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PubMed1966

Method of assay of red cell folate activity and the value of the assay as a test for folate deficiency.

A simplified microbiological assay for determining the folate content of red cells is described. As in previously reported methods Lactobacillus casei is used as test organism but two modifications are introduced. First, haemolysis is carried out in water containing 1 g.% of ascorbic acid; secondly, haemolysates are not incubated before the assay. Using this assay, recovery of pteroylglutamic acid added in two different concentrations to five different whole blood samples was 97.0 +/- 1.9 S.E. % and 106.1 +/- 4.7 S.E. % respectively. The coefficient of variation of the assay was between 11.2 and 15.0%. Haemolysates were best stored deep frozen, showing no significant loss of L. casei activity for three to five months at -20 degrees C. On the other hand, non-haemolysed blood samples were best stored at 4 degrees C. when there was no loss of activity for seven to 10 days. Experiments confirmed that plasma is necessary for the maximum release of red cell L. casei activity, and showed that only small amounts of plasma are necessary; folate- and B(12)-deficient plasma released slightly lower L. casei activities from red cells than did normal plasma. The red cell folate levels of 40 healthy normal subjects ranged from 160 to 640 mmug. per ml. of packed red cells. One hundred and twenty patients with subnormal serum folate levels due to idiopathic steatorrhoea, nutritional folate deficiency and Crohn's disease, partial gastrectomy, myelosclerosis, and polycythaemia vera were studied. Red cell folate levels were subnormal (range from 7 to 143 mmug. per ml.) in 40 patients with megaloblastic anaemia, the lowest levels occurring in the most anaemic patients. Subnormal red cell folate levels also occurred in 23 (29%) of the 80 non-anaemic patients. There was a good correlation between red cell folate level and severity of folate deficiency assessed by polymorph nuclear lobe counts, and, in the non-anaemic patients bone marrow morphology. It is concluded that, in the absence of B(12) deficiency, the red cell folate level is a precise guide to the severity of folate deficiency. Patients with serum folate levels less than 3.0 mmug. per ml. almost always had megaloblastic anaemia or obvious morphological changes of folate deficiency. In patients with borderline serum folate levels (3.0-5.9 mmug. per ml.) haematological changes varied widely. The degree of change correlated with the red cell folate level in these patients. The formiminoglutamic acid (Figlu) test was positive (range 20-660 mg. excreted in eight hours) in all 30 patients with megaloblastic anaemia due to folate deficiency tested and also in 17 (31%) of 54 non-anaemic patients who were folate deficient. The amount of Figlu excreted paralleled the red cell folate level in both the anaemic and non-anaemic, folate-deficient patients tested. Figlu excretion, like the red cell folate level, appeared to be a satisfactory index of tissue folate stores. In 46 patients with pernicious anaemia, the red cell folate levels ranged from 26 to 396 mmug. per ml., 29 (63%) of them having subnormal levels. The ratio of mean red cell to mean serum folate level, 13.0:1, was lower than that of normal subjects. As in folate deficiency the patients with the lowest haemoglobin concentrations had the lowest red cell folate levels. Figlu was positively excreted in 10 (59%) of 17 patients with pernicious anaemia tested, being particularly increased in those with low red cell folate levels. Reticulocytes of patients with pernicious anaemia on treatment and with haemolytic anaemia were shown to have higher folate levels than their corresponding mature cells. It is concluded that reticulocytes in general have relatively high folate levels.

Anemia, Macrocytic↗
PubMed1975

The relationships between vitamin B12 and folic acid and the effect of methionine on folate metabolism.

The relationship between vitamin B12 and folate and the effect of methionine on folate metabolism during B12 deficiency in rats is best explained by the prevention of the accumulation of 5-methyl-H4PteGlu by vitamin B12 and/or methionine. Although several points remain to be clarified, the 'methyl trap' hypothesis provides the most satisfactory explanation for the relation between vitamin B12, methionine and folic acid. This concept is extended by the hypothesis that H4PteGlu is the most active substrate for pteroylpolyglutamate synthetase, and thus accounts for the effect of methionine or vitamin B12 increasing liver folate levels.

Animals↗
PubMed1975

Kinetic mechanism of formininotransferase from porcine liver.

Formiminotransferase (EC 2.1.2.5) and cyclodeaminase (EC 4.3.1.4) constitute an enzyme complex that catalyses two sequential metabolic reactions. The activity of native formiminotransferase can be measured without interference from cyclodeaminase, and its kinetic mechanism has been investigated. Although initial velocity plots yield families of parallel lines suggesting that the transferase utilizes a ping-pong mechanism, product inhibition and alternate substrate studies with tetrahydropteroic acid clearly show the mechanism to be sequential. Of the possible mechanisms compatible with these observations, several could be ruled out through the effects of various dead-end inhibitors. The data indicate that the transferase mechanism is rapid equilibrium random with formation of a dead-end complex enzyme-tetrahydrofolate-glutamate.

Ammonia-Lyases↗
PubMed1989

An improved procedure for the purification of formiminotransferase-cyclodeaminase from pig liver. Kinetics of the transferase activity with tetrahydropteroylpolyglutamates.

Formiminotransferase-cyclodeaminase is stabilized and activated approx. 40% in the presence of low concentrations (equal or less than 0.2%) of Triton X-100, possibly because the average hydrophobicity (1.10 kcal per residue) and the frequency of large non-polar side-chains (0.34) of this protein are both somewhat higher than average. This stabilization enabled us to develop a new purification procedure for the enzyme using chromatography on Matrex Gel Orange A and heparin-Sepharose columns in the presence of Triton X-100. This procedure is easier, much more reproducible, and gives slightly higher yield than the previous method described by Drury, et al. Further investigations of the role of tetrahydropteroylpolyglutamates with formiminotransferase-cyclodeaminase reveal that the use of polyglutamylated folate substrates does not change the mechanism of the transferase reaction, but decreases the K(m) for formininoglutamate, the second substrate, more than 10-fold, bringing it closer to the expected physiological concentration.

Amino Acids↗
PubMed1995

Congenital errors of folate metabolism.

Congenital errors of folate metabolism can be related either to defective transport of folate through various cells or to defective intracellular utilization of folate due to some enzyme deficiencies. Defective transport of folate across the intestine and the blood-brain barrier was reported in the condition 'Congenital Malabsorption of Folate'. This disease is characterized by a severe megaloblastic anaemia of early appearance associated with mental retardation. Anaemia is folate-responsive, but neurological symptoms are only poorly improved because of the inability to maintain adequate levels of folate in the CSF. A familial defect of cellular uptake was described in a family with a high frequency of aplastic anaemia or leukaemia. An isolated defect in folate transport into CSF was identified in a patient suffering from a cerebellar syndrome and pyramidal tract dysfunction. Among enzyme deficiencies, some are well documented, others still putative. Methylenetetrahydrofolate reductase deficiency is the most common. The main clinical findings are neurological signs (mental retardation, seizures, rarely schizophrenic syndromes) or vascular disease, without any haematological abnormality. Low levels of folate in serum, red blood cells and CSF associated with homocystinuria are constant. Methionine synthase deficiency is characterized by a megaloblastic anaemia occurring early in life that is more or less folate-responsive and associated with mental retardation. Glutamate formiminotransferase-cyclodeaminase deficiency is responsible for massive excretion of formiminoglutamic acid but megaloblastic anaemia is not constant. The clinical findings are a more or less severe mental or physical retardation. Dihydrofolate reductase deficiency was reported in three children presenting with a megaloblastic anaemia a few days or weeks after birth, which responded to folinic acid. The possible relationship between congenital disorders such as neural tube defects or dihydropteridine reductase deficiency and disturbances of folate metabolism are discussed. Neurological symptoms present in most of these congenital disorders highlight the role of folate in the central nervous system.

Female↗
PubMed1995

Cobalamin and folate deficiency in the elderly.

Elderly persons are more likely to have low values for serum and erythrocyte folate, and for serum cobalamin. Many of those with low vitamin levels have biochemical abnormalities consistent with true deficiency, including increased formiminoglutamic acid excretion, abnormal marrow deoxyuridine suppression, and raised serum levels of methylmalonic acid and homocysteine. Therapy with the appropriate vitamin reverses the biochemical defect. Despite this, the clinical consequences for most elderly persons are remarkably few. True megaloblastic anaemia is rare, and the small number of therapeutic trials to date have not improved the levels of haemoglobin in the treated subjects, although the mean corpuscular volume has decreased significantly. There has been recent concern that these low blood vitamin levels might be important causes of nervous system damage, but studies specifically of the elderly have not demonstrated overall improvements in neurological function following therapy. Vascular damage from high blood homocysteine levels secondary to cobalamin or folate deficiency remains a potential hazard. Dietary insufficiency, malabsorption of protein-bound vitamin B12 secondary to atrophic gastritis, and defective absorption of folyl polyglutamates seem the likeliest possible causes. Pernicious anaemia, although a common cause of severe megaloblastic anaemia in the elderly, is an infrequent cause for the low cobalamin levels in population studies. Although the benefits are uncertain, the balance of the evidence suggests that one should treat elderly persons with low values of cobalamin or folate. Crystalline vitamin B12 and folic acid are absorbed normally and are therefore suitable for replacement therapy, provided that pernicious anaemia is excluded.

Aged↗
PubMed1975

Changes in folate metabolism in baboons Papio cynocephalus treated with 2-methyl-2-aminopropanol-B12.

After the intramuscular administration of the vitamin B12 analogue, 2-methyl-2-aminopropanol-B12, to vitamin B12-depleted baboons (Papio cynocephalus) the effects on vitamin B12 and folate metabolism have been studied. The 'apparent' serum vitamin B12 and the serum folate concentrations increased, the liver folate concentrations decreased, and the liver vitamin B12 concentrations were unchanged. The analogue caused a marked increase in the amount of formiminoglutamic acid excreted after a histidine load whereas the amount of methylmalonic acid excreted after a valine load decreased. The rate of red blood cell regeneration after venesection was normal in baboons treated with the analogue and there was no evidence of megaloblastic haemopoiesis. Two baboons given the analogue developed a partial loss of utilization and lack of co-ordination in the hind limbs.

Animals↗
PubMed1978

Bone marrow studies in myelomatosis.

The percentage of fat-cell areas in bone marrow particles from 22 patients with untreated myelomatosis was estimated. In only 1 patient was the mean fat cell area below 25% of the bone marrow area measured. A negative correlation was found between the area of fat cells and plasma cells, indicating a displacement of the fat cell area by the plasma cells. 28% of the patients had empty bone marrow deposits of iron. However, based on a normal iron saturation of S-transferrin and a normal sideroblast count in the bone marrow, the supply of iron to the erythropoiesis was considered sufficient. All patients but one had normoblastic bone marrows. Using a deoxyuridine suppression test in 10 patients, no biochemical defect could be demonstrated. To judge from the correlation coefficient a minor degree (9-14%) of the variation in Hb values could be predicted from the cellularity in the bone marrow while a major degree (70%) could be predicted from the renal glomerular filtration rate. The results do not support a displacement of blood-forming elements, iron deficiency, vitamin B12 or folic acid deficiency to be of general significance in the pathogenesis of anaemia, but agrees with a causal relationship between anaemia and renal failure.

Adult↗
PubMed1975

Investigation into diagnosis and treatment of cobalt deficiency in lambs.

The development of cobalt deficiency was studied in 30 Scottish Blackface lambs grazing pasture on a soil containing 0-17 ppm cobalt. By the end of an eight-week period 50 per cent of lambs were subjectively appraised as showing signs of cobalt deficiency. After a further period lasting four weeks, during which three groups of lambs were studied (one group, least affected by cobalt deficiency, acted as control, the second received a single cobalt bullet and the third received oral doses of 200 mg cobalt chloride at the beginning of the period and three weeks later). Mean urinary formiminoglutamic acid (FIGLU) concentrations were inversely related to serum vitamin B12 concentrations and increased from 0-08 to 0-20 mumole per ml in group 1, and decreased to virtually zero within one week of treatment in groups 2 and 3. The use of serum vitamin B12 and urinary FIGLU concentrations in the diagnosis of cobalt deficiency in sheep are discussed.

Administration, Oral↗
PubMed1975

Metabolic studies of a family with massive formiminoglutamic aciduria.

We have described two siblings who excrete massive amounts (up to 3.89 mmol/24 hr) of N-formiminoglutamic acid (FIGLU) in their urine. This unusual compound was isolated from urine, purified, and firmly identified as FIGLU by combined gas chromatography-mass spectrometry. The patients presumably have a deficiency in activity of the hepatic enzyme, glutamate formiminotransferase, which carries out the fourth sequential step in the main pathway of histidine degradation. Unlike children reported previously with this disorder, our patients had normal serum folate levels, had no hematologic abnormalities, and were not mentally retarded. Very small amounts of FIGLU were present in the plasma of one of the patients, but FIGLU was not detectable in the cerebrospinal fluid of either patient. Administration of pharmacologic doses of folic or folinic acid produced a decrease in excretion of FIGLU in urine. Histidine loading caused a small and comparable urinary excretion of FIGLU in the children's parents and in control adult subjects.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Erythrocyte formimino glutamate transferase in FIGLU aciduria.

A patient is described who presented at an early age with failure to thrive and vomiting, and had a gross excretion of formimino glutamic acid. She had normal concentration of serum folate and vitamin B12, and no haematological abnormalities, and is not mentally retarded. The Michaelis constant for erythrocyte formimino glutamate transferase was in the normal range, but the enzyme behaves differently from that from reference subjects with respect to inhibitors and activators.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

[Biochemical and hematological measures for determination of folate status in humans. 1. Relation between serum folate and segmentation of neutrophil granulocytes].

In a study on 130 student volunteers the segmentation of neutrophil granulocytes was measured. The serum folate concentration was used as biochemical reference. Both parameters indicate the state of folate supply or the degree of folate deficiency, respectively. Considering the haematologic response as an objective criterion only 71% of the examines showed an adequate folate status. 11% were found "deficient" and 18% were in a marginal state of folate supply. This result was confirmed by repeating the experiment. Further studies are to include folate concentration of erythrocytes and urine concentration of formiminoglutamic acid.

Adult↗