Plasmodium falciparum cytosolic phenylalanyl-tRNA synthetase (PfcFRS)

Plasmodium falciparum cytosolic phenylalanyl-tRNA synthetase (Pf-cFRS) is an essential enzyme in the malaria parasite responsible for the aminoacylation of tRNA-Phe with L-phenylalanine, a critical step in protein translation [3, 12]. It exists as a heterotetrameric complex composed of two alpha and two beta subunits, with the alpha subunit housing the catalytic active site [10, 12]. As an aminoacyl-tRNA synthetase (aaRS), it plays a vital role in maintaining the parasite's proteome across multiple life stages, including the blood and liver stages [3, 15]. Pf-cFRS has emerged as a high-priority therapeutic target because it is chemically and genetically validated, and its structural differences from the human ortholog allow for the development of selective inhibitors [3, 13]. Small molecules such as bicyclic azetidines (e.g., BRD7929) have been shown to potently inhibit the enzyme by competing with the L-phenylalanine substrate, leading to rapid parasite clearance in vivo [12, 15]. Targeting this enzyme offers a novel mechanism of action that is effective against drug-resistant strains of Plasmodium falciparum [3, 12].

Other names

Phenylalanine--tRNA ligasePfcFRSPfPheRScPheRSPhenylalanyl-tRNA synthetase

Inhibition of the aminoacylation reaction by competing with the L-phenylalanine substrate or binding to the active site, thereby preventing the formation of phenylalanyl-tRNA and halting protein synthesis.