Folate metabolism catabolism

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. 

Biochemical Functions. Ascorbic acid has various biochemical fimctions, involving, for example, coUagen synthesis, immune fimction, drug metabohsm, folate metabolism, cholesterol catabolism, iron metabolism, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting directly with nitrites, and consequently may potentially reduce cancer risk. 

FIG. 3. Two-pool model of folate metabolism with output only from the rapid turnover pool. Output represents the sum of urinary, fecal, and catabolic losses. 

A key aspect of folate metabolism is the catabolism. Folate catabolism occurs through oxidative cleavage of tetrahydrofolates at the C9-N10 bond... 

FIG. 6. Expanded model of in vivo folate metabolism. Tbe pools are defined as follows 1, rapid turnover folate 6, slow turnover folate (tissues) 2, irretrievable losses by fecal excretion and catabolism 3, cumulative excretion of urinary folate 4, fractional (daily) excretion of urinary folate. Analysis was performed with parallel models for labeled and nonlabeled folate. 

Figure 30-4. Catabolism of i-histidine to a-ketoglu-tarate. (H4 folate, tetrahydrofolate.) Histidase is the probable site of the metabolic defect in histidinemia.

Although catabolism of histidine is not a major source of substituted folate, the reaction is of interest because it has been exploited as a means of assessing folate nutritional stams. In folate deficiency, the activity of the formimi-notransferase is impaired by lack of cofactor. After a loading dose of histidine, there is impaired oxidative metabolism of histidine and accumulation of FIGLU, which is excreted in the urine (Section 10.10.4). 

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. 

The histidine catabolic pathway is discussed under Folate in Chapter 9. The material reveals that histidine is catabolized to produce glutamate. Glutamate in turn, can be converted to a-ketoglutarate and completely oxidized to CO in the Krebs cycle. In the study depicted in Figure 8,26, the dietary histidine was spiked with I Cjhistidine, The term "spiked" means that only a very small proportion of the histidine contained carbon-14. The metabolic behavior of the radioactive histidine, which can be followed, mirrors the metabolic fate of nonradioactive histidine in the diet. All of the CQz exhaled by the rats can be easily collected, The " COj present in the rat s breath can be measured by use of a liquid scintillation counter. The amount of CO2 produced directly mirrors the proportion of histidine, absorbed from the diet that was degraded the rat s body. 

The histidine load test is not used in the clinical setting and is only sometimes used by researchers however, a description of this test provides a clear-cut example of how folates behave in the mediation of 1-carbon metabolism. Histidine catabolism takes place in the liver according to the pathway sho vn (Figures 9.16 and 9.17). The intermediates, formiminoglulamic acid and j-forrnirnino-H folate, bear the formimino group —CH hJH. 

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. 

The metabolic role of folate is as a carrier of one-carbon fragments, both in catabolism and in biosynthetic reactions. As shown in Figure 11.19, these may be carried as formyl, formimino, methyl, methylene or methylene residues. The major sources of these one-carbon fragments and their major uses, as well as the interconversions of the substituted folates, are shown in Figure 11.20. 

The lack of hard evidence about the extent of supplementation required in pregnancy prompted the development of a laboratory-based assessment of metabolic turnover, which involved the assay of total daily folate catabolites (along with intact folate) in the urine of pregnant women. The rationale of the procedure was that this catabolic product represents an ineluctable daily loss of folate, the replacement of which should constitute the daily requirement. Correcting for individual variation in catabolite excretion and the bioavailability of dietary folate, the recommended allowances based on this mode of assessment are in close agreement with the latest recommendations of the USA/Canada and FAO/WHO. The data produced by the catabolite-excretion method may provide a useful adjunct to current methods... 

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