Thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and other folate-dependent enzymes (TS, DHFR, GARFT)

This target group represents a critical metabolic axis in one-carbon metabolism, comprising enzymes essential for the de novo synthesis of nucleotides. Thymidylate synthase (TS) catalyzes the conversion of dUMP to dTMP, a rate-limiting step in DNA synthesis, while dihydrofolate reductase (DHFR) maintains the pool of reduced folates necessary for these reactions. Glycinamide ribonucleotide formyltransferase (GARFT) and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT) are key enzymes in the purine biosynthetic pathway. Because rapidly proliferating cancer cells exhibit a high demand for DNA and RNA precursors, these enzymes are major therapeutic targets in oncology. Drugs like pemetrexed (Alimta) are designed as multi-targeted antifolates (MTAs) to simultaneously inhibit several of these enzymes, thereby disrupting multiple points in the folate cycle to overcome potential resistance and enhance antitumor efficacy. Clinical management of therapies hitting these targets requires careful monitoring of folate and vitamin B12 status, as deficiencies can lead to severe systemic toxicities such as myelosuppression and mucositis.

Other names

Multi-targeted antifolate (MTA) targetsFolate metabolism enzymesOne-carbon metabolism enzymesPurine and pyrimidine synthesis enzymes

Inhibition of multiple folate-dependent enzymes required for the de novo biosynthesis of thymidine and purine nucleotides, leading to the disruption of DNA and RNA synthesis and subsequent cell death (thymineless death).