Cobalamin inactivation decreases purine and methionine synthesis in cultured human lymphoblasts.

Abstract

Cobalamin (vitamin B12) is required by two enzymes in mammalian cells, specifically methionine synthetase (N5-methyltetrahydrofolate-homocysteine methyltransferase, EC 2.1.1.13) and methylmalonyl CoA mutase (EC 5.4.99.2). Cobalamin deficiency in humans leads to megaloblastic anemia which is probably secondary to decreased methionine synthetase activity and to subacute combined degeneration of the spinal cord which appears to be secondary to decreased methylmalonyl CoA mutase activity. A decrease in methionine synthetase activity should cause 5-methyltetra-hydrofolate to accumulate because this folate is a major storage form of intracellular folate and its production from 5, 10-methylene tetrahydrofo-late is essentially irreversible. in vivo. These were the data that originally formulated the methylfolate trap hypothesis to describe cobalamin deficiency. Trapping intracellular folates as 5-methyltetrahydro-folate should decrease intracellular purine synthesis and thus lead to decreased DNA synthesis and ultimately to megaloblastosis. However, not all of the data concerning B12 deficiency are totally explainable by the folate trap and animal studies only partially support this mechanism.