This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Researchers from the Singapore-MIT Alliance for Research & Technology's (SMART) Antimicrobial Resistance (AMR) interdisciplinary research group, alongside collaborators from Massachusetts Institute of Technology (MIT), Nanyang Technological University (NTU Singapore), and institutions in the United States, Poland and France, have discovered aminovaleramididine synthetase (AvaS), the first identified pyridoxal phosphate (PLP)-dependent enzyme responsible for producing a chemical modification linked to how bacteria respond to metabolic stress. This fundamental discovery sheds new light on how bacteria use RNA modification to control protein production, opening new avenues to study bacterial adaptation and identify future targets for antimicrobial therapeutics.
Antimicrobial resistance is one of the most pressing global health and development challenges of our time. Bacteria and other pathogens are rapidly developing resistance to existing treatments, making infections harder to treat. Without new approaches, minor inconveniences today, such as routine surgeries or even a paper cut, could become life-threatening tomorrow.
Against this backdrop, fundamental discoveries like the identification of AvaS, notably as the first PLP-dependent tRNA-modifying enzyme, offer researchers a critical new lens to study how bacteria survive, adapt and resist treatment and can contribute to better strategies for overcoming antimicrobial resistance. Bacteria can develop resistance to antibiotics using various strategies, many of which depend on their ability to regulate which proteins are made, when they are made and how accurately they are produced—whether by pumping drugs out of their cells, creating enzymes that break down drugs or developing new cellular processes to avoid antibiotics' targets. To build these proteins, bacteria rely on RNA molecules to read genetic instructions and direct protein production.
Among these RNA molecules are transfer ribonucleic acids (tRNAs), a specialized class of RNA that acts as molecular delivery vehicles, bringing chemical 'stickers' that help bacteria control how proteins are made in response to stress and changing conditions such as exposure to antibiotics. In a paper titled "Pyridoxal phosphate-dependent biosynthesis of aminovaleramide by AvaS in tRNA," published in Nature Chemical Biology, the researchers describe their discovery of a new enzyme, AvaS, and identified it as the enzyme responsible for creating a tRNA chemical modification known as aminovaleramide cytidine (ava²C) in Pseudomonas aeruginosa, a harmful bacterium responsible for a range of serious human infections such as pneumonia and sepsis. While ava²C had previously been detected in several bacteria and plants, the enzyme responsible for producing this modification was previously unknown.
Using SMART AMR's high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based RNA modification profiling platform, previously reported in Nucleic Acids Research, the team systematically screened thousands of Pseudomonas aeruginosa mutants and discovered AvaS. The researchers also confirmed the presence of ava²C in other organisms, including the bacteria Acinetobacter baumannii and Vibrio cholerae, as well as the plant Arabidopsis thaliana. The research revealed that AvaS uses PLP, a vitamin B6 derivative, to convert a known modification, lysidine (k²C), into ava²C.
This marks the first time that a PLP-dependent enzyme has been linked to tRNA modification. Traditionally, PLP-dependent enzymes have only been associated with amino acid metabolism and related biochemical pathways. Discover the latest in science, tech, and space with over 100,000 subscribers who rely on Phys.org for daily insights. d research that matter—daily or weekly.
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