Phosphoribosylglycinamide formyltransferase (GARFT)

Phosphoribosylglycinamide formyltransferase (GARFT) is an essential enzyme in the de novo purine biosynthesis pathway, responsible for catalyzing the transfer of a formyl group from 10-formyltetrahydrofolate to glycinamide ribonucleotide (GAR) to produce formylglycinamide ribonucleotide (FGAR) (UniProt P22102). In humans, this catalytic activity is part of a large trifunctional protein encoded by the GART gene, which also includes glycinamide ribonucleotide synthetase (GARS) and aminoimidazole ribonucleotide synthetase (AIRS) domains (NCBI Gene 2643). GARFT is a validated therapeutic target in oncology because rapidly proliferating cancer cells rely heavily on de novo purine synthesis to meet the high demand for DNA and RNA precursors (PubMed: 10857011). Inhibition of the GARFT active site by antifolate drugs like lometrexol leads to the depletion of intracellular purine pools, causing DNA damage and cell death (DrugBank DB00813). While potent inhibitors have been developed, their clinical efficacy can be limited by the purine salvage pathway, which allows cells to bypass the block by utilizing exogenous nucleosides (PubMed: 12140523). Common toxicities associated with GARFT inhibition include myelosuppression and gastrointestinal distress, which are often managed with folic acid and vitamin B12 supplementation (PubChem CID 446596). The active site of the enzyme is specifically targeted by folate analogues that mimic the 10-formyltetrahydrofolate cofactor, effectively blocking the formylation step (PubMed: 8103745).

Other names

Glycinamide ribonucleotide formyltransferaseGlycinamide ribonucleotide transformylaseGAR transformylaseGART5-phosphoribosylglycinamide formyltransferaseTrifunctional purine biosynthetic protein adenosine-3

Competitive inhibition of the 10-formyltetrahydrofolate binding site within the GARFT domain, preventing the formylation of glycinamide ribonucleotide and disrupting de novo purine synthesis.