Folate formiminoglutamate

Formiminoglycine -1- H4-folate -Formiminoglutamate - - H4-folate -Formylglutamate + H4-folate -Deoxyuridylate -1- 5,10-methylene H4-folate -Deoxycytidylate + 5,10-methylene H4-folate -... 

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. 

With the introduction in 1960 (B6) of an improved and sensitive microbiological assay for folate the measurement of formiminoglutamic acid was no longer used as a diagnostic test, although it continues to be used as a research tool. The microbiological assay has in turn now been replaced in many laboratories by isotope dilution techniques. 

In 1962, a physician (H14) placed himself on a diet which, when assayed, was found to provide only 5 pg of folate daily. Up to that time no diet had been devised that contained so little folate, and it was made possible only by boiling each 100 g portion of all those constituents that contained more than a trace of the vitamin for 10 minutes in two liters of water. Tlie water was then discarded and the procedure repeated twice (H15). On this diet early megaloblastic change was noted after 137 days. The serum level of the vitamin fell after 14 days followed by the appearance of hypersegmented neutrophils. Formiminoglutamic acid then appeared in the urine and shortly before the megaloblastic change occurred the red cell folate fell. This experiment provided important information on body stores and the sequence of events in folate deficiency. While the diet was not completely free of folate, its content had been carefully measured and was very small. It was calcu-... 

Formiminotransferase deBciency syndrome was first described in two patients by Arakawa (A7). It was characterized by mental retardation, a very high serum folate level, and excessive excretion of formiminoglutamic acid following a histidine load. A third patient with this syndrome was later... 

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. 

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 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. 

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

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