Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The Salmonella typhimurium LT2 metF gene, encoding 5,10-methylenetetrahydrofolate reductase, has been cloned. Strains with multicopy plasmids carrying the metF gene overproduce the enzyme 44-fold. The nucleotide sequence of the metF gene was determined, and an open reading frame of 888 nucleotides was identified. The polypeptide deduced from the DNA sequence contains 296 amino acids and has a molecular weight of 33,135 daltons. Mung bean nuclease mapping experiments located the transcription start point and possible transcription termination region for the gene. There is a 25 bp nucleotide sequence between the translation termination site and the possible transcription termination region. This region possesses a GC-rich sequence that could form a stable stem and loop structure once transcribed (delta G = -9 kcal/mol), followed by an AT-rich sequence, both of which are characteristic of rho-independent transcription terminators. The nucleotide and deduced amino acid sequences of the S. typhimurium metF gene are compared with the corresponding sequences of the Escherichia coli metF gene. The nucleotide sequences show 85% homology. Most of the nucleotide differences found do not alter the amino acid sequences, which show 95% homology. The results also show that a change has occurred in the metF region of the S. typhimurium chromosome as compared to the E. coli chromosome.
Mol Gen Genet 1988 May
PMID:Cloning and nucleotide sequence of the Salmonella typhimurium LT2 metF gene and its homology with the corresponding sequence of Escherichia coli. 284 68

Among various ubiquinone (Q) isoprenologues tested, only Q7 was more efficient than menadione in promoting the oxidation of 5-methyltetrahydrofolate (CH3FH4) by 5,10-methylenetetrahydrofolate reductase isolated from adult Brugia pahangi, whereas Q10 was the best cofactor in the same reaction catalysed by the analogous enzyme from adult Dirofilaria immitis. Menoctone (3-[1-cyclohexyloctyl] -2-hydroxy-1,4-naphthoquinone) was a strong competitive inhibitor of both these ubiquinone isoprenologues in the respective reactions. When incubated in the presence of D,L-[14C]-mevalonate, adult B. pahangi and D. immitis synthesized radiolabelled Q9 only, in addition to other isoprenoid derivatives in the neutral lipid fraction. In view of the inability of Q9 to promote the oxidation of CH3FH4 by 5,10-methylenetetrahydrofolate reductase from B. pahangi, it seems unlikely that this filaria uses Q9 as a cofactor in this reaction. Conceivably, D. immitis could use Q9 as a cofactor in its enzymatic oxidation of CH3FH4, since in this circumstance, it was a better cofactor than menadione.
Mol Biochem Parasitol 1981 Apr
PMID:Synthesis of ubiquinone 9 by adult Brugia pahangi and Dirofilaria immitis: evidence against its involvement in the oxidation of 5-methyltetrahydrofolate. 724 67

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%).
Mol Genet Metab 1998 Jul
PMID:A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. 1060 82

A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.
Mol Psychiatry 1998 Sep
PMID:C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. 1020 43

Periconceptional folate prevents neural tube defects (NTD) by a mechanism which is unclear. The present study found significant changes in the equilibrium of the homocysteine remethylation cycle in NTD affected mothers, possibly involving B12-dependent methionine synthase or 5,10-methylenetetrahydrofolate reductase. Data were consistent with impaired Hcy remethylation leading to poor regeneration of H4PteGlu1, the main intracellular precursor of all folates. This lesion leads to cellular folate deficiency indicated by a significantly lower radioassay RBC folate and 5CH3H4PteGlu4 in affected mothers. The drop in this tetraglutamate is associated with an increase in the abundance of longer chain oligo-gamma-glutamyl folate, again reflecting the underlying folate deficiency. This effect may compromise purine, DNA-thymine, and methionine production, particularly during embryogenesis when folate demand is high. At this time serine hydroxymethyltransferase may play a critical role in conserving H4PteGlu1 for purine synthesis. Many of these depletion effects were corrected with folate supplementation for 1 month.
Mol Genet Metab 1998 Sep
PMID:Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy. 978 91

Elevated homocysteine is an independent risk factor for cardiovascular disease and has been associated with a common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Estrogen use has been shown to reduce homocysteine concentrations, suggesting that this might contribute to the cardiovascular benefit of hormone replacement therapy. We examined 90 postmenopausal women to determine if MTHFR genotype affected the response of homocysteine to hormone replacement therapy. Women with the TT genotype did not show decreased homocysteine in response to hormone replacement therapy as demonstrated for women with the CC genotype and may receive decreased cardiovascular benefits from hormone replacement therapy.
Mol Genet Metab 1999 May
PMID:The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy. 1032 22

A common mutation in methylenetetrahydrofolate reductase (MTHFR), a homocysteine metabolic pathway enzyme, has been associated with increased homocysteine levels and increased risk for premature cardiovascular disease. The purpose of this study was to assess the association between the prevalence of the MTHFR mutation, hyperhomocysteinemia, and subtypes of ischemic stroke in an elderly population comprised of three age-balanced groups of patients. The presence of the C677T MTHFR mutation was determined by a direct polymerase chain reaction-based assay performed on blood samples from 136 patients with acute ischemic stroke, 95 patients with atherosclerotic risk factors for stroke (including some with a history of previous stroke or transient ischemic attack), and 52 healthy control subjects. The prevalence of the homozygous C677T mutation was not significantly higher in the elderly stroke patients (7%) than in the atherosclerotic risk (8%) or healthy elderly control (2%) groups. Plasma homocysteine levels were higher in the acute stroke patient group (14.5+/-4.5 micromol/L) and atherosclerotic risk patient group (14.6+/-6.2 micromol/L) compared with the control subjects (10.3+/-3.1 micromol/ L, P < 0.03). Homozygotes for the C677T MTHFR mutation did not have significantly higher homocysteine levels than non-homozygotes. Moderate hyperhomocysteinemia, though common in older patients with ischemic cerebrovascular disease, is not attributable, at least in this patient group, to a higher prevalence of the C677T MTHFR mutation.
Diagn Mol Pathol 1999 Mar
PMID:Role of a common mutation in the homocysteine regulatory enzyme methylenetetrahydrofolate reductase in ischemic stroke. 1040 94

A total of 821 women of Hispanic descent aged 21-65 years, were screened for total and high density lipoprotein (HDL) cholesterol through outpatient clinics and public screening. Of this group, 78 were invited back for further testing because they had a total cholesterol/HDL cholesterol ratio exceeding 4.5 indicative of high risk for cardiovascular disease. Written consent and a fasting blood sample was obtained from these women, and tested for serum homocysteine. The concentrations for 77 of the 78 women (mean 8. 40+/-2.24, range 4.21-13.99 micromol/l) were within the pre-established normal range for women. One subject had an exceptionally high homocysteine concentration of 137 micromol/l. This subject subsequently developed a stroke and has been institutionalized since that time. Blood from the subject and immediate family members were tested for the 5'-10'-methylenetetrahydrofolate reductase (MTHFR) polymorphism. The subject and her children were both hyperhomocysteinemic and heterozygous for the mutation. One of the children also had a low vitamin B12 concentration in blood. Although the high homocysteine and cardiovascular risk in these subjects were likely due to a dietary deficiency of the vitamins, the MTHFR mutation may have also been a contributing factor. With the availability of rapid assays, screening blood for homocysteine in subjects deemed at high risk for cardiovascular disease may be justified.
Int J Mol Med 1999 Sep
PMID:Homocysteine screening of a female Hispanic population. 1042 82

Impairment of folate and cobalamin (vitamin B(12)) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C-->T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A-->G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95% CI 0.58-14.8). This study provides the first genetic link between vitamin B(12) deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted.
Mol Genet Metab 1999 Aug
PMID:A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. 1044 42

Background: Elevated levels of homocysteine are an independent risk factor for venous thrombosis. A common mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile (tl-) enzyme with reduced activity that may predispose to hyperhomocysteinemia. Methods and Results: To assess whether this common mutation is a risk factor venous thromboembolism, a polymerase chain reaction-based genotyping assay was used to compare the prevalence of this mutation in a group with thrombosis versus several control groups. Of the 331 thrombosis subjects, 47% were heterozygous and 11% homozygous for tl-MTHFR. In comparison, heterozygotes constituted 42-47% and homozygous 15-16% of each of three control groups (totaling 593 subjects). There was no significant difference in the tl-MTHFR homozygote frequency or allele frequency between the thrombosis and control study groups. Although the prevalence of the factor V R506Q (Leiden) mutation causing activated protein C resistance was significantly higher in the thrombosis (19%) than in the control groups (4-9%), the concomitant presence of tl-MTHFR with factor V R506Q did not contribute to any excess thrombotic risk. Conclusions: Although the tl-MTHFR mutation may predispose to hyperhomocysteinemia, a known risk factor for venous thrombosis, this common genotype is not a direct genetic risk factor for venous thrombosis, either alone or in combination with the factor V R506Q mutation.
Mol Diagn 1997 Mar
PMID:Risk of Venous Thrombosis in Carriers of a Common Mutation in the Homocysteine Regulatory Enzyme Methylenetetrahydrofolate Reductase. 1046 93


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