Folate metabolism dietary factors

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

Many factors affect folate metabolism, including dietary folate level, nutritional status of vitamins B6, B12, and riboflavin, zinc status, alcoholism, and physical states such as pregnancy and lactation. In many cases, the effects of these factors are seen in altered excretion rates of intact folates and metabolites, but the effects on tissue levels of the various folates and transfer rates between tissues are not well understood. Preliminary human and animal kinetic models are being devek ed in our laboratory based on studies conducted under controlled dietary conditions. These models will provide a base from which to study the effects of altered folate nutriture as well as the influence of other factors such as pregnancy and aging on folate metabolism. 

An increased plasma level of homocysteine is regarded as a risk factor for cardiovascular disease and the development of arteriosclerosis. Homocysteine concentrations in plasma are reduced by remethylation and transsulfuration (Komarnisky et al. 2003). The remethylation is catalyzed by methionine synthase, which in turn is influenced by vitamin B12 and folate. The transsulfura-tions depend on cystathionine 3-synthase. A dietary deficiency of vitamins B, B12 and folate, accompanied by a high protein intake, can cause hyperhomocystinemia in humans (Jacobsen 1998). Furthermore, a genetic disorder of enzymes involved in the metabolism of homocysteine leads to hypercystinuria (Mudd et al. 1989). 

Methionine metabolism is very dependent on both FH4 and vitamin B12. Homocysteine is derived from methionine metabolism and can be converted back into methionine by using both methyl-FH4 and vitamin B12. This is the only reaction in which methyl-FH4 can donate the methyl group. If the enzyme that catalyzes this reaction is defective, or if vitamin B12 or FH4 levels are insufficient, homocysteine will accumulate. Elevated homocysteine levels have been linked to cardiovascular and neurologic disease. A vitamin B12 deficiency can be brought about by the lack of intrinsic factor, a gastric protein required for the absorption of dietary B12. A consequence of vitamin B12 deficiency is the accumulation of methyl-FH4 and a decrease in other folate derivatives. This is known as the... 

Folic acid was initially distinguished from vitamin Bi2 as a dietary anti-anemia factor by Wills in the 1930s. The subsequent chemical isolation of folic acid and the identification of its role as a cofactor in one-carbon metabolism led to the elucidation of deficiency diseases at the molecular level. The term folate encompasses the entire group of folate vitamin forms, comprising the naturally occurring... 

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