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Folate metabolism

Adequate folate intake is crucial for cell division and homeostasis. Folates act as essential coenzymes in many biological pathways including purine and thymidylate biosynthesis [deoxyribonucleic acid (DNA) synthesis], DNA methylation, amino acid metabolism, and the generation of methionine. The folate metabolism intersects with the methionine cycle and the choline pathway. Important functions are the methylation of Hcy and the formation of S-adenosylmethionine (SAM), the most important methyl donor in the cell. Most of the folate coenzymes exist in the liver (hepatic folate levels range from 10 – 35 µmol/L).

The dihydrofolate reductase (DHFR) reduces FA to dihydrofolate (DHF) and DHF to the active form, THF. The cytosolic folate metabolism consists of three interrelated cycles. One cycle starts from 10-formylTHF and produces purines, and two cycles use 5,10-methyleneTHF to form deoxy thymidine monophosphate (dTMP) and methionine.

5-MethylTHF is the predominant folate form, comprising 82 – 93% of total folate in the human serum (1). After cellular uptake, 5-methylTHF is converted into THF. This reaction is carried out by the cobalamin (vitamin B12)-dependent methionine synthase (MS). The methionine cycle is an important pathway for the conversion of Hcy to methionine and the formation of SAM. Elevated serum concentrations of total Hcy (tHcy) can be caused by deficiencies of B-vitamins (folate, vitamins B6, and B12) or genetic defects (2). 5,10-MethyleneTHF is converted to 5-methylTHF by 5,10-methylenetetrahydrofolate reductase (MTHFR) in an irreversible reaction.

Vitamin B12 deficiency causes a functional folate deficiency. The MS is inactive in B12 deficiency or after exposure to nitrous oxide. Because of the irreversible reaction of the enzyme MTHFR folate is “trapped” as 5-methylTHF and cannot be converted to THF via MS. The polyglutamate synthesis ceases, which limits the pool of intracellular polyglutamates causing a stop of the de novo synthesis of purines and thymidylates.



1.     Pfeiffer CM, Fazili Z, McCoy L, Zhang M, Gunter EW. Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay. Clin Chem 2004;50:423-32.
2.     Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 2003;62-81.