Phosphoribosylglycinamide formyltransferase and Phosphoribosylaminoimidazolecarboxamide formyltransferase (GART / ATIC)

Phosphoribosylglycinamide formyltransferase (GART) and Phosphoribosylaminoimidazolecarboxamide formyltransferase (ATIC) are two essential folate-dependent enzymes in the de novo purine biosynthesis pathway. GART catalyzes the third step of the pathway, converting glycinamide ribonucleotide (GAR) to formylglycinamide ribonucleotide (FGAR), while ATIC catalyzes the penultimate step, converting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to 5-formaminoimidazole-4-carboxamide ribonucleotide (FAICAR) [1, 2]. Both enzymes utilize 10-formyltetrahydrofolate as a carbon donor to produce inosine monophosphate (IMP), the precursor for all purine nucleotides. Because rapidly proliferating cancer cells have a high demand for purines to support DNA and RNA synthesis, these enzymes are significant targets for antifolate chemotherapy [3, 4]. Inhibition of these transformylases leads to purine starvation, resulting in DNA damage, cell cycle arrest, and apoptosis. Clinically, drugs like pemetrexed target these enzymes to treat solid tumors such as non-small cell lung cancer and mesothelioma [3]. Additionally, the inhibition of ATIC by methotrexate metabolites leads to the accumulation of AICAR, which promotes the release of adenosine, contributing to the drug's potent anti-inflammatory effects in conditions like rheumatoid arthritis [5].

Other names

Glycinamide ribonucleotide transformylaseAICAR transformylase5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolaseTrifunctional purine biosynthetic protein adenosine-3Bifunctional purine biosynthesis protein PURHPurine biosynthetic enzymes10-formyltetrahydrofolate-dependent transformylases

Inhibition of the formyltransferase domains by competing with the 10-formyltetrahydrofolate cofactor, thereby blocking de novo purine synthesis and depleting intracellular nucleotide pools.