Effect of Methionine on Specific Folate Coenzyme Pools in Vitamin B12 Deficient and Supplemented Rats

Vitamin B₁₂ Deprivation in the Rat: Effects on Folate Metabolism with Emphasis on the Nervous System

“…The lower proportion of 5-MTHF in the liver and brain of the starved, vitamin-B12-deprived animals can probably be ascribed to the lack o f methionine caused by starvation. The finding supports the view that either methionine or vitamin B 12 could maintain these liver folate coenzyme patterns (22) and suggests that the brain behaves like the liver in this respect.…”

The Effect of Vitamin B12 Deficiency on Methylfolate Metabolism and Pteroylpolyglutamate Synthesis in Human Cells

“…However, the synthesis and activity of the enzyme 5,lO-methylenetetrahydrofolate reductase, which synthesizes 5-methyltetrahydrofolate, and of the enzyme 5-methyltetrahydrofolate-homocysteine methyltransferase may be modified by a number of intracellular metabolites including homocysteine, methionine and S-adenosylmethionine (Kutzbach & Stokstad, 1967;Kamely, Littlefield & Erbe, 1973), and the effect of a block due to vitamin BIZ deficiency in conversion of homocysteine into methionine on the levels of these intermediates in human marrow and other cells may be important in determining how much tetrahydrofolate can be formed from methyltetrahydrofolate inside these cells. For instance, Thenen & Stokstad (1973) and Smith, Osborne-White & Gawthorne (1974) observed that methionine added to the diet substantially increased pteroylpolyglutamate synthesis in vitamin B,,-deficient rats and sheep respectively. Thenen & Stokstad (1973) attributed their results to conversion of methionine into S-adenosylmethionine, which then inhibited methylenetetrahydrofolate reductase (Kutzbach & Stokstad, 1967) and so maintained folate in the tetrahydrofolate and 10-formyltetrahydrofolate states.…”

“…For instance, Thenen & Stokstad (1973) and Smith, Osborne-White & Gawthorne (1974) observed that methionine added to the diet substantially increased pteroylpolyglutamate synthesis in vitamin B,,-deficient rats and sheep respectively. Thenen & Stokstad (1973) attributed their results to conversion of methionine into S-adenosylmethionine, which then inhibited methylenetetrahydrofolate reductase (Kutzbach & Stokstad, 1967) and so maintained folate in the tetrahydrofolate and 10-formyltetrahydrofolate states. Noronha & Silverman (1962) originally showed that added dietary methionine does indeed reduce the proportion of 5-methylfolate derivatives in vitamin B,,-deficient rat liver and increases 10-formylfolate derivatives.…”

“…Decreased liver folate, decreased synthesis of pteroylpolyglutamate from folic acid and an excess of methylated compared to formylated folates has also been described in the livers of vitamin B,,-deficient experimental animals (Thenen & Stokstad, 1973 ;Smith & OsborneWhite, 1973).…”

Folate Deficiency in Humans

“…These support the unchallenged concept that the final common pathway is depletion of 5,10-methylenetetrahydrofolate required for thymidylate synthesis. The proportion of folate in the methyl form is increased in experimental vitamin B12 deficiency and normalizes after B12 administration (Smith and Osborne-White, 1973;Thenen and Stokstad, 1973). Stokstad (1976), whose group has probably been the most active to investigate potential routes for demethylation of folate in vitamin B 12 deficiency, recently reviewed the large body of data indicating that direct transmethylation is wholly B12-dependent and that a potential indirect route via oxidation to 5,1O-methylenetetrahydrofolate is made even more unlikely in B12 deficiency.…”