Bacterial leucyl-tRNA synthetase (LeuRS)

Bacterial leucyl-tRNA synthetase (LeuRS) is an essential enzyme that catalyzes the attachment of leucine to its cognate tRNA(Leu), a critical step in protein synthesis [1, 3]. To ensure the accuracy of translation, LeuRS contains a distinct editing domain, known as the Connective Polypeptide 1 (CP1) domain, which proofreads and hydrolyzes incorrectly charged amino acids such as isoleucine or valine [1, 2]. The editing site–tRNA(Leu) complex is the specific target of the benzoxaborole class of antibiotics, including the FDA-approved antifungal tavaborole [1, 4]. These drugs employ a unique mechanism called oxaborole tRNA-trapping (OBORT), where the boron atom forms a covalent adduct with the 3'-terminal adenosine of the tRNA within the editing site [1, 2]. This trapping mechanism effectively locks the enzyme and tRNA in an inactive state, preventing further rounds of aminoacylation and halting bacterial growth [1, 4]. While LeuRS is present in all organisms, structural differences between the bacterial editing domain and the human cytoplasmic counterpart provide a basis for selective toxicity, though potential interactions with human mitochondrial LeuRS are a key safety consideration [2, 4].

Other names

Leucine--tRNA ligaseLeuSLARSBacterial LeuRS editing domainCP1 domain

Oxaborole tRNA-trapping (OBORT) mechanism involving the formation of a stable covalent adduct between the drug and the 2',3'-ribose oxygen atoms of the tRNA's terminal adenosine, which traps the tRNA in the editing site and inhibits the enzyme.