Folic acid catabolism

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

The evaluation of folic acid status must often also include evaluation of vilamin B1 because of its effect on folate metabolism. A vilamin Bu-dependenl reaction is necessary for an cit/vmc involved in the catabolism of branchcd-chain amino acids (mclhylmalonyl CoA to succinyl CoA). This reaction may provide the basis for a functional assessment method for vitamin Biz status. See also Hormones and Vitamin. 

Folic acid functions in the transfer of one-carbon fragments in a wide variety of biosynthetic and catabolic reactions it is therefore metaboUcaUy closely related to vitamin B12, which also functions in one-carbon transfer. Deficiency of either vitamin has similar clinical effects, and it seems likely that the main effects of vitamin B12 deficiency are exerted by effects on folate metabolism. 

Based on folate concentrations in liver biopsy samples, and assuming that the liver contains about half of ail body stores, total body stores of folate are estimated to be between 12 and 28 Kinetic studies that show both fast-turnover and very-slow-turnover folate pools indicate that about 0.5% to 1% of body stores are catabolized or excreted daily,suggesting a minimum daily requirement of between 60 and 280)Llg to replace losses. In calculating nutritional requirement, the concept of dietary folate equivalents (DFE) has been used to adjust for the nearly 50% lower bioavailabihty of food folate compared with supplemental folic acid, such that 1 p.g DFE = 0.6 Llg of folic acid from fortified food = 1 j,g of food folate 0.5 p.g foUc acid supplement taken on an empty stomach. Before the fortification program of cereal grains with folic acid conducted between 1988 and 1994, the median intake of folate from food in the United States was approximately 250p.g/day this figure is expected to increase by about 100 Llg/day after fortification. Recommendations... 

There is reason to conclude that vitamin deficiency might contribute to arteriosclerosis. There is a correlation between elevated homocysteine levels and incidence of cardiovascular disease (59). There is debate as to whether homocysteine contributesto the dam e of cells on the interior of blood vessel or whether homocysteine is a marker of intensive cell repair and formation of replacement cells. Nevertheless, administration of pyridoxine, folic acid, and (yanocobalamin are being recommended along with the two antioxidant vitamins, a-tocopherol and ascorbic acid for arteriosclerosis. Vitamin Bg is required for two of the steps in the catabolism of homocysteine to succinyl CoA (Fig. 8.52). Note in Fig. 8.52 (bottom) that biotin and a coenzyme form of cobalamin also are required for... 

Folic acid also has an important role in histidine catabolism (Fig. 4), where the formimino group of the end-stage product formiminoglutamic acid is transferred to tetrahydrofolate, giving formiminotetrahydrofolate. 

Tyrosine is not an essential amino acid in animals because it is synthesized from phenylalanine in a hydroxylation reaction. The enzyme involved, phenylala-nine-4-monoxygenase, requires the coenzyme tetrahydrobiopterin (Section 14.3), a folic acid-like molecule derived from GTP. Because this reaction also is a first step in phenylalanine catabolism, it is discussed further in Chapter 15. 

FIGURE 53-6 Interrelationships and metabolic roles of vitamin and folic acid. See text for explanation and Figure 53-9 for structures of the various folate coenzymes. FIGLU, formiminoglutamic acid, which arises from die catabolism of histidine Tell, transcobalamin II CH3H4PteGlUj, mediyltetrahydrofolate. 

Depletion/repletion studies to determine folate requirements using folic acid monoglutamate suggest a requirement of the order of 80-100 fig (170-220 nmol)/ day. The total body pool of folate in adults is some 17 Jmol(7.5 mg), with a biological half-life of 101 days. This suggests a minimum requirement for replacement of 85 nmol (37 Jg)/day. Studies of the urinary excretion of folate metabolites in subjects maintained on folate-free diets suggest that there is catabolism of some 80 fig of folate per day. 

Another active folic acid compound was formed during the conversion of serine to glycine. This compound, a hydroxymethyl derivative of FH , was enzymically oxidized to iV ,JVi -anhydroformyl-FH4 (108, IIS). The anhydro derivative was also produced in the catabolism of formiminoglycine (114, 115) and formiminoglutamic acid (114) via AT -formimino-FH4. An active formyl-FH4 derivative, presumably JVi -formyl-FH4, also arose when IMP and FH4 reacted to produce AICAR (108) (see Section II, B, 5). iV -Formyl-FH4 reacted with glutamic acid to form iV-formyl utamic acid... 

The N-5 position is considerably more basic than the N-10 position, and this basicity is one of several factors that control certain preferences in the course of reactions involving tetrahydrofolate. Thus, for-mylation occurs more readily at N-10 while alkylation occurs more readily at N-5. Benkovic and Bullard (1973) have reviewed evidence for an iminium cation at N-5 as the active donor in formaldehyde oxidation-level transfers. Recently, Barrows et al. (1976) have further studied such a mechanism for folic acid. The interconversion of these forms of folate coenzymes by enzymatic means has been reviewed by Stokstad and Koch (1967), and the reader is directed there for further details. Folate coenzymes are involved in a wide variety of biochemical reactions. These include purine and pyrimidine synthesis, conversion of glycine to serine, and utilization and generation of formate. In addition, the catabolism of histidine, with the formation of formiminoglu-tamic acid (FIGLU), is an important cellular reaction involving folate. 

---