Abstract
Discovery of mupirocin, an antibiotic that targets isoleucyl-tRNA synthetase, established aminoacyl-tRNA synthetase as an attractive target for the discovery of novel antibacterial agents. Despite a high degree of similarity between the bacterial and human aminoacyl-tRNA synthetases, the selectivity observed with mupirocin triggered the possibility of targeting other aminoacyl-tRNA synthetases as potential drug targets. These enzymes catalyse the condensation of a specific amino acid to its cognate tRNA in an energy-dependent reaction. Therefore, each organism is expected to encode at least twenty aminoacyl-tRNA synthetases, one for each amino acid. However, a bioinformatics search for genes encoding aminoacyl-tRNA synthetases from Mycobacterium smegmatis returned multiple genes for glutamyl (GluRS), cysteinyl (CysRS), prolyl (ProRS) and lysyl (LysRS) tRNA synthetases. The pathogenic mycobacteria, namely, Mycobacterium tuberculosis and Mycobacterium leprae, were also found to possess two genes each for CysRS and LysRS. A similar search indicated the presence of additional genes for LysRS in gram negative bacteria as well. Herein, we describe sequence and structural analysis of the additional aminoacyl-tRNA synthetase genes found in M. smegmatis. Characterization of conditional expression strains of Cysteinyl and Lysyl-tRNA synthetases generated in M. smegmatis revealed that the canonical aminoacyl-tRNA synthetase are essential, while the additional ones are not essential for the growth of M. smegmatis.
Highlights
In bacterial cells, like transcription and replication, translation is one of the key processes which leads to the synthesis of every protein required for the cell to function irrespective of their final localization [1]
Aminoacyl-tRNA synthetases are one of the key players in the translation process [17]. They catalyse the coupling of an aminoacyl group to its cognate tRNA in a two-step process (Fig C in S1 File), in the first step an amino acid gets activated which is transferred to its cognate tRNA in the second step
M. smegmatis does not code for AsnRS and GlnRS and should have 18 genes coding for the other 18 essential aminoacyl-tRNA synthetases (aaRS) [16]
Summary
Like transcription and replication, translation is one of the key processes which leads to the synthesis of every protein required for the cell to function irrespective of their final localization [1]. A large number of antibiotics discovered till date are inhibitors of translation, thereby establishing the importance of this process for bacterial cell survival [2]. Each of these antibiotic seems to affect a unique step in the protein synthesis cascade [3]. Synthesis of aminoacyl-tRNA (aa-tRNA) is a critical step in translation and aaRS are considered essential for bacterial survival The mechanism of this class of enzymes suggest that each cell should possess at least twenty aaRS as there are 20 different natural amino acids [17].
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