Thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) (TS/DHFR/GARFT)

Thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) are three essential enzymes in the folate metabolic pathway that collectively drive the de novo synthesis of nucleotides [1, 2]. TS catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, providing the only de novo source of thymidylate for DNA synthesis [3]. DHFR maintains the intracellular pool of reduced folates by reducing dihydrofolate to tetrahydrofolate, a cofactor required for numerous one-carbon transfer reactions [4]. GARFT is a key enzyme in the purine biosynthetic pathway, facilitating the formylation of glycinamide ribonucleotide [1]. These enzymes are the primary targets of multi-targeted antifolates, most notably pemetrexed, which inhibits all three to disrupt DNA and RNA production in cancer cells [2, 8]. This simultaneous inhibition leads to a 'thymineless death' and effectively halts the proliferation of rapidly dividing cells, making it a standard therapy for non-small cell lung cancer and malignant pleural mesothelioma [7, 2]. The expression levels of these enzymes, particularly TS, are often used as biomarkers to predict patient response and resistance to antifolate therapy [5, 6]. Due to the systemic impact on folate metabolism, treatment typically requires supplementation with folic acid and vitamin B12 to mitigate hematological and gastrointestinal toxicities [2].

Other names

TYMS/DHFR/GARTFolate-dependent enzymesMultitargeted antifolate targetsTS/DHFR/GARFT

Simultaneous inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, leading to the depletion of nucleotide pools and inhibition of DNA/RNA synthesis.