Trifunctional purine biosynthetic protein adenosine-3 (GART) (GART)

Trifunctional purine biosynthetic protein adenosine-3, commonly known as GART, is a multi-domain enzyme essential for the de novo synthesis of purine nucleotides. It catalyzes three distinct steps in the pathway: the synthesis of glycinamide ribonucleotide (GARS activity), its formylation (GARFT activity), and the subsequent synthesis of aminoimidazole ribonucleotide (AIRS activity). The GARFT activity is a significant therapeutic target in oncology, as its inhibition by antifolate drugs like lometrexol leads to the depletion of intracellular purine pools, effectively halting DNA replication and cell division in cancer cells. Beyond its role in nucleotide metabolism, GART is overexpressed in individuals with Down syndrome due to its location on chromosome 21 and has been linked to cancer stemness and poor prognosis in various solid tumors. Recent research also suggests GART may possess novel methyltransferase activity that promotes tumor progression through the Wnt/beta-catenin signaling pathway.

Other names

Glycinamide ribonucleotide formyltransferaseGARFTGARS-AIRS-GARTPhosphoribosylglycinamide formyltransferasePhosphoribosylglycinamide synthetasePhosphoribosylaminoimidazole synthetaseGlycinamide ribonucleotide transformylasePGFTPRGS

Inhibition of the glycinamide ribonucleotide formyltransferase (GARFT) activity of the GART protein prevents the formylation of glycinamide ribonucleotide (GAR) to formylglycinamide ribonucleotide (FGAR), leading to the depletion of intracellular purine nucleotides, inhibition of DNA and RNA synthesis, and induction of cell cycle arrest and apoptosis.