Researchers from Switzerland, Croatia, and Japan discovered on October 12, 2026, that evolutionary changes in the protein synthesis enzyme isoleucyl-tRNA synthetase allow bacteria to streamline their molecular machinery and fine-tune protein production speeds.
Tracing Enzyme Evolution Across Domains
Protein synthesis requires cells to convert genetic instructions from DNA into active protein molecules with the help of transfer RNA, or tRNA. These carrier molecules deliver specific amino acids to ribosomes. Before tRNA can perform this duty, an enzyme family known as aminoacyl-tRNA synthetases must correctly charge it with the appropriate building block. Researchers investigated one member of this family, isoleucyl-tRNA synthetase (IleRS), which pairs isoleucine with its corresponding tRNA.
Scientists from the Institute of Science Tokyo in Japan, the University of Zagreb Faculty of Science in Croatia, and ETH Zürich in Switzerland analyzed sequences from bacteria, archaea, and eukaryotes. Their phylogenetic analysis uncovered three distinct clades: IleRS1, IleRS2, and a newly identified group of deep-branching archaeal enzymes designated as IleRS-A. This newly recognized group shares a C-terminal organization with IleRS2 alongside a synthetic domain more typical of IleRS1.
Remodeling the C-Terminal Region
Investigators observed that an approximately 80-amino-acid segment called the INS subdomain was independently lost across multiple prokaryotic lineages. In IleRS2 enzymes, this subdomain typically contacts the D-loop of tRNA molecules. To evaluate the function of this region, the research team determined the first reported crystal structure of an IleRS containing the INS subdomain, using an enzyme extracted from the bacterium Priestia megaterium bound to Escherichia coli tRNA.
Targeted mutations and kinetic experiments revealed that while the INS subdomain assists with initial binding, it is not strictly required for aminoacyl transfer under tested conditions. When researchers weakened the interaction between the INS region and the tRNA D-loop, the enzyme’s catalytic turnover increased by about fourfold.
Our findings suggest that bacteria have repeatedly streamlined parts of this enzyme, potentially enhancing aminoacylation rate and contributing to faster protein synthesis.
Liam M. Longo, Institute of Science Tokyo, via Brightsurf
Testing Enzymatic Flexibility in Cells
To test whether these modified enzymes could sustain living cells, the team introduced the mutated versions into E. coli bacteria with blocked native IleRS genes.
We observed that evolutionary changes to the C-terminal region can alter how IleRS interacts with tRNA without necessarily disrupting its essential catalytic function.
Ita Gruic-Sovulj, University of Zagreb Faculty of Science, via Brightsurf
The study, published in Nature Communications, was led by Liam M. Longo, Ita Gruic-Sovulj, and Nenad Ban. The Institute of Science Tokyo itself was established on October 1, 2024, following the merger of Tokyo Medical and Dental University and the Tokyo Institute of Technology.