compartment and set up a whole new type of reaction,” Kerfeld said. “This strategy could be applied in many different ways for many different uses, even uses that are not compatible with bacteria.”
“I think that’s the main accomplishment,” Kirst said. “We have taken a big step towards making a synthetic bacterial organelle.”
Reference: Kirst H, Ferlez BH, Lindner SN, Cotton CAR, Bar-Even A, Kerfeld CA. Towards a glycyl radical enzyme containing a synthetic bacterial microcompartment to produce pyruvate from formate and acetate. PNAS. 2022;119(8):e2116871119. do I: 10.1073/pnas.2116871119
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