Glycine--tRNA ligase (GARS1)

Glycine--tRNA ligase (GARS1) is an essential enzyme belonging to the aminoacyl-tRNA synthetase family, responsible for catalyzing the attachment of glycine to its cognate tRNA during protein biosynthesis in all cell types[1][3][4][5][6]. It functions as an (alpha)₂ dimer, classified in the class II tRNA synthetases, and enables the accurate incorporation of glycine in polypeptide chains, as well as the production of diadenosine tetraphosphate (Ap4A) involved in signaling homeostasis[3][4]. Genetic variants in GARS1 are causative in inherited neuropathies (e.g., Charcot-Marie-Tooth disease type 2D, distal hereditary motor neuropathy and spinal muscular atrophy) by impairing motor neuron function[1][3][5]. GARS1 is highly expressed in many tumor types, correlates with poor prognosis, and is associated with cancer immunology, including immune cell infiltration and checkpoint activity[2][7]. It is implicated in protein metabolism, cell cycle progression, and is a promising diagnostic biomarker and therapeutic target for cancer. Select therapeutic agents—such as ifosfamide, auranofin, DMAPT, and A-1331852—may be suitable for patients with GARS1-upregulated tumors[2]. Mutations or overactivity of GARS1 can lead to neuropathies, trigger autoimmunity, or promote tumorigenesis, representing key safety challenges in therapeutic targeting.

Other names

GARS1GARSGlyRSGlycine tRNA ligaseGlycyl-tRNA synthetaseAp4A synthetaseDiadenosine tetraphosphate synthetaseCharcot-Marie-Tooth neuropathy type 2D (CMT2D)Distal spinal muscular atrophy, James type (DSMAV)SMAD1HMN5/ HMN5A/ HMND5/ SMAJISYG_HUMAN

Alkylating agents, redox-active compounds, and apoptosis modulators may exploit GARS1's role in protein synthesis and cell cycle regulation in cancer. Some drugs may target GARS1-mediated cell proliferation, migration, and immune interaction mechanisms.