Scientists from the Singapore-MIT Alliance for Research and Technology (SMART), in collaboration with teams from MIT, Nanyang Technological University, and other institutions, have identified a new enzyme called aminovaleramididine synthetase (AvaS). This enzyme is the first known pyridoxal phosphate (PLP)-dependent protein responsible for a specific chemical modification of bacterial transfer RNA (tRNA). Published in Nature Chemical Biology, this discovery uncovers a novel mechanism that bacteria use to regulate protein production and adapt to metabolic stress, with notable implications for combating antimicrobial resistance.
What Happened
Using a high-throughput RNA modification profiling platform based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), the research team systematically screened thousands of Pseudomonas aeruginosa mutants. They identified AvaS as the enzyme that converts lysidine (k2C), a previously known tRNA chemical modification, into aminovaleramide cytidine (ava2C), a modification linked to stress responses. This marks the first time a PLP-dependent enzyme has been directly connected to tRNA modification. The enzyme and this modification were also found in other bacteria species, such as Acinetobacter baumannii and Vibrio cholerae, as well as in the plant Arabidopsis thaliana.
Key Facts
The discovery was published on September 9 in the peer-reviewed journal Nature Chemical Biology. The work was led by the SMART AMR group with co-lead principal investigator Professor Peter Dedon of MIT. The platform used allowed screening of thousands of bacterial mutants, confirming the enzyme’s role in tRNA modification. The chemical modification ava2C was identified in multiple bacterial pathogens, including Pseudomonas aeruginosa, a cause of pneumonia and sepsis. The modification is produced via a vitamin B6 derivative, pyridoxal phosphate (PLP), conventionally known for roles in amino acid metabolism.
What This Means
This discovery expands the biological functions known for PLP-dependent enzymes, showing they do more than participate in metabolic pathways—they also chemically modify RNA to control protein synthesis. Understanding how AvaS modifies bacterial tRNA sheds light on a previously unknown layer of gene expression regulation in bacteria. It reveals a new strategy bacteria use to fine-tune protein production in response to environmental stresses, including exposure to antibiotics. This insight has practical significance: it could guide the development of novel antimicrobial therapies that target bacterial adaptation mechanisms rather than just killing bacteria outright, which is crucial as antibiotic resistance rises. By interfering with RNA modification processes like those mediated by AvaS, future drugs might disable bacterial stress responses and reduce drug resistance, ultimately improving infection treatment outcomes.
Background
The research builds on previous knowledge of RNA modifications, which have been studied for decades as key regulators of protein production and cellular function. While many chemical modifications of tRNA—such as methylation and thiolation—are well characterized, the role of PLP-dependent enzymes in modifying RNA was previously unknown. Avi2C had been detected earlier in some bacteria and plants, but the biosynthetic enzyme responsible remained elusive.
What Remains Unclear
The researchers have yet to fully elucidate how exactly the ava2C modification affects bacterial metabolism and stress responses at the mechanistic level. It also remains to be determined how widespread this RNA modification system is across different organisms and what roles it plays in eukaryotic systems such as plants. Further biochemical and functional studies are required to clarify these aspects.
What Comes Next
The SMART AMR team plans to investigate the precise influence of ava2C on bacterial stress adaptations and metabolism. They will also explore ways to disrupt this tRNA modification, providing potential new targets to counteract antibiotic-resistant bacteria. Given ava2C’s presence in plants, future studies might explore its functions beyond bacteria, potentially uncovering broader biological roles.
Sources
This article is based on reporting and publicly available information from the following sources:
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