Researchers from the Shanghai Institute of Biochemistry and Cell Sciences of the Chinese Academy of Sciences used a new research system: Mycobacterium tuberculosis leucine-tRNA synthetase (MtbLeuRS) and found that the C-terminal extension domain of the prokaryotic pathogen leucine-tRNA synthetase An important mechanism for maintaining the interaction between enzymes and nucleic acids, the relevant results are published in the journal Nucleic Acids Research.

The research was completed by Wang Enduo's research group, and the first author was Dr. Hu Qinghua. Academician Wang Enduo has long been engaged in the study of enzymology and the interaction between enzymes and nucleic acids. He has made important contributions to the study of the key aminoacyl-tRNA synthetase and tRNA interactions in protein biosynthesis and was elected to China in 2005 Academician of the Academy of Sciences. He was elected as a member of the Third World Academy of Sciences in 2006.

Tuberculosis (TB) is a major infectious disease that threatens human health worldwide. As of the end of 2009, the WHO's statistical report shows that about one-third of the world's population is infected with Mycobacterium tuberculosis, the main pathogen of tuberculosis. Currently, the spread of multi-drug resistant TB (MDR-TB) poses a challenge to clinical antibiotic therapy, and there is an urgent need to develop new antibiotics.

The process of gene expression regulation in bacteria has always been a way for drug developers to find targets. In recent years, aminoacyl-tRNA synthetase (aaRS), which plays a role in the initiation of protein synthesis, has become an ideal target for the development of new antibiotic drugs with its unique advantages.

First of all, aaRS is ubiquitous in the living body with cells in nature, which maintains the basic life activities of cells, and the loss of its function will affect the growth of cells. Second, the differences in the structure and molecular catalytic mechanism of aaRS from different species provide the possibility of developing selective drugs. Again, up to 20 kinds of aaRS increase the selectivity of drug targets. In addition, the bacterial isoleucyl-tRNA synthetase inhibitor, mupirocin (trade name Baidubang), which has been used in clinical trauma infection for nearly 30 years, and entered the clinical phase III trial will be used for onychomycosis treatment Leucyl-tRNA Synthetase Inhibitor-5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoborane (AN2690), which adds more to the development of antibiotics targeting aaRS Confidence.

In this article, the researchers used the established research system of Mycobacterium tuberculosis leucine-tRNA synthetase (MtbLeuRS) to carry out a series of work around the C-terminal extension domain (CTD), they use E. coli gene expression The system obtained highly viable MtbLeuRS and Mycobacterium tuberculosis leucine tRNA (Mtb-tRNALeu), established an efficient MtbLeuRS / Mtb-tRNALeu research system, and through quantitative analysis of MtbLeuRS editing and proofing reactions, it was found that it was corrected for valine (Nva) prefers tRNA-dependent pre-transfer editing pathways, accounting for 70% of the total editing and editing responses, the highest among the reported LeuRS.

And the researchers identified key amino acid residues that maintain the conformation of the enzyme and the interaction between the enzyme and the nucleic acid. With the help of fluorescence titration and yeast three-hybrid methods, it was found that mutations at these sites will affect the binding of the enzyme to the tRNA. The researchers also analyzed the relationship between the flexibility of the connecting peptide of CTD and the main body of the enzyme from the three-dimensional structure and the activity of the enzyme, revealing the flexibility of CTD in regulating substrate binding, aminoacylation, and the interaction between the enzyme and tRNA in the editing reaction The importance of the role identifies a crucial site for regulating conformation.

This research has enriched people's understanding of the first step in the precise identification of enzymes and tRNA and quality control of protein synthesis. At the same time, the established MtbLeuRS / Mtb-tRNALeu research system has also provided a research platform for screening new anti-tuberculosis drugs.

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