Folate cycle

The folate cycle is a fundamental metabolic pathway responsible for the transfer of one-carbon units required for the synthesis of purines, thymidylate, and the remethylation of homocysteine to methionine (StatPearls: Biochemistry, Folate Metabolism, 2023). It involves a series of enzymatic reactions centered around the reduction of dietary folate to tetrahydrofolate (THF) and its subsequent conversions by enzymes such as dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR) (NIH Office of Dietary Supplements, 2022). Because rapidly dividing cells have a high demand for nucleotides, the folate cycle is a major therapeutic target for anticancer, antimicrobial, and antiprotozoal therapies (PubMed: PMC6132531). Antifolate drugs, such as methotrexate, inhibit specific enzymes like DHFR to deplete the cellular pool of reduced folates, thereby arresting DNA synthesis and inducing apoptosis in malignant cells (PubChem: Methotrexate). Dysregulation or deficiency within this cycle is linked to various clinical conditions, including megaloblastic anemia, neural tube defects, and increased cardiovascular risk due to hyperhomocysteinemia (Mayo Clinic: Folate Deficiency, 2023). Furthermore, genetic polymorphisms in folate cycle enzymes can influence drug efficacy and toxicity, making the pathway a focus for pharmacogenomic research (PubMed: 21605012).

Other names

Folate metabolismOne-carbon metabolismFolic acid cycleFolate-mediated one-carbon metabolism

Drugs targeting the folate cycle typically act as competitive inhibitors of specific enzymes within the pathway, such as dihydrofolate reductase (DHFR) or thymidylate synthase (TS), to deplete the intracellular pool of reduced folate cofactors (e.g., tetrahydrofolate), which effectively halts the synthesis of DNA, RNA, and proteins (StatPearls, 2023; PubChem, 2024).