Diidrofolato

Diidrofolato, known in English as dihydrofolate (DHF), is a reduced form of folate and an intermediate in cellular folate metabolism. It is produced during thymidylate synthesis, when 5,10-methylene-THF donates a one-carbon unit to deoxyuridylate (dUMP) to form deoxythymidylate (dTMP), generating DHF as a byproduct. Dihydrofolate is subsequently reduced back to tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR) using NADPH. THF and its one-carbon derivatives serve as carriers of single-carbon units used in the synthesis of thymidylate, purines, and other biomolecules, supporting DNA synthesis and cell proliferation.

In physiology, DHF represents a transient intermediate within the folate cycle. The balance between DHF and THF is essential for maintaining adequate pools of THF derivatives that participate in one-carbon transfer reactions, critical for nucleic acid synthesis and amino acid metabolism.

Clinically, inhibitors of dihydrofolate reductase, such as methotrexate and trimethoprim, block the reduction of DHF to THF. This impairs thymidylate and purine synthesis, yielding antiproliferative effects that underpin their use in cancer chemotherapy and bacterial infections, respectively. Toxicity can affect rapidly dividing tissues, including bone marrow and the gastrointestinal tract. Folate deficiency or DHFR impairment can also disrupt DNA synthesis, potentially causing megaloblastic anemia and immunosuppression.