Fungal cytoplasmic leucyl-tRNA synthetase (LeuRS) (LeuRS)

Fungal cytoplasmic leucyl-tRNA synthetase (LeuRS) is an essential enzyme responsible for the two-step aminoacylation reaction that attaches leucine to its cognate tRNA, a process vital for fungal protein synthesis (UniProt, 2023). It belongs to the Class I family of aminoacyl-tRNA synthetases and contains a specialized editing domain, the connective polypeptide 1 (CP1) domain, which prevents translational errors by hydrolyzing mischarged aminoacyl-tRNAs (PubMed, PMID: 16804544). Because this enzyme is indispensable for fungal viability, it serves as a key therapeutic target for antifungal drug development (PubChem, CID: 11271397). The drug tavaborole specifically targets this enzyme to treat onychomycosis by utilizing a unique oxaborole-tRNA-trapping (OBORT) mechanism (FDA, 2014). In this mechanism, the drug forms a stable covalent adduct with the tRNA at the enzyme's editing site, effectively blocking the catalytic cycle and halting protein production (PubMed, PMID: 17606854). This targeted approach provides high selectivity for fungal LeuRS over human counterparts, minimizing potential host toxicity.

Other names

Leucine--tRNA ligaseLeuSLARSCytoplasmic leucyl-tRNA synthetaseLeucyl-tRNA synthetaseLeucine--tRNA ligase, cytoplasmic

The drug inhibits the enzyme by binding to the editing site (CP1 domain) and forming a stable covalent adduct with the 3' terminal adenosine of tRNA(Leu), a process known as the oxaborole-tRNA-trapping (OBORT) mechanism, which prevents the release of tRNA and halts protein synthesis (PubMed, PMID: 17606854).