Plasmodium falciparum lysyl-tRNA synthetase (PfKRS)

Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) is an essential enzyme in the malaria parasite responsible for the aminoacylation of tRNA with lysine, a fundamental step in protein translation (UniProt Q8I5R7). As a Class II aminoacyl-tRNA synthetase, it catalyzes the two-step reaction involving the formation of a lysyl-adenylate intermediate followed by the transfer of the lysyl group to the 3-prime end of tRNA-Lys. PfKRS is a highly attractive therapeutic target because it is essential across all major stages of the parasite's life cycle, including the liver, asexual blood, and sexual stages, offering potential for both treatment and transmission blocking (Kato et al., 2016, Nature). Small molecule inhibitors like cladosporin and bicyclic azetidines have demonstrated potent antimalarial activity by binding to the ATP-binding site or the amino acid pocket of the enzyme (Hoepfner et al., 2012, Nature Chemical Biology). The primary challenge in drug development is achieving high selectivity for the parasite enzyme over the human ortholog to avoid host toxicity. Resistance can emerge through specific point mutations in the PfKRS gene, which necessitates the monitoring of these genetic markers in clinical settings.

Other names

Lysine--tRNA ligaseLysRSPfLysRSKRSLysyl-tRNA synthetase

Inhibition of the aminoacylation of tRNA-Lys by competing with ATP or L-lysine binding, thereby halting protein synthesis in the parasite.