Glutamine-dependent enzymes in de novo nucleotide biosynthesis (GATases)

Glutamine-dependent enzymes in de novo nucleotide biosynthesis are a specialized group of amidotransferases that catalyze the transfer of the amide nitrogen from glutamine to various substrates to form the purine and pyrimidine rings required for nucleic acid synthesis (Altman et al., 2016). This group includes key enzymes such as phosphoribosylpyrophosphate amidotransferase (PPAT), phosphoribosylformylglycinamidine synthase (PFAS), carbamoyl-phosphate synthetase II (CPSII), and CTP synthase (CTPS) (UniProt Consortium, 2023). Because rapidly dividing cells, particularly cancer cells and activated immune cells, exhibit a 'glutamine addiction' to support their heightened demand for DNA and RNA, these enzymes are critical therapeutic targets (Lemberg et al., 2018). Historically, glutamine antagonists like 6-diazo-5-oxo-L-norleucine (DON) showed potent anti-tumor activity but were limited by severe gastrointestinal toxicity. Recent drug development has focused on tumor-targeted prodrugs, such as DRP-104 (Sirpiglenastat) and JHU-083, which aim to deliver the inhibitor specifically to the tumor microenvironment while sparing healthy tissues (Rais et al., 2022). These strategies leverage the metabolic vulnerabilities of tumors while mitigating the off-target effects on the gut and immune system.

Other names

Glutamine amidotransferasesGATasesGlutamine-utilizing enzymes of nucleotide synthesisAmidophosphoribosyltransferase (PPAT)Phosphoribosylformylglycinamidine synthase (PFAS)Carbamoyl-phosphate synthetase II (CPSII)CTP synthase (CTPS)GMP synthetase (GMPS)

Irreversible inhibition of glutamine amidotransferase domains by structural analogs of glutamine, leading to the depletion of intracellular nucleotide pools and subsequent inhibition of DNA and RNA synthesis (Altman et al., 2016; Lemberg et al., 2018).