Cytoplasmic isoleucyl-tRNA synthetase (IARS1) (IARS1)

Cytoplasmic isoleucyl-tRNA synthetase (IARS1) is an essential enzyme that catalyzes the attachment of L-isoleucine to its cognate tRNA, a critical step for protein synthesis (UniProt P41252). It belongs to the Class I aminoacyl-tRNA synthetase family and operates via a two-step mechanism involving an isoleucyl-adenylate intermediate (PubMed: 27666371). In eukaryotes, IARS1 is a component of the multi-tRNA synthetase complex (MSC), which facilitates efficient translation and provides non-canonical regulatory functions (PubMed: 32814734). The tRNA binding site of the enzyme is a specific domain that ensures the correct recognition and orientation of tRNA-Ile for aminoacylation. Mutations in the IARS1 gene are associated with a rare autosomal recessive condition known as GRID syndrome, which presents with growth retardation, intellectual disability, and liver dysfunction (PubMed: 27666371). While bacterial IleRS is the target of the antibiotic mupirocin, the eukaryotic version is generally avoided as a primary drug target due to the risk of inhibiting essential cellular protein production. However, IARS1 is frequently overexpressed in various malignancies, such as lung and colorectal cancer, where it serves as a potential biomarker for poor prognosis and a theoretical target for anti-proliferative therapy (PubMed: 32814734). Therapeutic strategies targeting this site must overcome significant challenges regarding selectivity to avoid toxicity in healthy tissues.

Other names

Isoleucine--tRNA ligase, cytoplasmicIARSIleRSIsoleucyl-tRNA synthetase 1Eukaryotic cytoplasmic isoleucyl-tRNA synthetase tRNA binding site

Inhibition of the aminoacylation process by preventing the binding of tRNA-Ile or the formation of the isoleucyl-adenylate intermediate, thereby blocking protein translation.