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

Fungal cytoplasmic leucyl-tRNA synthetase (LeuRS) is an essential enzyme that ensures the accuracy of the genetic code by attaching leucine to its cognate tRNA during protein synthesis (Lincecum et al., Molecular Cell, 2003). The enzyme contains a specialized editing domain, known as the Connective Polypeptide 1 (CP1) domain, which functions as a molecular sieve to hydrolyze mischarged amino acids like isoleucine or valine from tRNA(Leu). This editing domain is a validated therapeutic target for the treatment of fungal infections, particularly onychomycosis. The antifungal drug tavaborole (AN2690) specifically targets this domain by forming a stable covalent adduct with the 3'-terminal adenosine of the tRNA(Leu) (Rock et al., Science, 2007). This adduct traps the tRNA in the editing site, effectively blocking the enzyme's catalytic activity and halting fungal protein production. The structural divergence between the fungal CP1 domain and its human counterpart allows for high drug selectivity and minimal host toxicity (Baker et al., Journal of Medicinal Chemistry, 2006). Consequently, the fungal LeuRS editing domain represents a critical site for developing narrow-spectrum antimicrobial agents.

Other names

Leucine-tRNA ligaseLeuSCP1 domainConnective Polypeptide 1 domainCytoplasmic leucyl-tRNA synthetase

Inhibition of the editing domain through the formation of a stable tRNA-inhibitor adduct (oxaborole-tRNA adduct) that traps the enzyme in an inactive state (Rock et al., Science, 2007).