5-MTHF (5-Methyltetrahydrofolate)
Primary circulating folate; methyl donor for homocysteine remethylation via MTR; product of MTHFR.
5-Methyltetrahydrofolate (5-MTHF, also called methylfolate or L-methylfolate) is the predominant form of folate in blood and the form that donates a methyl group to homocysteine via methionine synthase (MTR), regenerating methionine and THF.
5-MTHF is produced by the essentially irreversible reduction of 5,10-methyleneTHF by MTHFR.
Because this reaction is irreversible, 5-MTHF accumulates when MTR is blocked (B12 deficiency), causing the 'methyl trap' - folate is stuck as 5-MTHF and unavailable for other functions like nucleotide synthesis, explaining why B12 deficiency causes folate-responsive anemia. Supplemental 5-MTHF bypasses MTHFR and DHFR, which may be beneficial for those with variants affecting these enzymes.
Metabolic Connections
5-MTHF (5-Methyltetrahydrofolate) connects to 12 other pathways.
B Vitamins
B12
B12-dependent MTR is required to use 5-MTHF; B12 deficiency traps folate as 5-MTHF
Cobalamin - essential for methylation, nerve function, DNA synthesis, and red blood cell formation.
B12
B12-dependent MTR is required to use 5-MTHF; B12 deficiency causes methyl-trap with 5-MTHF accumulation
Cobalamin - essential for methylation, nerve function, DNA synthesis, and red blood cell formation.
Folate
5-MTHF is the primary circulating form of folate
Vitamin B9 - essential for DNA synthesis, methylation, and cell division. Critical during pregnancy for neural tube development.
Folate
5-MTHF is the primary active circulating form of folate
Vitamin B9 - essential for DNA synthesis, methylation, and cell division. Critical during pregnancy for neural tube development.
Enzymes
GNMT (Glycine N-Methyltransferase)
5-MTHF inhibits GNMT, preserving SAMe when folate is adequate
Enzyme that methylates glycine to sarcosine using SAMe; major regulator of SAMe levels; folate-inhibited.
SHMT (Serine Hydroxymethyltransferase)
One-carbon units from SHMT ultimately contribute to 5-MTHF pool via MTHFR
Enzyme interconverting serine and glycine; major source of one-carbon units for folate pool; B6 dependent.
Methylation
Homocysteine
5-MTHF provides the methyl group to convert homocysteine to methionine
Sulfur-containing amino acid at the crossroads of methylation. Elevated levels indicate impaired methylation or B-vitamin deficiency.
MTHFR
5-MTHF is produced by MTHFR from 5,10-methyleneTHF
Methylenetetrahydrofolate reductase - converts folate to methylfolate for the methylation cycle. Common genetic variants reduce function.
MTHFR
MTHFR produces 5-MTHF by reducing 5,10-methyleneTHF; this reaction is irreversible
Methylenetetrahydrofolate reductase - converts folate to methylfolate for the methylation cycle. Common genetic variants reduce function.
MTR
5-MTHF donates its methyl group to homocysteine via MTR
Methionine synthase - regenerates methionine from homocysteine using methylfolate and B12. Central to methylation cycle.
