Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B12 Deficiency

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Abstract
The activity of methionine synthetase (MS) is important for the rapid growth of human hematopoietic cells and cultured lymphoblastoid cells. The MS reaction is the only known metabolic step in which both vitamin B12 and folate are essential in a single enzyme reaction. In vitamin B12 deficiency the MS activity in bone marrow cells is significantly lower than that in normal bone marrow. Free tetrahydrofolic acid (H4PteGlu) is normally liberated from its metabolically inactive storage form, 5-methyl-H4PteGlu (CH3H4PteGlu), in the cobalamin-dependent MS reaction. In vitamin B12 deficiency, H4PteGlu is not available in sufficient concentration to maintain the de novo synthesis of thymidylate and purines and accords with the methyl-folate-trap hypothesis. After treatment with amethopterin (methotrexate), the incorporation of 3H-deoxyuridine into cellular DNA is reduced. In proliferating normal cells this effect of methotrexate can be prevented (and the cells rescued) with CH3-H4PteGlu or with CHO-H4PteGlu (5-formyl-H4PteGlu; Leucovorin). In vitamin B12 deficient bone marrow cells this so-called rescue-effect could only be achieved with CHO-H4PteGlu and not with CH3-H4PteGlu. These observations support the hypothesis of the methyl-folate-trap in vitamin B12 deficiency. Decreased MS activity in vitamin B12 deficiency seems to be the essential metabolic fault, which is responsible for secondary alterations of folate metabolism. Measurement of MS activity may allow direct functional assessment of vitamin B12 deficiency, at least with regard to DNA metabolism.