Leucyl-tRNA synthetase (LeuRS) (LeuRS)

Bacterial leucyl-tRNA synthetase (LeuRS) is an essential enzyme responsible for the accurate attachment of leucine to its cognate tRNA during protein synthesis. To ensure high fidelity, LeuRS contains a distinct connective polypeptide 1 (CP1) domain, also known as the editing domain, which identifies and hydrolyzes incorrectly charged amino acids (such as isoleucine or norvaline) from the tRNA (UniProt P0A7B1). This editing function is critical for preventing the accumulation of misfolded proteins that would otherwise lead to bacterial cell death. In drug discovery, the editing domain is a validated target for a class of boron-containing compounds known as oxaboroles. These drugs work by forming a stable covalent adduct with the 3-terminal adenosine of the tRNA within the editing site, effectively trapping the tRNA and halting protein synthesis (Rock et al., 2007). This mechanism is particularly effective against pathogens like Mycobacterium tuberculosis and various Gram-negative bacteria, making it a significant focus for developing new classes of antibiotics (Yao et al., 2020).

Other names

Leucine-tRNA ligaseLeuSBacterial leucyl-tRNA synthetase editing domainCP1 domainConnective polypeptide 1

Inhibition of protein synthesis via the Oxaborole tRNA-trapping (OBORT) mechanism, where the drug forms a covalent complex with the tRNA's terminal adenosine in the editing site (Rock et al., 2007; PMID: 17588934).