Folate transport and one-carbon metabolism pathway

Folate transport and one-carbon metabolism (OCM) represent a critical network of biochemical pathways responsible for the transfer of one-carbon units essential for cellular processes (Ducker & Rabinowitz, 2017, Cell Metabolism). This system facilitates the synthesis of purines and thymidylate, which are necessary for DNA replication and repair, and supports the methionine cycle for the production of S-adenosylmethionine (SAM), the primary methyl donor for DNA and protein methylation (StatPearls, 2023). Because of its central role in nucleotide biosynthesis, OCM is a major therapeutic target in oncology, where antifolate drugs like methotrexate are used to inhibit rapid cell division by targeting enzymes such as dihydrofolate reductase (DHFR) (PubChem, 2024). Beyond cancer, deficiencies or genetic polymorphisms in this pathway are associated with megaloblastic anemia, cardiovascular disease, and developmental issues such as neural tube defects (NIH ODS, 2022). Therapeutic strategies include the use of enzyme inhibitors, as well as the exploitation of folate receptors (e.g., FOLR1) for targeted delivery of imaging agents and toxins (PubMed, 2021).

Inhibition of folate-dependent enzymes (e.g., DHFR, TYMS) to deplete nucleotide pools and disrupt DNA synthesis, or targeting folate receptors for cytotoxic drug delivery.