Alanyl-tRNA synthetase 1 (AARS1) (AARS1)

Human alanyl-tRNA synthetase 1 (AARS1) is a cytoplasmic enzyme belonging to the class II aminoacyl-tRNA synthetase family. Its primary canonical function is to catalyze the attachment of alanine to its cognate tRNA, a critical step in protein translation that ensures the fidelity of the genetic code (UniProt P49588). Beyond its role in translation, AARS1 has recently been identified as a metabolic sensor for L-lactate and a non-canonical lactyltransferase. In this capacity, it mediates lysine lactylation of various proteins, such as p53 and YAP, thereby influencing oncogenic signaling and tumor progression (PubMed: 38724618). Mutations in the AARS1 gene are linked to several neurological disorders, including Charcot-Marie-Tooth disease type 2N and developmental and epileptic encephalopathy (GeneCards). In the context of autoimmune disease, AARS1 serves as the autoantigen for anti-PL-12 antibodies in antisynthetase syndrome, a condition characterized by interstitial lung disease and myositis (NIH). While no direct inhibitors are currently approved for clinical use, research into AARS1 as a therapeutic target in cancer is ongoing, with beta-alanine being explored as a potential modulator of its lactyltransferase activity. The dual role of AARS1 in both essential protein synthesis and disease-associated signaling makes it a complex but promising target for precision medicine.

Other names

AARSAlaRSAlanine--tRNA ligase, cytoplasmicAlanyl-tRNA synthetase, cytoplasmicCMT2NEIEE29DEE29TTD8PL-12 antigenHuman alanyl-tRNA synthetase

Immunosuppression to reduce autoantibody-mediated damage in antisynthetase syndrome; competitive inhibition of the lactate-binding site to block non-canonical lactyltransferase activity in cancer; inhibition of aminoacylation activity to disrupt protein synthesis.