5Methyltetrahydrofolate

5-methyltetrahydrofolate (5-MTHF) is the methylated form of tetrahydrofolate and the principal circulating folate in humans. It is the metabolically active folate used in one-carbon transfer reactions and is readily available to cells for methylation processes.

The key role of 5-MTHF is as a methyl donor in the remethylation of homocysteine to methionine, a reaction catalyzed by methionine synthase with vitamin B12 as a cofactor. This pathway supports the production of S-adenosylmethionine (SAM), a universal methyl donor involved in numerous methylation reactions, including nucleic acid and protein modifications.

In metabolism, dietary folates are absorbed and converted along a folate cycle. The enzyme methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylene-THF to 5-MTHF, which then participates in homocysteine remethylation. 5-MTHF circulates in plasma and can cross cell membranes; tetrahydrofolate is regenerated after the methionine synthase step.

Clinically, MTHFR gene variants can reduce 5-MTHF production, potentially elevating homocysteine and affecting cardiovascular risk. Because some individuals have limited capacity to convert folic acid to 5-MTHF, supplements or fortified foods containing 5-MTHF are used to improve folate status, particularly during pregnancy or when malabsorption or specific genetic variants are present.

Dietary folates are found in leafy greens, legumes, and fortified foods. 5-MTHF is available as supplements (often calcium or magnesium salts) and is proposed to have advantages in terms of bioavailability for certain individuals. Safety considerations include avoiding excessive folate intake, which can mask vitamin B12 deficiency; long-term high-dose effects require ongoing evaluation.