Introduction

Folate is a critical nutrient in maintaining normal cell growth and division and is thus important for human development. Food (fresh green vegetables, liver, yeast, and some fruits) largely contains folate polyglutamates that are hydrolyzed by folylpolyglutamate conjugase (enzyme commission [EC] number 3.4.19.9) to monoglutamates before absorption in the jejunum (reviewed in detail in refs. 1 and 2). After uptake in the enterocytes, intrac-ellular polyglutamate synthesis occurs, followed by reconversion into monoglutamates that are reduced to biologically active tetrahydrofolate. After methylation, the folates enter the portal circulation as 5-methyltetra-hydrofolate. The majority of this folate is taken up by the liver, which plays a central role in folate homeostasis. The cellular uptake is mediated via specific folate receptors. Plasma 5-methyltetrahydrofolate (30-40%) is bound to albumin, a2 macroglobulin, transferrin, and folate-binding protein.

In the cell, 5-methyltetrahydrofolate serves as a methyl donor and as a source of tetrahydrofolate. Tetrahydrofolate acts as an acceptor of one-carbon units, producing a variety of other folates, which, in turn, are specific coenzymes in intracellular reactions. One of these is 5,10-methylenetetra-hydrofolate that is reduced by the enzyme 5,10-methylenetetrahydrofolate reductase to 5-methyltetrahydrofolate. 5-Methyltetrahydrofolate carries the methyl group required for conversion of homocysteine to methionine (remethylation pathway of homocysteine). This methyl group is initially transferred to cob(I)alamin, revealing methylcobalamin that is demethylated by homocysteine to form methionine by the cobalamin-dependent enzyme

From: Folate and Human Development Edited by: E. J. Massaro and J. M. Rogers © Humana Press Inc., Totowa, NJ

methionine synthase. Occasionally, cob(I)alamin may be oxidized to cob(II)alamin, resulting in the inhibition of methionine synthase. To maintain the enzyme activity, a reductive methylation by the enzyme methionine synthase reductase is required.

Because cobalamin serves as an acceptor of the methyl group from 5-methyltetrahydrofolate, cobalamin deficiency can be associated with "folate trapping," where folates are metabolically dead because they cannot be recycled as tetrahydrofolate back into the folate pool. The resulting failure to regenerate methionine causes depletion of methionine and ultimately leads to hyperhomocysteinemia.

Characterization of inherited disorders of folate transport and metabolism revealed that folate status is under genetic control. The recent cloning of genes encoding proteins required for intestinal absorption of folates, delivery of folates to the cells, as well as the folate cycle provided the basis to identify rare mutations associated with severe enzyme deficiencies and genetic polymorphisms affecting folate and homocysteine status. These include the gene coding for 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), folate receptor 1 (FOLR1), reduced folate carrier 1 (SLC19A1), folate hydrolase (FOLH1), and the serine hydroxymethyltransferase genes (SHMT1 and SHMT2).

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