Phenylalanyl-tRNA synthetase (PheRS)

Phenylalanyl-tRNA synthetase (PheRS) is an essential housekeeping enzyme responsible for the precise attachment of the amino acid phenylalanine to its cognate tRNA (tRNA^Phe), a fundamental step in the translation of the genetic code into proteins. Structurally, the cytoplasmic enzyme is unique among the aminoacyl-tRNA synthetase family as a heterotetramer composed of two alpha (FARSA) and two beta (FARSB) subunits, and it is the only Class II enzyme that aminoacylates the 2'-OH group of the tRNA terminal ribose rather than the 3'-OH. In addition to its canonical role in translation, PheRS exhibits non-canonical functions such as DNA binding and the regulation of cell signaling pathways like Notch, which can promote cell growth and proliferation. Because of significant structural divergence between bacterial/parasitic PheRS and human counterparts, it has become a high-priority target for the development of novel anti-infectives, including antibacterials for resistant pathogens like Staphylococcus aureus and antimalarials for Plasmodium falciparum. Pathologically, mutations in the human mitochondrial variant (FARS2) lead to severe neurological disorders such as infantile-onset epileptic encephalopathy, while overexpression of the cytoplasmic subunits is frequently observed in various malignancies, correlating with poor prognosis and metastasis.

Other names

Phenylalanyl-tRNA ligasePhenylalanine--tRNA ligaseL-phenylalanine:tRNA(Phe) ligaseFARSAFARSBFARS2Phe-tRNA synthetasePhenylalanine translase

Competitive inhibition of the phenylalanine or ATP binding sites to prevent the formation of phenylalanyl-adenylate (Phe-AMP) and subsequent tRNA charging.