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  The ‘folate trap’

 

 

 

 


The conversion of 5,10-methylen-THF into 5-methyl-THF, which is catalysed by MTHFR, is irreversible. The only way to make further use of 5-methyl-THF and to maintain the folate cycle consists in the vitamin-B12-dependent remethylation of homocysteine to methionine (regenerating THF). The methyl group transfer is therefore greatly dependent on 5-methyl-THF and the availability of vitamin-B12. In humans, this is the only known direct link of the metabolism of two vitamins; folic acid and vitamin-B12 both need each other.

In cases of vitamin-B12 deficiency, it is possible that, in spite of sufficient availability of folates (and 5-methyl-THF), an intracellular deficiency of biologically active THF arises. This situation is called a ‘folate trap’ (or methyl group trap) because, on the one hand, the concentration of 5-methyl-THF continues to rise but, on the other hand, due to it being prevented from releasing methyl groups, a ‘metabolic dead-end situation’ develops, which leads to the inevitable blockage of the methylation cycle. The co-factors for the C1-transfers decrease and replication as well as the cell division rate are reduced. Hence, the principal problem is the decreasing activity of methionine synthase under vitamin-B12 deficiency with secondary disorders affecting the folate metabolism and insufficient de-novo synthesis of purines and pyrimidines. The deficiency in active folic acids first affects the quickly dividing and highly proliferating haematopoiesis cells in the bone marrow and can even lead to pancytopenia.

Clinically, there is now no difference between vitamin-B12 deficiency anaemia and folic acid deficiency anaemia. If such an anaemia is treated with vitamin-B12, the blockage is immediately stopped and the blood count quickly normalises. However, if the anaemia is exclusively treated with folic acid, it is simply converted to dihydrofolate and THF.

Long-term therapy using high doses of folic acid could therefore conceal the real cause i.e. pernicious (vitamin B12-deficiency) anaemia for a long time. The serum folate continues to rise (congestion of non-regenerated 5-methyl-THF) while the intracellular folate concentration (erythrocytes) drops. This situation interrupts the methylation cycle with numerous cell processes, among them the synthesis of myelin, the nerve fibre lining, being blocked due to a deficiency of methyl groups. A long undetected (causal) vitamin-B12-deficiency can therefore result in serious neurological damage.
Exclusive folic acid therapy can lead to damage progression or even damage irreversibility.

   

‘Folic acid trap’. Situation during cobalamin deficiency.
 

 

  Literature (selection):

 
    Fujii K, et al. Accumulation of 5-methyltetrahydrofolate in cobalamin-deficient L1210 mouse leukemia cells. J Biol Chem 1982;157:2144–2146.

PubMed

    Sauer H, et al. Cobalamin dependent methionine synthesis and methyl-trap in human vitamin B12 deficiency. Br J Haematol 1977;36:189–198.

PubMed

    Hoffbrand AV, et al. Evidence in favour of the methyl-trap hypothesis as the cause of megaloblastic anaemia in vitamin B12 deficiency. Br J Haematol 1993;83:643–647

PubMed

    Gutstein S, et al. Failure of response to N5-methyltetrahydrofolate in combined folate and B12 deficiency. Am J Dig Dis 1973;18:142–146.

PubMed

    Ubbink JB, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927–1933.

PubMed

    Dierkes J, et al. Supplementation with vitamin B-12 decreases homocysteine and MMA but also serum folate in patients with end-stage renal disease. Metab Clin Exp 1999.

PubMed

    Scott JM, et al. The methylfolate trap. Lancet 1981;2:337–340.

PubMed