Thymidylate synthase (TS) and additional folate-dependent enzymes (TS/Folate enzymes)

Thymidylate synthase (TS) and additional folate-dependent enzymes, including dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT), are essential components of the folate metabolic pathway (UniProt P04818, P00374). These enzymes facilitate the transfer of one-carbon units required for the de novo synthesis of thymidine and purine nucleotides, which are the building blocks of DNA and RNA (StatPearls, 2023). Thymidylate synthase specifically catalyzes the conversion of deoxyuridylate to thymidylate, a rate-limiting step in DNA replication. Because rapidly proliferating cancer cells depend heavily on these pathways, these enzymes serve as critical therapeutic targets for antifolate drugs (PubMed, 2021). Multi-targeted antifolates, such as pemetrexed, are designed to inhibit several of these enzymes simultaneously to maximize antitumor activity and reduce the likelihood of metabolic bypass (PubChem CID 135335308). Inhibition of these targets leads to nucleotide depletion, resulting in DNA damage and induction of apoptosis in malignant cells. Clinical management of drugs hitting these targets often requires vitamin supplementation to mitigate systemic toxicities like myelosuppression and mucositis (NIH, 2022).

Other names

TYMSDHFRGARFTAICARFTFolate pathway enzymesMulti-targeted antifolate targets

Inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, which depletes the intracellular pools of thymidine and purine nucleotides, thereby halting DNA and RNA synthesis and inducing cell cycle arrest (PubChem, 2023).