Tetrahydrofolate (THF) (THF)

Tetrahydrofolate (THF) is the biologically active derivative of folic acid (Vitamin B9) and serves as a fundamental coenzyme in the one-carbon metabolism cycle. It facilitates the transfer of single-carbon units—such as methyl, methylene, and formyl groups—required for the de novo synthesis of purines and thymidylate, which are essential building blocks for DNA and RNA. Additionally, THF plays a critical role in the metabolism of amino acids like methionine and serine, as well as in cellular methylation reactions through the regeneration of S-adenosylmethionine. Because rapidly dividing cells have a high demand for THF to support DNA replication, the folate pathway is a major focus in clinical medicine; drugs like methotrexate inhibit dihydrofolate reductase (DHFR) to deplete the cellular pool of THF, thereby inducing cell cycle arrest and apoptosis. Beyond its role in cancer therapy, THF status is critical for preventing megaloblastic anemia and congenital neural tube defects, and its biosynthetic pathway is a primary target for antimicrobial agents like sulfonamides and trimethoprim.

Other names

Tetrahydrofolic acidTHFAFH4Coenzyme FVitamin B9 active form5,6,7,8-tetrahydrofolate

Drugs typically act by inhibiting the enzymatic reduction of dihydrofolate to tetrahydrofolate (e.g., DHFR inhibition), blocking the de novo synthesis of folate precursors in pathogens (e.g., DHPS inhibition), or through competitive inhibition of THF-dependent enzymes like thymidylate synthase to deplete the one-carbon pool required for DNA synthesis.