Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thermolability of 5,10-methylenetetrahydrofolate reductase (MTHFR) was examined as a possible cause of mild hyperhomocysteinemia in patients with premature vascular disease. Control subjects and vascular patients with mild hyperhomocysteinemia and with normohomocysteinemia were studied. The mean (+/- SD) specific MTHFR activity in lymphocytes of 22 control subjects was 15.6 (+/- 4.7) nmol CH2O/mg protein/h (range: 9.1-26.6), and the residual activity (+/- SD) after heat inactivation for 5 min at 46 degrees C was 55.3 (+/- 12.0)% (range: 35.9-78.3). By measurement of MTHFR activity, two distinct subgroups of hyperhomocysteinemic patients became evident. One group (n = 11) had thermolabile MTHFR with a mean (+/- SD) specific activity of 8.7 (+/- 2.1) nmol CH2O/mg protein/h (range: 5.5-12.7) and a residual activity, after heat inactivation, ranging from 0% to 33%. The other group (n = 28) had normal specific activity (+/- SD) of 21.5 (+/- 7.2) nmol CH2O/mg protein/h (range: 10.0-39.0) and a normal residual activity (+/- SD) of 53.8 (+/- 9.2)% (range: 33.1-71.5) after heat inactivation. The mean (+/- SD) specific activity of 29 normohomocysteinemic patients was 20.7 (+/- 6.5) nmol CH2O/mg protein/h (range: 9.4-33.8), and the mean (+/- SD) residual activity after heat inactivation was 58.2 (+/- 10.2)% (range: 43.0-82.0). Thus, in 28% of the hyperhomocysteinemic patients with premature vascular disease, abnormal homocysteine metabolism could be attributed to thermolabile MTHFR.
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PMID:Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. 782 69

We have investigated various micronutrients important to folate metabolism in women with two previous neural tube defect (NTD)-affected pregnancies. Results suggest the disposition of plasma 5-methyltetrahydrofolate (5CH3-H4PteGlu) with respect to dietary intake may differ from that of the control population. It appears that to achieve a given plasma level of 5CH3-H4PteGlu, the population with a history of NTD pregnancies needs to take in more dietary folate than controls. We discuss this in the context of a potential lesion at or upstream from 5,10-methylenetetrahydrofolate reductase (MTHFR). This metabolic axis, which is responsible for the multienzymic conversion of PteGlu to 5CH3-H4PteGlu, has been investigated in a rat model using liver homogenate. The anticonvulsant drug (ACD) carbamazepine was found to inhibit the reaction in terms of a reduced Vmax and increased Km. Inhibition approaching maximal was found to occur at therapeutic levels of ACD. Various potential inhibitory sites along the methylfolate axis are considered and possible relationships to congenital malformations discussed. We describe folate and one carbon metabolism in relation to potential NTD lesion sites, not only in the light of present findings, but with respect to the published findings of other workers. Based on our hypothesis that an NTD lesion exists upstream from MTHFR, we expound how pteroylmonoglutamate supplementation may protect against NTD (i) by reducing endotoxic homocysteine and (ii) through inhibiting MTHFR (as do dihydrofolates) and thus diverting one carbon units into DNA thymine.
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PMID:The methylfolate axis in neural tube defects: in vitro characterisation and clinical investigation. 799 56

Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR) leads to deficient remethylation of homocysteine and is one of the causes of homocystinuria. Only 28 patients have been reported so far. A 15-year-old boy with mild mental retardation was admitted in our hospital because of progressive difficulty in walking. He is the second child. The paternal grandparents are first cousins. On admission, clinical examination revealed mild disturbance of consciousness, left hemiparesis, truncal ataxia, pyramidal tract signs in the lower limbs and sensory disturbance in his feet. There was no marfanoid symptoms nor ectopia lentis. EEGs showed slow activity with sporadic spike and wave complexes. Peak latencies of N20 of median nerves SEPs, the third and 5th wave of ABR and P100 of VEP were delayed. The CT scan showed mild cortical atrophy and MRI revealed increased intensity on T2-weighted images in the cerebral white matter. Biochemical studies revealed homocystinuria with homocystinemia. Both plasma methionine and serum folic acid were low. Serum vitamin B12 and methylmalonic acid in urine were normal. The lymphoblastoid cell line, transformed by Epstein-Barr virus of lymphocytes of the patient, could not grow when homocysteine was substituted in the culture medium for methionine. The normal control cell line grew naturally under the same condition. A diagnosis of homocystinuria due to MTHFR deficiency was made. The patient was on various therapeutic regimens for about 70 days. Treatment with high doses of folic acid (400 mg/day) resulted in disappearance of homocysteine in plasma, remarkable decrease of homocysteine in urine and increase of methionine in plasma of the patient.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effect of folic acid for treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency]. 812 71

Prenatal diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency and family studies were performed because of a severely affected first child in this family. The fetus at risk was found to be heterozygous as confirmed by the enzymatic activity assay performed several times after birth. In the father, MTHFR activity was normal in lymphocytes and decreased in fibroblasts, whereas in the asymptomatic mother, the activity was not detectable in fibroblasts and was very low in lymphocytes. The absence of any clinical symptoms in the mother despite a clear MTHFR deficiency and hyperhomocystinemia emphasizes the heterogeneity of this disease.
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PMID:Methylenetetrahydrofolate reductase deficiency: prenatal diagnosis and family studies. 818 35

Swelling of proximal axon is a morphological similarity between patients with amyotrophic lateral sclerosis (ALS) and beta, beta'-iminodipropionitrile (IDPN)-injected animals. In order to investigate whether these two states have something in common biochemically with each other, we measured free amino acids (FAAs) and activities of folate-derivative converting enzymes which participate in the metabolic turnover of the folate cycle. Thirty male Wistar rats weighing about 125 g were administered intraperitoneally with 2 g/kg of IDPN. These rats and 10 control rats injected with physiological saline were sacrificed 1, 3 and 6 weeks after injection. Subsequently organs were immediately removed and stored at -80 degrees C until analyzed. FAAs were quantitated by a JLC-6AH amino acid analyzer, and activities of the enzymes were measured by established methods. Changes in FAAs were detected not only in the central and peripheral nervous systems, but also in the other tissues examined, suggesting diverse action of IDPN. Among the various changes, elevation of taurine content in the cerebrum and spinal cord seems to be important, because the same alteration has been reported in the central nervous system (CNS) of ALS patients. In relation to the increase in taurine, metabolic slowing-down of the folate cycle which has been reported in ALS was suggested from reduced activity of N5,N10-methylenetetrahydrofolate reductase (MTR), one of the three enzymes of this metabolic cycle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Free amino acids and activities of folate-derivative converting enzymes in nervous system of rats administered with beta, beta'-iminodipropionitrile]. 826 98

We describe a patient with methylenetetrahydrofolate reductase (MTHFR) deficiency in whom clinical and electrophysiologic fluctuations paralleled exacerbations of hyperhomocyst(e)inemia. MRI demonstrated abnormalities characteristic of a leukodystrophy.
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PMID:Intermittent encephalopathy, reversible nerve conduction slowing, and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency. 830 89

Plasmodium falciparum, P. knowlesi and P. chabaudi showed a significant activity of methylenetetrahydrofolate reductase (MTHFR). The presence of this enzyme completes the methionine synthesis cycle, in which the one-carbon fragment from serine side-chain can be transferred to methionine. However, while metabolic labelling of methionine from L-3 [14C]serine could not be demonstrated in P. falciparum, the significance of MTHFR was implicated by a novel pathway for salvage of exogenous 5-methyltetrahydrofolate from the host cell. The methyl group of the cofactor was incorporated into methionine, and the folate cofactor was found in the same pool as that derived from de novo synthesis with p-aminobenzoic acid as the precursor, shown previously as polyglutamylated 5-methyltetrahydrofolate. It is proposed from these results that the function of MTHFR and the methionine synthesis cycle is not the supply of methionine, but the generation of active folate cofactors from more stable precursors salvaged by the parasites.
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PMID:The methionine synthesis cycle and salvage of methyltetrahydrofolate from host red cells in the malaria parasite (Plasmodium falciparum). 835 92

It is now well-established that folic acid, taken peri-conceptionally, can reduce the risk of neural tube defects (NTDs). Recent work has demonstrated that an abnormality of homocysteine metabolism is a critical factor. The gene for 5,10 methylenetetrahydrofolate reductase, an enzyme important in homocysteine metabolism, was studied in relation to NTDs. To determine the frequency of the allele for the thermolabile form of the reductase, DNA samples were collected from people with NTDs, parents of people with NTDs, and normal controls. Of 82 people with NTDs, 15 (18.3%) were homozygous for the abnormal, thermolabile allele. This was significantly higher (p = 0.01) than the rate of 6.1% in the control population (odds ratio 3.47, 95% CI 1.28-9.41). This is the first specific genetic abnormality to be identified in NTDs. It explains the association between some NTDs and elevated homocysteine, given that the reductase is important in homocysteine metabolism. It also explains how folic acid supplementation prevents some NTDs, by overcoming a partial block in the conversion of 5,10 methylenetetrahydrofolate to 5 methyltetrahydrofolate. Genetic screening could identify women who will require folic acid supplements to reduce their risk of having a child with an NTD.
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PMID:A genetic defect in 5,10 methylenetetrahydrofolate reductase in neural tube defects. 854 60

Mild hyperhomocysteinemia is an established risk factor for cardiovascular disease. Genetic aberrations in the cystathionine beta-synthase (CBS) and methylenetetrahydrofolate reductase (MTHFR) genes may account for reduced enzyme activities and elevated plasma homocysteine levels. In 15 unrelated Dutch patients with homozygous CBS deficiency, we observed the 833T-->C (I278T) mutation in 50% of the alleles. Very recently, we identified a common mutation (677C-->T; A-->V) in the MTHFR gene, which, in homozygous state, is responsible for the thermolabile phenotype and which is associated with decreased specific MTHRF activity and elevated homocysteine levels. We screened 60 cardiovascular patients and 111 controls for these two mutations, to determine whether these mutations are risk factors for premature cardiovascular disease. Heterozygosity for the 833T-->C mutation in the CBS gene was observed in one individual of the control group but was absent in patients with premature cardiovascular disease. Homozygosity for the 677C-->T mutation in the MTHFR gene was found in (15%) of 60 cardiovascular patients and in only 6 (approximately 5%) of 111 control individuals (odds ratio 3.1 [95% confidence interval 1.0-9.2]). Because of both the high prevalence of the 833T-->C mutation among homozygotes for CBS deficiency and its absence in 60 cardiovascular patients, we may conclude that heterozygosity for CBS deficiency does not appear to be involved in premature cardiovascular disease. However, a frequent homozygous mutation in the MTHFR gene is associated with a threefold increase in risk for premature cardiovascular disease.
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PMID:Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. 855 53

Hyperhomocyst(e)inemia (HCY) is caused either by genetic or nongenetic defect(s), and the clinical severity of HCY is correlated with the biochemical abnormality. Treatment of HCY is approached on the basis of its etiology and severity of defect. The preferred method of treatment for genetic HCY is activation of mutant enzyme activity with the cofactor or the precursor of cofactor. If HCY does not respond to this treatment, pharmacological doses of betaine or folic acid should be used to enhance the alternative pathway of homocysteine turnover. Phenotypic expression of minor genetic defects, such as heterozygous cystathionine synthase deficiency and thermolabile methylenetetrahydrofolate reductase (MTHFR) can be amplified or masked by nongenetic (nutritional) factor(s). Hence, supplementation of folic acid, vitamin B-12, pyridoxine and choline to maintain their serum concentrations above low normal range may satisfactorily prevent the development of moderate HCY due to a minor genetic defect.
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PMID:Treatment of hyperhomocyst(e)inemia: physiological basis. 864 69


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