Folic acid oxidation states

Folic acid derivatives (folates) are acceptors and donors of one-carbon units for all oxidation levels of carbon except that of CO2 (where biotin is the relevant carrier). The active coenzyme form of folic acid is tetrahydrofolate (THF). THF is formed via two successive reductions of folate by dihydrofolate reductase (Figure 18.35). One-carbon units in three different oxidation states may be bound to tetrahydrofolate at the and/or nitrogens (Table 18.6). These one-carbon units... 

The chemical structure of folate (or folic acid) is shown in Figure 5.8. In humans, folate usually occurs as polyglutamate derivatives. The active form of folate is THF, sometimes shown as FH4) is derived from folate via two reductase reactions. THF functions as a carrier of one-carbon groups in varying oxidation states (Table 5.1). 

Tetrahydrofolate (THF, 6) is a coenzyme that can transfer Cj residues in different oxidation states. THF arises from the vitamin folic acid (see p. 366) by double hydrogenation of the heterocyclic pterin ring. The Ci units being transferred are bound to N-5, N-10, or both nitrogen atoms. The most important derivatives are ... 

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

Pterin coenzymes such as folic acid (pteroylglutamic acid) and biopterin, which contain a dicyclic pteridine ring, a part of the skeleton of flavins, are also known to play versatile roles in biological redox reactions [67]. The oxidizing ability of the excited state of a pteridine derivative (lumazine [Lu])... 

The metabolism of folic acid involves reduction of the pterin ting to different forms of tetrahydrofolylglutamate. The reduction is catalyzed by dihydtofolate reductase and NADPH functions as a hydrogen donor. The metabolic roles of the folate coenzymes are to serve as acceptors or donors of one-carbon units in a variety of reactions. These one-carbon units exist in different oxidation states and include methanol, formaldehyde, and formate. The resulting tetrahydrofolylglutamate is an enzyme cofactor in amino acid metabolism and in the biosynthesis of purine and pyrimidines (10,96). The one-carbon unit is attached at either the N-5 or N-10 position. The activated one-carbon unit of 5,10-methylene-H folate (5) is a substrate of T-synthase, an important enzyme of growing cells. 5-10-Methylene-H folate (5) is reduced to 5-methyl-H,j folate (4) and is used in methionine biosynthesis. Alternatively, it can be oxidized to 10-formyl-H folate (7) for use in the purine biosynthetic pathway. 

Tyrosine monooxygenase uses biopterin as a cofactor. Biopterin is made in the body and is not a vitamin. Its structure resembles that of folic acid. Dopa decarboxylase is a vitamin B -requiring enzyme. Dopamine hydroxylase is a copper metalloenzyme. The active form of the enzyme contains copper in the reduced state (cuprous, Cu+). With each catalytic event, the copper is oxidized to the cupric state (Cu ). The enzyme uses ascorbic acid as a cofactor for converting the cupric copper back to cuprous copper. Thus, each catalytic event also results in the conversion of ascorbic acid to semidehydroascorbate. The semidehydroascorbate, perhaps by disproportionation, is converted to ascorbate and dehydroascorbate. The catalytic cycle of dopamine hydroxylase is shown in Figure 9,86. Dopamine hydroxylase, as well as the stored catecholamines, are located in special vesicles... 

Folic acid is easily lost during storage of fresh vegetables at room temperature and through many heat processes. Oxidative destruction of 50-95% of the folate can occur with protracted cooking or canning. Currently in the United States folate is added to all enriched or fortified cereal and flour products in order to increase this nutrient to prevent neural tube defects and to reduce coronary disease and some cancers. Thus, the processed, fortified product will have more folate. 

Tetrahydrofolate (THF) The active form of the vitamin folic acid. THF is one of the major carriers of one-carbon units at various oxidation states for biosynthetic reactions. It is required for the synthesis of the nucleotide thymidylate (dTMP). Although bacteria can synthesize folic acid, eukaryotes must obtain folate from the diet. Dietary sources of folate include leafy green vegetables (e.g., spinach and turnip greens), citrus fruits, and legumes. Many breakfast cereals, breads, and other grain products are fortified with folate. 

Different forms of folate may differ in the oxidation state of the one-carbon group, in the number of glutamate residues attached, or in the degree of oxidation of the pteridine ring. When the terni folate or folic acid is applied to a specific chemical form, it is the most oxidized form of the pteridine ring (see Fig. 40.2). Folate is reduced to dihydrofolate and then to tetrahydrofolate by dihydrofolate reductase present in cells. Reduction is the favored direction of the reaction therefore, most of the folate present in the body is present as the reduced coenzyme form, FH4. 

FIGURE 23.11 Structure and reactions of folic acid, (a) The structure of folic acid, shown in non-ionized form, (b) The reactions that introduce one-carbon units into tetrahydrofo-late (THF) link seven different folate intermediates that carry one-carbon units in three different oxidation states (-2, 0, and +2). (Adapted from T. Brody etal, inL.J. Machlin. Handbook of Vitamins. New York Marcel Dekker, 1984.)... 

Both acute and chronic, experimentally-induced homocysteinaemia are associated with a proinflammatory, pro-oxidant state. In animal models, treatment with B vitamins suppresses vascular wall inflammation and reverses Hcy-mediated expression of adhesion molecules and matrix metalloproteinases in the vasculature (Hofmann et al. 2001). Clinical studies, however, have yielded conflicting results. Folic acid administration has been shown to reduce the release of chemokines from mononuclear cells in subjects with homocysteinaemia, but other studies have failed to document any effect of Hey lowering treatment on circulating levels of proinflammatory cytokines. 

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