Formiminoglutamate metabolism

B37. Brown, D. D., Silva, O. L., Gardiner, R. C., and Silverman, M., Metabolism of formiminoglutamic acid by vitamin B12 and folic acid deficient rats fed excess methionine. J. Biol. Chem. 235, 2058-2062 (1960). 

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). 

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 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 shown (Figures 9.16 and 9.17). The intermediates, formiminoglutamic acid and 5-formimino-H4folate, bear the formimino group —CH=NH. 

There have been other single reports of megaloblastic anemia associated with an apparent abnormality of folate metabolism. One child had a normal serum folate of 6 p,g/liter, an erythrocyte folate of 1480 p.g/liter, and a megaloblastic anemia which responded to treatment with folic acid (VI). Lampkin (Lll) described two sisters with a severe megaloblastic anemia and normal vitamin 6 2 folate levels. Absorption of vitamin 6, 2 normal and both patients excreted an increased amount of formiminoglutamic acid. It was thought that they required both vitamin B 2 and folate to restore normoblastic hemopoiesis. 

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. 

Histidine metabolism. H PteGlu also acts as an acceptor of aformimino group in the conversion of formiminoglutamic acid to glutamic acid. 

Enzymes with folate coenzymes in human metabolism (examples, 20 enzymes). Thymidylate-synthase (EC 2.1.1.45) serine-hydroxymethyl-transferase (EC 2.1.2.1) formiminoglutamate-formiminotrans-ferase (EC 2.1.2.5). 

The metabolism of formiminoglutamic acid varies in different organisms. In Psevdomonas extracts, formiminoglutamic acid is converted to formylglutamic acid and ammonia by an enzyme that has not been purified, but is active in the presence of sulfhydryl compounds that inhibit... 

The normal metabolism of histidine contains a step in which formiminoglutamic acid is converted to glutamate by an enzyme which uses folate as a cofactor. In individuals with folate... 

An in vivo test for the investigation of suspected folic acid deficiency. The normal metabolism of histidine contains a step in which formiminoglutamic acid (FIGLU) is converted to glutamate by an enzyme which uses folate as a cofactor. In patients with folate deficiency, administration of oral histidine results in a greater than normal urinary excretion of FIGLU. 

Noronha, J, M. and Silverman, M. (1962) On folic acid, vitamin B12, methionine and formiminoglutamic acid metabolism, in ... 

Figure 2 Physiology and metabolism of folate. GAR, glycinamide ribonucleotide FGAR, formylglycinamide ribonucleotide AlCAR aminoimidazolecarboxamide ribonucleotide figlu, formiminoglutamic acid IMP, inosine monophosphate.

Fig. 16.9 The normal and abnormal metabolism of L-histidine and formiminoglutamic acid (FIGLU) in man. Abnormal metabolites are underlined and the positions of known metabolic defects are shown.

Perry, T.L., Applegarth, D.A., Evans, M.E., Hansen, S. and Jellum, E. (1975), Metabolic studies of a family with massive formiminoglutamic aciduria. Pediatr. Res., 9,117. 

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