Metabolic Functions of Folate

The metaboUcally active forms of folate cue cdl substituted tetrahydropteroyl polyglutamates. Whereas some folate-dependent enzymes will use the monoglutamate in vitro, most have a considerably lower for polyglutamates, and 

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The Methyl Folate Trap Hypothesis The reduction of meth-ylene-tetrahydrofolate to methyl-tetrahydrofolate is irreversible (Section 10.3.2.1), and the major source of folate for tissues is methyl-tetrahydrofolate. The only metabolic role of methyl-tetrahydrofolate is the methylation of homocysteine to methionine, and this is the only way in which methyl-tetrahydrofolate can be demethylated to yield free tetrahydrofolate in tissues. Methionine synthetase thus provides the link between the physiological functions of folate and vitamin B12. 

Chronic alcoholism is the major cause of folate deficiency in the United States. Alcoholics generally have poor diets — for example, one liter of whiskey per day. It is not dear if the alcohol induces metabolic defects that interfere with the metabolism and function of folate. Beer docs contain folate, as this product is brewed with yeast, an organism containing high levels tif the vitamin. Wine and hard liquors, on the other hand, contain little or no folate. The elderly may also be at risk for folate deficiency. It is thought that in the elderly the deficiency is due to poor diets rather than age-related defects in the absorption and utilization of folate. 

The function of folate binders in folate metabolism remains unclear, except in the case of milk where they have recently been shown to enhance the absorption of folate in breast-fed infants and possibly protect the folate against utilization by intestinal bacteria (C7). The binder may also have a function in sequestering folate from the mother s circulation. It has not been shown to have a role in polyglutamate synthesis nor does it appear to play a part in enabling cells to take up folate on the contrary, Waxman and Schrei-ber (W12) have shown that the binder prevents the uptake of folate by cells in tissue culture. 

Serine, tryptophan and histidine donate 1-carbon units to folate metabolites that are used for DNA and RNA synthesis during cell division and growth. NB Vitamin B12 is needed for the metabolism and function of folate. 

Prevention of scurvy multiple roles in optimizing health and resistance to infectious diseases numerous functions proposed Folate coenzymes participate in one-carbon transfer reactions in cellular metabolism Prevention of pellagra in humans and black tongue in dogs metabolic functions of nicotinamide coenzymes... 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Its significance in metabolism is not clear. Perhaps it serves as a storage form of folate in cells that have a dormant stage, e.g., of seeds or spores.412 It may also have a regulatory function.413 In some ants and in certain beetles, it is stored and hydrolyzed to formic acid. The carabid beetle Galerita lecontei ejects a defensive spray that contains 80% formic acid.414... 

Experimental animals that have been exposed to ititrous oxide to deplete vitamin B12 show an increase in the proportion of liver folate present as methyl-tetrahydrofolate (85% rather than the normal 45%), largely at the expense of unsubstituted tetrahydrofolate and increased urinary loss of methyl-tetrahydrofolate (Horne et al., 1989). Tissue retention of folate is impaired because methyl-tetrahydrofolate is a poor substrate for polyglutamyl-folate synthetase, compared with unsubstituted tetrahydrofolate (Section 10.2.2.1). As a result of this, vitamin B12 deficiency is frequently accompanied by biochemical evidence of functional folate deficiency, including impaired metabolism of histidine (excretion of formiminoglutamate Section 10.3.1.2) and impaired thymidylate synthetase activity (as shown by abnormally low dUMP suppression Section 10.3.3.3), although plasma concentrations of methyl-tetrahydrofolate are normal or elevated. 

The ability to metabolize a test dose of histidine provides a sensitive functional test of folate nutritional status as shown in Figure 10.6, forrnirninoglu-tamate (FIGLU) is an intermediate in histidine catabolism and is metabolized by the tetrahydrofolate-dependent enzyme FIGLU forrnirninotransferase. In folate deficiency, the activity of this enzyme is impaired, and FIGLU accumulates and is excreted in the urine, especially after a test dose of histidine - the FIGLU test. 

L-Tyrosine metabolism and catecholamine biosynthesis occur laigely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andUpid metabolism. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bile acids and the detoxification process of aromatic drugs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabolism related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

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. 

Folate status may be reliably assessed by direct measurement of serum and erythrocyte or whole blood concentrations, and its metabolic function as coen2yme assessed by metabolite concentrations, such as plasma homocysteine (see Chapters 20 and 26). Serum folate concentrations are considered indicative of recent intake and not of tissue stores, but serial measurements have been used to confirm adequate intake. Whole blood or erythrocyte folate concentrations are more indicative of tissue stores and have been shown to have a moderate correlation with liver folate concentrations taken through a biopsy. Because folate is taken up only by the developing erythrocyte in the bone marrow and not by the mature cell, erythrocyte concentrations reflect folate status over the 120-day lifespan of the ceU. Urine folate excretion is not considered to be a sensitive indicator of folate status. ... 

Several analytes are known to be indicative of folate metabolism. Plasma total homocysteine increases when there is a deficiency of 5-MTHF, such that the methylation of homocysteine to methionine is compromised. However, though plasma homocysteine is considered to be a sensitive functional indicator, it is not specific because its concentration can be influenced by deficiency of other vitamins (Bg and B12) involved in the metabolism of homocysteine. Similarly the methylation of DNA is dependent upon adequate 5-MTHF. A sensitive new method for the rapid detection of abnormal methylation patterns in global DNA patterns has been reported and may have promise as a functional marker, as may the measurement of the degree of uracil incorporation into DNA, 5,10-metliylene THF being required for die conversion of deoxyuridine monophosphate (dUMP) to dTMP by thymidylate synthetase. ... 

There are several one-carbon derivatives of folate (of different redox states) that function as one-carbon carriers in different metabolic processes. In all of these reactions, the one-carbon moiety is carried in a covalent linkage to one or both of the nitrogen atoms at the 5- and 10-positions of the pteroic acid portion of tetrahydrofolate. Six known forms of carrier are shown in Figure 27-4. Folinic acid (N -formyl FH4), also called leucovorin or citrovorum factor, is chemically stable and is used clinically to prevent or reverse the toxic effect of folate antimetabolites, such as methotrexate and pyrimethamine. The formation and interconversion of some metabolites of... 

Inherited disorders of folate transport and metabolism include defects in folate carrier (hereditary folate malabsorption, previously discussed), deficiency of N, N °-methylene FH4 reductase (Chapter 17), or functional deficiency of N -methyl FH4 methyltransferase due to defects... 

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