Leucyl-tRNA synthetase (Mycobacterium tuberculosis) (LeuRS)

Mycobacterial leucyl-tRNA synthetase (LeuRS) is an essential enzyme in Mycobacterium tuberculosis (UniProt: P9WGC1) [1] responsible for the precise attachment of leucine to its cognate tRNA during protein synthesis [2]. As a Class I aminoacyl-tRNA synthetase, it plays a critical role in maintaining translational fidelity through its aminoacylation and editing domains [3]. The enzyme is a validated therapeutic target for tuberculosis, particularly multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains [4]. Small molecule inhibitors, most notably benzoxaboroles like GSK3036656 (also known as GSK656), target the editing site of the enzyme [5]. These inhibitors utilize an oxaborole-tRNA-trapping (OBORT) mechanism, where they form a covalent adduct with the 3'-terminal adenosine of tRNA(Leu), effectively locking the enzyme in an inactive state [2, 5]. This inhibition halts protein synthesis, leading to a potent bactericidal effect against the pathogen [4]. Development efforts focus on ensuring high selectivity for the bacterial enzyme over human cytoplasmic and mitochondrial LeuRS to minimize host toxicity [5]. Sources: [1] UniProt P9WGC1; [2] Palencia et al. (2017) Nature Communications; [3] Li et al. (2017) Science; [4] Ten Hacken et al. (2022) Antimicrobial Agents and Chemotherapy; [5] GSK Clinical Pipeline (NCT03075410).

Other names

Leucine--tRNA ligaseLeuSMtb LeuRSMycobacterial leucyl-tRNA synthetase

Inhibition of the editing domain through the formation of a stable tRNA-inhibitor adduct via the oxaborole-tRNA-trapping (OBORT) mechanism, which prevents the release of tRNA and halts protein synthesis.