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Folate–vitamin B12 interrelationships in the central nervous system

The most accepted explanation as to how the anaemia arises is that vitamin B12 deficiency interferes with the functioning of the folate cofactors as put forward by Herbert & Zalushy (1962) and commonly called the ‘methyl trap hypothesis’. The folates normally function as coenzymes that accept so-called CI units, which are transferred to them by enzymes involved in the degradation of histidine, formate, sarcosine and glycine or by the enzyme serine hydroxymethyltransferase (EC 2.1.2.1) which converts serine to glycine. This last reaction is quantitatively and functionally the most important, particularly in replicating cells. The C1 cofactors produced in this and the other reactions are then used in biosynthetic reactions. Thus, 10-formyltetrahydrofolate is used as a ccifactor for two of the enzymes involved in purine biosynthesis, while 5,lO-methylenetetrahydrofolate is involved in pyrimidine biosynthesis (Fig. 1). Apart from this role in the biosynthesis of purines and pyrimidines and, thus, DNA and RNA, the folates provide a source of methyl groups for dozens of methyltransferase enzymes. This is done by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate with this latter being used to methylate homocysteine to methionine by the vitamin B~dependen t enzyme methionine synthase (EC 2.1.1.13) (Fig. 1). This methionine can then be activated with ATP to produce S-adenosylmethionine (SAM) which in turn can donate its methyl group to a methyltransferase giving a methylated product and S-adenosylhomocysteine (SAH). Normally in cells this SAH is not permitted to accumulate and is enzymically hydrolysed to homocysteine. This can then be recycled back to methionine and SAM via methionine synthase with a new methyl group which would be donated by 5-methyltetrahydrofolate. The methyl trap hypothesis suggests that the enzymic conversion of 5,lOmethylenetetrahydrofolate to 5-methyltetrahydrofolate is irreversible in vivo and that once this latter cofactor is formed it requires a functioning methionine synthase for it to become available again as part of the pool of other folate cofactors. It is suggested that in vitamin B12 deficiency or when the enzyme methionine synthase is inactivated by, for example, the anaesthetic gas nitrous oxide (see p. 221), the cellular folate cofactors become metabolically trapped as 5-methyltetrahydrofolate. The inability of a cell to demethylate this cofactor results in its accumulation at the expense of those forms used in DNA and RNA biosynthesis. Thus, such cells would be in a sort of pseudo folatedeficient state most obviously seen as an anaemia. It might at first seem improbable that cells would so readily and foolishly participate in their own destruction. However, this was resolved by the finding by Kutzbach & Stokstad (1967) that the synthesis of 5-methyltetrahydrofolate in cells is controlled by the level of SAM. Falling levels of SAM, as might be expected to occur when the activity of methionine synthase is