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PubMed1979

Altered erythrocyte pyrimidine activity in vitamin B12 or folate deficiency.

The net activity of orotidylic pyrophosphorylase and decarboxylase, sequential enzymes which catalyse the formation of uridine monophosphate from orotic acid in de novo pyrimidine biosynthesis, has been evaluated in erythrocytes of patients with folate or cobalamin deficiency. In patients with normoblastic haemopoiesis and normal cobalamin and folate status a direct relationship exists between the maturity of the peripheral blood erythrocyte population, as indicated by G6PD activity, and net orotidylic activity. In contrast in cobalamin or folate deficiency this co-ordinate relationship is not observed and net orotidylic activity is relatively reduced. Fractionation of erythrocytes by centrifugation demonstrates that this inordinately low orotidylic activity consistently occurs in the young erythrocyte population and is reversed by specific replacement therapy. In vitamin B12 or folate deficiency an impressive array of evidence now exists to implicate altered folate metabolism for the observed alterations in purine and pyrimidine metabolism (Das & Herbert, 1976). Of these changes the cornerstone defect resulting in megaloblastic maturation is impaired methylation of deoxyuridine monophosphate to thymidine monophosphate (Hoffbrand et al, 1976). In this context the reduced serum uridine plus uracil levels in patients with vitamin B12 deficiency (Parry & Blackmore, 1976) and the haematological response of these patients to orotic acid therapy (Rundles & Brewer, 1958) are not readily explicable. Since the conversion of orotic acid to uridine monophosphate depends on the integrity of the coupled activities of orotidylic pyrophosphorylase and decarboxylase, this study has quantitated this capacity in peripheral blood erythrocytes in patients with vitamin B12 or folate deficiency.

Erythrocytes↗
PubMed1981

The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia.

It is suggested that in man the methyl folate trap is a normal physiological response to impending methyl group deficiency resulting from a very low supply of methionine. This decreases cellular S-adenosyl-methionine (SAM), which puts at risk important methylation reactions, including those required to maintain myelin. In order to protect these methylation reactions, the cell has evolved two mechanisms to maintain supplies of methionine and SAM as a first priority. (a) Decreased SAM causes the folate co-factors to be directed through the cycle involving 5-methyl-tetrahydrofolate (5-methyl-THF) and methionine synthetase and away from the cycles that produce purines and pyrimidines for DNA synthesis. This enhances the remethylation of homocysteine to methionine and SAM. In addition, by restricting DNA biosynthesis and with it cell, division, competition for methionine for protein synthesis is reduced. Thus, whatever methionine is available is conserved for the vital methylation reactions in the nerves, brain, and elsewhere. (b) 5-methyl-THF, the form in which almost all folate is transported in human plasma, must react with intracellular homocysteine before it can be retained by the cell as a polyglutamate. Since homocysteine is derived entirely from methionine, methionine deficiency will cause intracellular folate deficiency, and the rate of mitosis of rapidly dividing cells will be reduced. although these two processes have evolved as a response to methionine deficiency, they also occur in B12 deficiency, which the cell mistakenly interprets as lack of methionine. the resulting response is inappropriate and gives rise to a potentially lethal anaemia. In these circumstances the methylation reactions are also partly protected by the reduced rate of cell division. This explains why administration of folic acid, which induces cell division and use of methionine in protein synthesis, impairs methylation of myelin and precipitates or exacerbates subacute combined degeneration (SCD). During folate deficiency methionine biosynthesis is also diminished. As in methionine deficiency, the body responds to decreasing availability of SAM by diverting folate away from DNA biosynthesis towards the remethylation of homocysteine to methionine and SAM. The selective use pf available folate to conserve methionine, together with the ability of nerve tissue to concentrate folate form the plasma, explains the absence of SCD in folate deficiency.

Acute Disease↗
PubMed1988

Folate deficiency in rats fed diets containing free amino acids or intact proteins.

Development of folate deficiency (FD) was evaluated in weanling rats fed diets containing mixtures of free amino acids or of vitamin-free casein and gelatin as sources of dietary nitrogen. FD could be produced in 21 d with amino acid diets that promoted maximum growth rate, were completely devoid of folate and contained 1% succinylsulfathiazole. Growth retardation and blood dyscrasia associated with FD could not be demonstrated in rats fed diets containing casein and gelatin as nitrogen sources because the vitamin-free casein contained low but measurable levels of folate. The most effective protocol to produce experimental FD in rats is to feed a folate-free diet that otherwise supports maximum growth in young animals. Additional modifications such as use of methotrexate or amino acid-imbalanced or protein-deficient diets are unnecessary.

Animals↗