Metabolism of Folates

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

Methylation of dUMP to give thymidylate is catalyzed by thymidylate synthase and utilizes 5,10-methylenetetra-hydrofolate as the source of the methyl group. This reaction is unique in the metabolism of folate derivatives because the folate derivative acts both as a donor of the one-carbon group and as its reductant, using the reduced pteridine ring as the source of reducing potential. Consequently, in this reaction, unlike any other in folate metabolism, dihydrofolate is a product (fig. 23.16). Since folate derivatives are present in cells at very low concentrations, continued syn-... 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

Vitamin 13]2 deficiency induces deficiency in folate, because vitamin Bn is required for the conversion of folate from a form that has limited use (5-melhyl H.tfolate) to a form (H folate) that can be readily assimilated and used in a variety of reactions. Vitamin is the cofactor of methionine synthase, the enzyme required for conversion of 5-methyl-H4folate to H4folate. The metabolism of folate and that of vitamin B12 are, in part, intimately related. Because of this relationship, the symptoms of deficiencies in both of these vitamins are shared. 

Figure 2 Physiology and metabolism of folate. GAR, glycinamide ribonucleotide FGAR, formylglycinamide ribonucleotide AlCAR aminoimidazolecarboxamide ribonucleotide figlu, formiminoglutamic acid IMP, inosine monophosphate.

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