Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts.

Boss, Gerry R.

doi:10.1172/jci111948

Cited by 22 publications

(17 citation statements)

References 37 publications

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“…39 Despite the similarities in morphologic appearance, MDS and megaloblastic anemia caused by vitamin deficiency are 2 distinct pathophysiologic entities 40 that in some cases can occur simultaneously. 41,42 The clear mechanistic association of altered nucleotide pools with megaloblastic anemia [43][44][45] suggests that other disruptions of the nucleotide pool available for rapid DNA synthesis in erythroblasts could be responsible for the megaloblastic changes observed in Polg A mice. One mechanism whereby mitochondrial dysfunction could result in alterations in nucleotide pools is the mitochondrial dependence of a key enzyme in de novo pyrimidine biosynthesis, dihydroorotate dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

105

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Recent reports describe hematopoietic abnormalities in mice with targeted instability of the mitochondrial genome. However, these abnormalities have not been fully described. We demonstrate that mutant animals develop an age-dependent, macrocytic anemia with abnormal erythroid maturation and megaloblastic changes, as well as profound defects in lymphopoiesis. Mice die of severe fatal anemia at 15 months of age. Bonemarrow transplantation studies demonstrate that these abnormalities are intrinsic to the hematopoietic compartment and dependent upon the age of donor hematopoietic stem cells. These abnormalities are phenotypically similar to those found in patients with refractory anemia, suggesting that, in some cases, the myelodysplastic syndromes are caused by abnormalities of mitochondrial function. (Blood. 2009;114:4045-4053)

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Section: Discussionmentioning

confidence: 99%

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Chen

Logan

Hochberg

et al. 2009

Blood

105

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“…Radioactivity on the filters was quantitated by liquid scintillation counting, and the assay was linear with time from 1 to 3 h and with cell number from 2 to 5 ϫ 10 6 . Measurement of Rates of Methionine and Serine Synthesis-Rates of methionine and serine synthesis were measured as described previously following [ 14 C]formate incorporation into methionine and serine in protein (22)(23)(24) (Fig. 1).…”

Section: Measurement Of [ 14 C]methyl-tetrahydrofolate Incorporation mentioning

confidence: 99%

“…Cells-Decreased cellular methionine synthase activity should decrease not only methionine synthesis from homocysteine, but because of trapping of folates as 5-methyltetrahydrofolate, it should also decrease carbon flow through the folate pathway and thereby decrease serine synthesis (2,22) (Fig. 1).…”

Section: No Decreases Rates Of Methionine and Serine Synthesis In Culmentioning

confidence: 99%

“…1). To test this hypothesis, we measured [ 14 C]formate incorporation into methionine and serine in HL-60 human leukemic cells and BHK fibroblasts; as described previously, this assay measures in vivo rates of methionine and serine synthesis and carbon flux through the folate pathway (22,23). We found that three different NO donors, SNAP, PAPA-NONOate, and GS-NO, at concentrations known to have physiological effects (28,29), decreased methionine and serine synthesis in both cell types (Fig.…”

Section: No Decreases Rates Of Methionine and Serine Synthesis In Culmentioning

confidence: 99%

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Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway

Danishpajooh

Gudi

Chen

et al. 2001

Journal of Biological Chemistry

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Many of nitric oxide's biological effects are mediated via NO binding to the iron in heme-containing proteins. Cobalamin (vitamin B 12 ) is structurally similar to heme and is a cofactor for methionine synthase, a key enzyme in folate metabolism. NO inhibits methionine synthase activity in vitro, but data concerning NO binding to cobalamin are controversial. We now show spectroscopically that NO reacts with all three valency states of cobalamin and that NO's inhibition of methionine synthase activity most likely involves its reaction with monovalent cobalamin. By following incorporation of the methyl moiety of [ 14 C]methyltetrahydrofolic acid into protein, we show that NO inhibits methionine synthase activity in vivo, in cultured mammalian cells. The inhibition of methionine synthase activity disrupted carbon flow through the folate pathway as measured by decreased incorporation of [ 14 C]formate into methionine, serine, and purine nucleotides. Homocysteine, but not cysteine, attenuated NO's inhibition of purine synthesis, providing further evidence that NO was acting through methionine synthase inhibition. NO's effect was observed both when NO donors were added to cells and when NO was produced physiologically in co-culture experiments. Treating cells with an NO synthase inhibitor increased formate incorporation into methionine, serine, and purines and methyl-tetrahydrofolate incorporation into protein. Thus, physiological concentrations of NO appear to regulate carbon flow through the folate pathway.Vitamin B 12 deficiency leads to pernicious anemia and subacute combined degeneration of the spinal cord (1). Pernicious anemia is characterized by megaloblastic erythropoiesis and is secondary to decreased activity of methionine synthase, one of two mammalian enzymes that requires vitamin B 12 (cobalamin) as a cofactor (2, 3). Methionine synthase catalyzes the transfer of the methyl group of 5-methyltetrahydrofolate to homocysteine via a methylcobalamin intermediate with cycling of cobalamin between the ϩ1 valency state (i.e. cbl(I)) 1 and the ϩ3 valency state (i.e. cbl(III)) (2, 3). Methyltetrahydrofolate is the major intracellular storage form of folates, and its synthesis from 5,10-methylene tetrahydrofolate is essentially irreversible in vivo (2, 4) (Fig. 1). Thus, decreased methionine synthase activity leads to trapping of intracellular folates as 5-methyltetrahydrofolate, and the megaloblastic anemia of vitamin B 12 deficiency is virtually indistinguishable from the megaloblastosis of folate deficiency (1).Nitric oxide (NO) is produced by most cell types and regulates a diverse array of biological functions (5, 6). NO has been reported to inhibit methionine synthase activity in vitro (7-9), and it might be expected to bind to the cobalt in cobalamin because (i) NO binds tightly to the iron in heme (10); (ii) ferrous heme and cbl(III) are isoelectronic; and (iii) in both heme and cobalamin, the metal ion is coordinated to four in-plane nitrogen atoms of a tetrapyrrole ring and has two out-of-plane ligands (3...

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“…On the other hand, serine levels are depressed in some individuals with excess homocysteine who are treated with folic acid, cobalamin, and vitamin B 6 [Boss, 1985]. Serine is required for the conversion of folic acid to its active form, as a shuttle for methyl groups between cytosol and mitochondria, and as a cofactor in the transsulfuration pathway of methionine/homocysteine metabolism.…”

Section: Betainementioning

confidence: 99%

The homocysteine pathway: A new target for Alzheimer disease treatment?

Lao¹,

Beyer

Ariza

2004

Drug Development Research

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One of the known risk factors for developing Alzheimer disease (AD) is hyperhomocysteinemia. The latter may result from mutations of the genes coding for three key enzymes involved in homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MS], and cystathionine beta-synthase [CBS]). Polymorphisms within the three genes have been shown to be positively associated with AD in some populations. Whereas MS and MTHFR polymorphisms have been described as AD risk factors independently on age at onset of the disease, two of the CBS polymorphisms were found to depend on age at onset of AD. The division of AD patients and controls into age-at-onset/ age dependent subgroups (o65 years, 65-74 years, Z75 years) revealed that the 844ins68 mutation and variable number of tandem repeats allele 19 are independent risk factors for AD development in subjects aged 75 years or more. Although homocysteine levels can be regulated by dietary intake of folic acid, B vitamins, and other components, the genotype-dependent design of strategies for the maintenance of adequate homocysteine levels could be helpful for AD treatment. In addition to each specific genotype, age and age at onset of AD are important factors for specific regulation of the homocysteine metabolism. One of the molecules to take into account in the case of AD is choline, which serves as methyl-group donor when MS activity is impaired. Drug Dev.

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Cobalamin inactivation decreases purine and methionine synthesis in cultured lymphoblasts.

Cited by 22 publications

References 37 publications

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction

Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway

The homocysteine pathway: A new target for Alzheimer disease treatment?

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