Isoleucyl-tRNA synthetase (bacterial) (IleRS)

Bacterial isoleucyl-tRNA synthetase (IleRS) is an essential enzyme belonging to the Class I aminoacyl-tRNA synthetase family, responsible for the accurate attachment of L-isoleucine to its cognate tRNA [1, 15]. This process, known as aminoacylation or tRNA charging, is a critical step in the translation of genetic information into functional proteins [6, 13]. The enzyme operates via a two-step mechanism: first activating the amino acid with ATP to form an isoleucyl-adenylate intermediate, and then transferring the isoleucyl moiety to the tRNA [1, 12]. IleRS is a validated therapeutic target for antibacterial agents, most notably mupirocin, which is used to treat skin infections and eradicate methicillin-resistant Staphylococcus aureus (MRSA) colonization [3, 8]. Mupirocin acts as a competitive inhibitor that mimics the isoleucyl-adenylate intermediate, effectively blocking the enzyme's active site and halting bacterial protein synthesis [5, 10]. While the enzyme is essential for all life, structural differences between bacterial and eukaryotic IleRS allow for high selective toxicity [2, 10]. However, the emergence of resistance, particularly through the acquisition of the plasmid-borne mupA gene (encoding a resistant IleRS2 isoform), remains a significant clinical challenge [5, 18].

Other names

Isoleucine—tRNA ligaseIsoleucyl-tRNA synthetaseIRSileSileS1ileS2mupR

Competitive inhibition of the enzyme's active site by mimicking the isoleucyl-adenylate (Ile-AMP) intermediate, which prevents the binding of L-isoleucine and ATP, thereby halting the formation of isoleucyl-tRNA and stopping protein synthesis.