Folate-dependent enzymes (Thymidylate synthase, Dihydrofolate reductase, and Glycinamide ribonucleotide formyltransferase) (TS, DHFR, GARFT)

Folate-dependent enzymes, primarily thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), are essential components of the metabolic pathways required for the de novo synthesis of purine and pyrimidine nucleotides [1, 8]. These enzymes facilitate the transfer of one-carbon units, a process critical for the production of thymidine and purine precursors necessary for DNA and RNA replication [3, 9]. Because of their vital role in cell proliferation, these enzymes are prominent therapeutic targets in oncology, most notably for the multi-targeted antifolate drug pemetrexed [2, 15]. Pemetrexed enters the cell via the reduced folate carrier and is converted into polyglutamate forms that exhibit high-affinity inhibition of TS, DHFR, and GARFT [4, 5]. This simultaneous inhibition of multiple steps in nucleotide metabolism leads to the depletion of nucleotide pools, resulting in cell cycle arrest and apoptosis [6, 13]. Clinically, these targets are primarily exploited in the treatment of non-squamous non-small cell lung cancer and malignant pleural mesothelioma [5, 17]. Effective targeting requires the co-administration of folic acid and vitamin B12 to mitigate systemic toxicities, such as myelosuppression, which arise from the inhibition of these enzymes in healthy, rapidly dividing tissues [11, 16].

Other names

Multi-targeted antifolate targetsFolate metabolism enzymesThymidylate synthase/Dihydrofolate reductase/Glycinamide ribonucleotide formyltransferase complex

Pemetrexed acts as a multi-targeted antifolate that, upon intracellular activation via polyglutamylation, potently inhibits three key folate-dependent enzymes: thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT) [1, 3]. This simultaneous inhibition disrupts the de novo synthesis of thymidine and purine nucleotides, leading to the cessation of DNA and RNA synthesis and subsequent induction of apoptosis in rapidly dividing cells [2, 4].