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

The fungal leucyl-tRNA synthetase (LeuRS) editing domain, also known as the Connective Polypeptide 1 (CP1) domain, is a critical structural component of the LeuRS enzyme responsible for maintaining the fidelity of the genetic code. Its primary biological function is to proofread aminoacylation products, specifically hydrolyzing mischarged tRNAs (such as norvalyl-tRNA(Leu)) to prevent the incorporation of incorrect amino acids into proteins (Rock et al., 2007). This editing activity is essential for fungal survival, as the accumulation of mistranslated proteins leads to cellular stress and death. In the field of drug development, this domain is the primary target for the oxaborole class of antifungals, with tavaborole being the first FDA-approved agent in this category (Hernandez et al., 2013). The mechanism of action involves the formation of a stable covalent adduct between the drug and the 3'-terminal adenosine of tRNA(Leu) within the editing site, a process known as oxaborole tRNA-trapping (OBORT). This trapping effectively blocks the enzyme's catalytic cycle, inhibiting protein synthesis and providing broad-spectrum activity against various fungal pathogens, including those causing onychomycosis (Baker et al., 2006).

Other names

CP1 domainConnective Polypeptide 1 domainLeucine--tRNA ligase editing domainFungal LeuRS editing site

Inhibition of protein synthesis via the oxaborole tRNA-trapping (OBORT) mechanism, where the drug forms a stable covalent adduct with the 3'-terminal adenosine (A76) of tRNA(Leu) within the editing site (Rock et al., 2007).