5-Methyltetrahydrofolate homocysteine cobalamin methyltransferase in human bone marrow and its relationship to pernicious anemia

Taylor, Robert T.; Hanna, M.Leslie; Hutton, John J.

doi:10.1016/0003-9861(74)90308-7

Cited by 40 publications

(5 citation statements)

References 29 publications

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“…Our studies show a striking decrease of cobalamin dependent inethionine synthetase activity in the bone marrow cells of patients with pernicious anaemia, the activity returning to normal after vitamin B, , therapy. These findings alone give little information about the significance of this enzyme in the development of megaloblastic transformation of bone marrow (Taylor et al, 1974; Kass & Boroush, 1976) but other findings show that decreased methionine synthetase activity is the main metabolic fault in vitamin B12 deficiency.…”

Section: Discussionmentioning

confidence: 99%

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

Sauer

Wilmanns

1977

Br J Haematol

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The activity of methionine synthetase (MS) is important for the rapid growth of human haematopoietic cells and cultured lymphoblastoid cells. The MS reaction is the only known metabolic step in which both vitamin B12 and folate are essential in a single enzyme reaction. In vitamin B12 deficiency the MS activity in bone marrow cells is significantly lower than that in normal bone marrow. Free tetrahydrofolic acid (H4PteGlu) is normally liberated from its metabolically inactive storage form, 5-methyl-H4PteGlu (CH3H4PteGlu), in the cobalamin-dependent MS reaction. Thus, in vitamin B12 deficiency H4PteGlu is not available in sufficient concentration to maintain the de novo synthesis of thymidylate and purines, and accords with the methyl-folate-trap hypothesis. After treatment with amethopterin (Methotrexate), the incorporation of 3H-deoxyuridine into cellular DNA is reduced. In proliferating normal cells this effect of methotrexate can be prevented (and the cells rescued) with CH3-H4PteGlu or with CHO-H4PteGlu (5-formyl-H4PteGlu; Leucovorin). On the other hand, in vitamin B12 deficient bone marrow cells this so-called rescue-effect could only be achieved with CHO-H4PteGlu and not with CH3-H4PteGlu. These observations also support the hypothesis of the methyl-folate-trap in vitamin B12 deficiency. Decreased MS activity in vitamin B12 deficiency seems to be the essential metabolic fault, which is responsible for secondary alterations of folate metabolims. Thus, measurement of MS activity may allow direct functional assessment of vitamin B12 deficiency, at least with regard to DNA metabolism.

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Section: Discussionmentioning

confidence: 99%

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

Sauer

Wilmanns

1977

Br J Haematol

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“…The total activity of MS in cell extracts from confluent monolayer cultures was determined by the method of Taylor et al (1974) as modified (Hall, 1984). In contrast to the incorporation studies which measure the comprehensive ability of the intact cell to synthesize Met, the assay of cell extracts measures enzyme activity when all essential substances, except for the enzyme, are provided in excess.…”

Section: Enzyme Activity Of Cell Extractsmentioning

confidence: 99%

Cobalamin metabolism in cultured human chorionic villus cells

Begley

Colligan

Chu

et al. 1993

Journal Cellular Physiology

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Cobalamin (Cbl, vitamin B12) metabolism was analyzed in cultures of human chorionic villus (CV) cells obtained at 9-10 weeks of gestation. CV cells were shown to synthesize transcobalamin II (TCII) and to possess a high affinity receptor for that molecule. The cells bound and internalized radioactive cyanocobalamin (CN[57Co]Cbl) complexed to TCII. This internalized CN[57Co]Cbl was found to be converted to both methylCbl and adenosylCbl, the two intracellular coenzyme forms of Cbl, and bound to the two known intracellular Cbl requiring enzymes, methionine synthase (MS) and methylmalonyl-CoA mutase. Both enzyme systems were found to be functional in the intact cell by demonstrating the incorporation of the radioactive label from both [14C]CH3-tetrahydrofolate and [14C]propionate into acid insoluble products. MS activity was also detected in lysed cell material. CV cells were shown not to be auxotrophic for methionine since they were able to utilize homocysteine in place of methionine for cell division. Since CV cells are capable of performing many of the complex events associated with Cbl metabolism, it may be possible to use these cells to diagnose genetic defects of Cbl metabolism.

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“…Failure of methiortine synthesis (Fig 1). Impaired activity of the enzyme, methionine synthetase, has been demonstrated in marrow from patients with untreated pernicious anaemia (Taylor et al, 1974;Sauer & Wilmanns, 1977) as well as in the N20-treated experimental animal (Deacon et al, 1978). In the rat the activity of the enzyme falls after 30 min exposure to N20 and is barely detectable after 6 h. There is no recovery as long as exposure to N 2 0 Failure oftissue uptake offoolate.…”

Section: H O W Vitamin B12 Actsmentioning

confidence: 99%

HOW VITAMIN B₁₂ ACTS

et al. 1981

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5-Methyltetrahydrofolate homocysteine cobalamin methyltransferase in human bone marrow and its relationship to pernicious anemia

Cited by 40 publications

References 29 publications

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

Cobalamin metabolism in cultured human chorionic villus cells

HOW VITAMIN B₁₂ ACTS

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5-Methyltetrahydrofolate homocysteine cobalamin methyltransferase in human bone marrow and its relationship to pernicious anemia

Cited by 40 publications

References 29 publications

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B12 Deficiency

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B12 Deficiency

Cobalamin metabolism in cultured human chorionic villus cells

HOW VITAMIN B12 ACTS

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Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

Cobalamin Dependent Methionine Synthesis and Methyl‐Folate‐Trap in Human Vitamin B₁₂ Deficiency

HOW VITAMIN B₁₂ ACTS