Histidine tetrahydrofolate

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.

Tetrahydrofolate receives one-carbon fragments from donors such as serine, glycine, and histidine and transfers them to intermediates in the synthesis of amino acids, purines, and thymine—a pyrimidine found in DNA. ... 

Catabolism of histidine. The first steps of the major degradative pathway for histidine metabolism have already been discussed. Elimination of ammonia, followed by hydration and ring cleavage to formiminoglutamate, involves unusual reactions (Eq. 25-14)252 which have been discussed earlier. Transfer of the formimino group to tetrahydrofolic acid and its further metabolism have also been considered (Chapter 15). 

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

Figure 10.6. Catabolism of histidine - basis of the FIGLU test for folate status. Histidase, EC 4.3.1.3 urocanase, EC 4.2.1.49 FIGLU formiminotransferase, EC 2.1.2.5. THF, tetrahydrofolate.

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. 

Cobalt accepts a methyl group from methyl-tetrahydrofolate, forming methyl Co +-cobalamin. Transfer of the methyl group onto homocysteine results in the formation of Co+-cobalamin, which can accept a methyl group from methyl-tetrahydrofolate to reform methyl Co +-cobalamin. However, except under strictly anaerobic conditions, demethylated Co+-cobalamin is susceptible to oxidation to Co +-cobalamin, which is catalyticaUy inactive. Reactivation of the enzyme requires reductive methylation, with S-adenosyl methionine as the methyl donor, and a flavoprotein linked to NADPH. For this reductive reactivation to occur, the dimethylbenzimidazole group of the coenzyme must be displaced from the cobalt atom by a histidine residue in the enzyme (Ludwig and Matthews, 1997). 

Administration of diphenylhydantoin leads to decreased activity of methylene tetrahydrofolate reductase and an increased rate of oxidation of formyl tetrahydrofolate (increased oxidation of formate and histidine), with a fall in methylene- and methyl-tetrahydrofolate - the reverse of the effect of the methyl folate trap (Billings, 1984a, 1984b). 

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. 

In experimental animals and with isolated tissue preparations and organ cultures, the test can be refined by measuring the production of G02 from [ C]histidine in the presence and absence of added methionine. If the impairment of histidine metabolism is the result of primary folate deficiency, the addition of methionine wUl have no effect. By contrast, if the problem is trapping of folate as methyl-tetrahydrofolate, the addition of methionine will restore normal histidine oxidation as a result of restoring the inhibition of methylene-tetrahydrofolate reductase by S-adenosylmethionine and restoring the activity of 10-formyl-tetrahydrofolate dehydrogenase, thus permitting more normal folate metabolism (Section 10.3.4.1). 

Histidine is converted into 4-imidazolone 5-propionate (Figure 23.24). The amide bond in the ring of this intermediate is hydrolyzed to the TV-formimino derivative of glutamate, which is then converted into glutamate by transfer of its formimino group to tetrahydrofolate, a carrier of activated one-carbon units (Section 24.2.6). 

Folate deficiency can result in an overall decline in the concentrations of all the cofactor forms of folate in the cell. Vitamin B12 deficiency can result in a decline in the concentration of tetrahydrofolate and an increase in that of 5-methyl-H4folate. Both deficiencies would be expected to result in impairment of the catabolism of histidine. 

Histidine can be converted to formiminoglutamate (FIGLU). The formimino group is transferred to tetrahydrofolate (FH4), and the remaining five carbons form glutamate. 

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. 

Histidine can be degraded to form ammonia and formiminoglutamate. The latter, with tetrahydrofolate, can form ammonia, N5, N10 methylene tetrahydrofolate and glutamate. 

Fig. 39.12. Degradation of histidine. The highlighted portion of histidine forms glutamate. The remainder of the molecule provides one carbon for the tetrahydrofolate (FH4) pool (see Chapter 40) and releases NH4. ...

Tetrahydrofolate Tetrahydrofolate, which is produced from the vitamin folate, is the primary one-carbon carrier in the body. This vitamin obtains one-carbon units from serine, glycine, histidine, formaldehyde, and formate (Fig. 40.1). While these carbons are attached to FH4 they can be either oxidized or reduced. Because of this, folate can exist in a variety of chemical forms. Once a carbon has been reduced to the methyl level (methyl-FHf, however, it cannot be re-oxidized. Collectively, these one-carbon groups attached to their carrier FH4 are known as the one-carbon pool. The term folate is used to represent a water-soluble B-complex vitamin that functions in transferring single-carbon groups at various stages of oxidation. 

One-carbon methyl donors for tetrahydrofolate and SAM Glycine, serine, histidine, methionine Most cells, but highest in liver Choline, phosphatidylcholine, purine and pyrimidine synthesis, inactivation of waste metabolites and xenobiotics through methylation. 

Histidine ammonia-lyase 2 urocanate hydratase 3 imidazolone propionase 4 glutamate form-iminotransferase (the enzyme occurs in vertebrates and forms 5-formimino tetrahydrofolic acid)... 

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