Phosphoribosylaminoimidazole synthetase (AIRS)

Phosphoribosylaminoimidazole synthetase (AIRS) is an essential enzyme in the de novo purine nucleotide biosynthetic pathway, catalyzing the fifth step: the ATP-dependent cyclization of 5-phosphoribosylformylglycinamidine (FGAM) to form 5-aminoimidazole ribonucleotide (AIR) (UniProt P22102). In humans, this enzymatic activity is part of a large trifunctional protein encoded by the GART gene, which also possesses phosphoribosylglycinamide synthetase (GARS) and phosphoribosylglycinamide formyltransferase (GARFT) activities (NCBI Gene ID: 2643). This enzyme is a significant therapeutic target in oncology because malignant cells rely heavily on de novo purine synthesis to meet the high demand for nucleotides required for rapid DNA and RNA replication (PubMed: 31433963). Inhibition of AIRS leads to the depletion of cellular ATP and GTP pools, resulting in cell cycle arrest and apoptosis. Furthermore, the GART gene is located on chromosome 21, and its overexpression is associated with the metabolic disturbances and neurodevelopmental pathology observed in Down syndrome (PubMed: 10857770). Beyond cancer, AIRS is also explored as a target for antimicrobial agents due to structural differences between human and bacterial purine biosynthetic enzymes.

Other names

AIR synthetase5-aminoimidazole ribonucleotide synthetasePhosphoribosylformylglycinamidine cyclo-ligaseGART (AIRS domain)FGAM cyclaseAminoimidazole ribonucleotide synthetase

Inhibition of the de novo purine biosynthetic pathway, leading to depletion of intracellular purine pools and subsequent inhibition of DNA and RNA synthesis.