THF (Tetrahydrofolate)

Tetrahydrofolate (THF) is the active, reduced form of folate (vitamin B9) that serves as a carrier for one-carbon units in various oxidation states. THF can accept one-carbon units from serine (via SHMT), formate, or histidine, forming various folate derivatives: 5,10-methyleneTHF, 10-formylTHF, 5-methylTHF, etc.

Methotrexate inhibits DHFR, depleting THF - this is its mechanism in cancer and autoimmune disease.

Metabolic Connections

THF (Tetrahydrofolate) connects to 9 other pathways.

Cofactors

5-MTHF (5-Methyltetrahydrofolate)

THF is methylated through the folate cycle to eventually form 5-MTHF

Primary circulating folate; methyl donor for homocysteine remethylation via MTR; product of MTHFR.

Enzymes

DHFR (Dihydrofolate Reductase)

DHFR reduces dihydrofolate back to THF

Enzyme reducing dihydrofolate to THF; target of methotrexate; essential for maintaining folate pool.

DHFR (Dihydrofolate Reductase)

DHFR produces THF by reducing dihydrofolate

Enzyme reducing dihydrofolate to THF; target of methotrexate; essential for maintaining folate pool.

SHMT (Serine Hydroxymethyltransferase)

SHMT transfers one-carbon units between serine/glycine and THF

Enzyme interconverting serine and glycine; major source of one-carbon units for folate pool; B6 dependent.

SHMT (Serine Hydroxymethyltransferase)

SHMT uses THF as acceptor for one-carbon unit from serine

Enzyme interconverting serine and glycine; major source of one-carbon units for folate pool; B6 dependent.

Processes

DNA

THF-carried one-carbon units are essential for nucleotide synthesis for DNA

Genetic material encoding all proteins. Requires B vitamins for synthesis and methylation for regulation.

B Vitamins

Folate

THF is the active reduced form of dietary folate

Vitamin B9 - essential for DNA synthesis, methylation, and cell division. Critical during pregnancy for neural tube development.

Folate

THF is the active reduced form of folate that carries one-carbon units

Vitamin B9 - essential for DNA synthesis, methylation, and cell division. Critical during pregnancy for neural tube development.

Methylation

MTHFR

MTHFR reduces 5,10-methyleneTHF to 5-MTHF using THF pathway intermediates

Methylenetetrahydrofolate reductase - converts folate to methylfolate for the methylation cycle. Common genetic variants reduce function.