Engineers Create Bacteria That Can Synthesize an Unnatural Amino Acid

by Henrik Andersen
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Engineers Develop Bacteria Capable of Producing Unnatural Amino Acid

A group of scientists has successfully engineered bacteria to synthesize pN-Phe, an unconventional amino acid with potential applications in medicine. Ongoing research will focus on optimizing this process and investigating its potential in the development of vaccines and immunotherapies.

The groundbreaking results, recently published in the journal Nature Chemical Biology, lay the foundation for future advancements in creating unique vaccines and immunotherapies.

Amino acids play a fundamental role in the composition of proteins, which are essential for the proper functioning of biological structures. While all living organisms are made up of 20 core amino acids, nature offers a vast array of over 500 distinct amino acids. In addition, through human ingenuity, numerous synthetic amino acids have been synthesized. These unconventional amino acids hold promise in the development of innovative pharmaceuticals and therapeutic treatments.

Researchers at the University of Delaware, working under the guidance of Aditya Kunjapur, an assistant professor in the Department of Chemical and Biomolecular Engineering within the College of Engineering, have now successfully engineered bacteria to produce an amino acid containing a rare functional group that has been shown to have implications in immune system regulation. Additionally, the researchers have trained a single strain of bacteria to create this amino acid and insert it at specific locations within target proteins. These findings, published in Nature Chemical Biology, provide a solid basis for the future development of distinctive vaccines and immunotherapies.

The Kunjapur Lab employs synthetic biology and genetic engineering tools to create microorganisms capable of synthesizing various compounds and molecules, particularly those with functional groups or properties that are not commonly found in nature.

For this specific study, the researchers focused their efforts on para-nitro-L-phenylalanine (pN-Phe), a non-standard amino acid that does not belong to the set of twenty standard amino acids and has not been observed in nature. Other research teams have used pN-Phe as a tool to stimulate the immune system’s response to proteins that it typically ignores.

“The nitro chemical functional group possesses valuable properties that have been largely overlooked by researchers aiming to modify metabolism,” explained Kunjapur. “pN-Phe also has a significant presence in the literature — when added to a protein from a mouse and reintroduced to mice, the immune system no longer tolerates the original version of that protein. This ability holds promise for treating or preventing diseases caused by rogue proteins that the immune system struggles to target.”

Through genetic code expansion techniques, the researchers expanded the “alphabet” of amino acids encoded by DNA. By combining metabolic engineering techniques with genetic code expansion, they developed a system that autonomously produces nitrated proteins.

“Due to the unique chemistry of the nitro functional group, the unconventional amino acid we selected as our target for this project surprised many scientists in our field who did not anticipate its biosynthesis,” noted Kunjapur.

The next phase of this research involves optimizing the methods for synthesizing larger quantities of nitrated proteins and extending these techniques to other microorganisms. The ultimate goal is to refine this platform for applications related to vaccines and immunotherapies, which is supported by Kunjapur’s 2021 AIChE Langer Prize and the 2022 National Institutes of Health Director’s New Innovator Award. To further support this long-term objective, Kunjapur and Neil Butler, the doctoral candidate and first author of the published paper, co-founded Nitro Biosciences.

“The implications are quite intriguing since we can harness the central metabolism and compound production abilities of bacteria and, with a few modifications, expand their chemical capabilities,” commented Butler. “The nitro functionality is rare in biology and absent from the standard 20 amino acids, but we have demonstrated that bacterial metabolism is adaptable enough to be rewired and accommodate this functionality.”

Kunjapur added, “Bacteria have the potential to serve as effective vehicles for drug delivery. We believe that we have developed a tool that can leverage the bacteria’s ability to produce target antigens within the body while also using nitration to illuminate those antigens.”

Reference: “A platform for distributed production of synthetic nitrated proteins in live bacteria” by Neil D. Butler, Sabyasachi Sen, Lucas B. Brown, Minwei Lin, and Aditya M. Kunjapur, 15 May 2023, Nature Chemical Biology.
DOI: 10.1038/s41589-023-01338-x

This research received funding from a grant provided by the National Science Foundation.

Frequently Asked Questions (FAQs) about Bacteria, Unnatural Amino Acid, Medical Applications

What is the main focus of this research?

The main focus of this research is on engineering bacteria to produce an unnatural amino acid called pN-Phe and exploring its potential in medical applications such as vaccines and immunotherapies.

How did the researchers achieve the production of the unnatural amino acid?

The researchers employed synthetic biology and genetic engineering techniques to modify bacteria and enable them to synthesize the non-standard amino acid. They utilized genetic code expansion methods to expand the “alphabet” of amino acids encoded by DNA.

What is unique about the synthesized amino acid, pN-Phe?

pN-Phe is an unconventional amino acid that is not part of the standard set of 20 amino acids found in all living organisms. It contains a rare functional group, the nitro functional group, which has implications in the regulation of the immune system.

What are the potential applications of this research?

The research opens up possibilities for developing unique vaccines and immunotherapies. The synthesized amino acid can be used to stimulate the immune system’s response to proteins that it typically ignores, potentially aiding in the treatment or prevention of diseases caused by rogue proteins.

How does this research contribute to the field of medicine?

By engineering bacteria to produce the unnatural amino acid, researchers have expanded the chemical repertoire available for the development of pharmaceuticals and therapeutic treatments. The ability to create and integrate the nitro functionality into proteins offers new avenues for drug discovery and delivery.

What are the future directions for this research?

The next steps involve optimizing the synthesis process to produce larger quantities of nitrated proteins and extending the methodology to other microorganisms. The long-term goal is to refine the platform for applications related to vaccines and immunotherapies, leveraging the potential of bacteria as drug delivery vehicles.

Who supported this research?

The research was supported by a grant from the National Science Foundation. Additionally, Aditya Kunjapur, the lead researcher, received the 2021 AIChE Langer Prize and the 2022 National Institutes of Health Director’s New Innovator Award, further supporting the long-term goals of this research.

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