Phosphoribosylformylglycinamidine synthase (PFAS) (PFAS)

Phosphoribosylformylglycinamidine synthase (PFAS), historically and frequently referred to in pharmacological literature as 2-N-amidotransferase, is a crucial enzyme in the de novo purine biosynthetic pathway. It catalyzes the fourth step of the pathway, which is the second glutamine-utilizing reaction, converting formylglycinamide ribotide (FGAR), glutamine, and ATP into formylglycinamidine ribotide (FGAM), glutamate, ADP, and inorganic phosphate. Because rapidly dividing cells like tumor cells have a vastly increased requirement for nucleotides, PFAS is a major therapeutic target in oncology. Inhibition of this enzyme leads to the depletion of purine nucleotides, thereby stunting DNA replication and RNA synthesis. The enzyme is a primary target of glutamine antagonists such as 6-diazo-5-oxo-L-norleucine (DON) and its clinical-stage prodrugs like sirpiglenastat, which act as irreversible inhibitors by covalently modifying the enzyme's glutamine-binding site. Although highly effective at blocking tumor growth in preclinical models, systemic inhibition of PFAS and related amidotransferases is associated with significant gastrointestinal and hematological toxicities, necessitating the development of targeted prodrug delivery strategies.

Other names

2-N-amidotransferaseFormylglycinamide ribotide amidotransferaseFGAR amidotransferaseFGAR-ATPhosphoribosylformylglycinamidine synthetaseFGAM synthaseFormylglycinamidine ribonucleotide synthase

Irreversible competitive inhibition of the glutamine amidotransferase domain by covalent binding to a conserved active-site cysteine residue.