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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of phenytoin (DPH) on folate metabolism have been studied in female Swiss Webster mice. Doses of DPH which produce steady-state plasma levels of DPH in the therapeutic range of 10-20 micrograms/ml were found to decrease plasma folate levels. In addition, the in vivo oxidation rate of [14C] formate and [2-14C] histidine to 14CO2 was increased. The increased metabolic rates were accompanied by a decrease in the hepatic activity of N5, N10-methylenetetrahydrofolate (5, 10-CH2-H4folate) reductase. N5-methyltetrahydrofolate-homocysteine transmethylase (methionine synthase); EC 2.1.1.13) activity in the liver was unchanged. The distribution of folates in the liver was determined by high-pressure liquid chromatography (HPLC) and it was found that the concentration of tetrahydrofolate (H4folate) was increased in DPH-treated mice whereas the concentration of N5-methyltetrahydrofolate was decreased. These effects were observed in mice treated with DPH for 4 days, but not in mice given a single DPH injection 24 hr previously. Decreased activity of hepatic 5, 10-CH2-H4folate reductase is postulated to account for the other effects which were observed. Decreased activity presumably results in increased tissue concentrations of 5, 10-CH2-H4folate, which is in equilibrium with its dissociation products, H4folate and formaldehyde. Increased concentrations of H4folate lead to increases in the oxidation rate of formate and histidine. These effects on folate metabolism may have important implications in the pharmacological and toxicological effects of DPH.
Mol Pharmacol 1984 May
PMID:Decreased hepatic 5, 10-methylenetetrahydrofolate reductase activity in mice after chronic phenytoin treatment. 637 25

Nitrous oxide administration to experimental animals leads to significant alterations in the hepatic folate pathway. This pathway is closely linked to the metabolism of methionine and S-adenosylmethionine (AdoMet), two compounds that play a central role in biologically important methylation reactions. This study was carried out to assess whether nitrous oxide administration to animals can affect the metabolism of AdoMet and the AdoMet-dependent methylation reactions. Exposure of rats to a mixture of nitrous oxide and oxygen (50:50) for 2 hr reduced hepatic AdoMet levels. However, when methionine was administered to these rats, hepatic AdoMet rapidly increased to levels that were significantly higher than those observed in air-exposed animals. Concomitant with this increase, there was a significant and marked increase in the rate of methylation of phospholipids and carboxymethylation of proteins. Thus, nitrous oxide, in addition to its inhibitory effect on 5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase, EC 2.1.1.13) activity, possesses another effect. It increases the rate of conversion of exogenously administered methionine into AdoMet with a subsequent increase in the rate of methylation of key cellular constituents.
Mol Pharmacol 1983 Jul
PMID:Effect of nitrous oxide and methionine treatments on hepatic S-adenosylmethionine and methylation reactions in the rat. 686 21

Chlamydomonas gametes of opposite mating types interact through flagellar adhesion molecules called agglutinins leading to a signal transduction cascade that induces cell wall loss and activation of mating structures along with other cellular responses that ultimately result in zygote formation. To identify molecules involved in these complex cellular events, we have employed subtractive and differential hybridization with cDNA from mt+ gametes activated for fertilization and non-signaling, vegetative (non-gametic) cells. We identified 55 cDNA clones whose transcripts were regulated in activated gametes. Here we report the molecular cloning and characterization of the complementary DNA (cDNA) for one clone whose transcripts in activated gametes were several-fold higher than in normal gametes. Regulation of the transcript was not related simply to protein synthesis because it was not increased in cells synthesizing new cell wall proteins. The cDNA contained a single open reading frame (ORF) of 815 amino acids encoding a polypeptide of calculated relative mass of 87 kDa. Database search analysis and sequence alignment indicated that the deduced amino acid sequence exhibited 42% identity and 62% similarity to a class of prokaryotic methyl transferases (5-methyltetrahydrofolate-homocysteine methyl transferase; EC 2.1.1.14) known to be involved in the terminal step of de novo biosynthesis of methionine. This enzyme catalyzes transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine resulting in methionine formation. Affinity-purified polyclonal antibodies raised against a bacterially produced GST-fusion protein identified a 85 kDa soluble protein in Chlamydomonas gametes. Southern blot hybridization indicated that the enzyme is encoded by a single-copy gene. The evidence presented in this paper raises the possibility that, in addition to its participation in de novo biosynthesis and regeneration of methionine, Chlamydomonas methionine synthase may play a role in adhesion-induced events during fertilization.
Plant Mol Biol 1995 Dec
PMID:Increased transcript levels of a methionine synthase during adhesion-induced activation of Chlamydomonas reinhardtii gametes. 861 21

Two cDNA clones coding for S-adenosyl-L-methionine synthase (SAMs, EC 2.5.1.6) have been isolated from a cDNA library of gibberellic acid-treated unpollinated pea ovaries. Both cDNAs were sequenced showing a high degree of identity but coding for different SAMs polypeptides. The presence of two SAMs genes in pea was further confirmed by Southern analysis. Expression of the SAMs genes in the pea plant was found at different levels in vegetative and reproductive tissues. We characterized the expression levels of SAMs genes during the development or senescence of pea ovaries. Northern analysis showed that transcription of SAMs genes in parthenocarpic fruits was upregulated by auxins in the same manner as in fruits from pollinated ovaries. In both pollinated and 2,4-dichlorophenoxyacetic acid-treated ovaries, and benzyladenine, although able to induce parthenocarpic development, did not affect SAMs mRNA levels. These data are consistent with an active participation of auxins in the upregulation of SAMs during fruit setting in pea and suggest that, at the molecular level, parthenocarpic development of pea ovaries is different for gibberellin- and cytokinin-treated ovaries than for auxin-induced parthenocarpic biosynthesis since treatment of the ovaries with aminoethoxyvinylglycine resulted in a delay of senescence and prevention of SAMs mRNA accumulation. A possible mechanism for hormonal regulation of SAMs during ovary development is discussed.
Plant Mol Biol 1996 Feb
PMID:Hormonal regulation of S-adenosylmethionine synthase transcripts in pea ovaries. 862 12

Inborn errors resulting in isolated functional methionine synthase deficiency fall into two complementation groups, cblG and cblE. Using biochemical approaches we demonstrate that one cblG patient has greatly reduced levels of methionine synthase while in another, the enzyme is specifically impaired in the reductive activation cycle. The biochemical data suggested that low levels of methionine synthase activity in the first patient may result from mutations in the catalytic domains of the enzyme, reduced transcription, or generation of unstable message or protein. Using Northern analysis, we demonstrate that the molecular basis for the biochemical phenotype in this patient is associated with greatly diminished steady-state levels of methionine synthase mRNA. The biochemical data on the second patient cell line implicated mutations specific to reductive activation, a function that is housed in the C-terminal AdoMet-binding domain and the intermediate B12-binding domain, in the highly homologous bacterial enzyme. We have detected two mutations in a compound heterozygous state, one that results in conversion of a conserved proline (1173) to a leucine residue and the other a deletion of an isoleucine residue (881). The crystal structure of the C-terminal domain of the Escherichia coli MS predicts that the Pro to Leu mutation could disrupt activation since it is embedded in a sequence that makes direct contacts with the bound AdoMet. Deletion of isoleucine in the B12-binding domain would result in shortening of a beta-sheet. Our data provide the first evidence for mutations in the methionine synthase gene being culpable for the cblG phenotype. In addition, they suggest directly that mutations in methionine synthase can lead to elevated homocysteine, implicated both in neural tube defects and in cardiovascular diseases.
Hum Mol Genet 1996 Dec
PMID:Defects in human methionine synthase in cblG patients. 896 36

Methionine synthase catalyzes the remethylation of homocysteine to methionine in a methylcobalamin-dependent reaction. We used specific regions of homology within the methionine synthase sequences of several lower organisms to clone a human methionine synthase cDNA by a combination of RT-PCR and inverse PCR. The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint identified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique. We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high frequency in the general population. We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mild hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.
Hum Mol Genet 1996 Dec
PMID:Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. 896 37

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

We report a transient drop in plasma Hcy and Cys following a single oral dose of PteGlu. The thiol change was concomitant with both the peak plasma 5CH3H4PteGlu1 level (by HPLC) and the maximum plasma Lactobacillus casei activity which reflects absorption of unmodified PteGlu. The significant reciprocal association of Hcy with radioassay RBC folate (r = -0.28, 99% CI -0.48, -0.05, P = 0.0016), serum folate (r = -0.37, 99% CI -0.56, -16, P = 0.0001), and vitamin B12 (r = -0.42, 99% CI -0.59, -21, P = 0.0001) is shown and reflects the long-term nutritional effect of B vitamins on this important, potentially atherogenic thiol. These are now well-established associations. We extend the potential for investigation of folate metabolism in health and disease by evaluating a range of new folate indices which are based on erythrocyte coenzymes. These have been looked at independently and in association with established parameters. Erythrocyte methylfolates (mono- to hexaglutamate-5CH3H4PteGlu1-6), formylfolates (tri- to pentaglutamate-5CHOH4PteGlu3-5),formiminotetrahydrofolate (formiminoH4PteGlu1), unsubstituted tetrahydrofolate (H4PteGlu1), andpara-aminobenzoylglutamate (P-ABG) have been measured by HPLC with fluorescence detection. A positive linear association exists between (i) H4PteGlu1 and radioassay RBC folate (r = 0.50, 99% CI 0. 07, 0.77, P = 0.0036), and (ii) H4PteGlu1 and tetraglutamates of both formyl- and methylfolate (r = 0.52, 99% CI 0.10, 0.78, P = 0. 0022, and r = 0.56, 99% CI 0.15, 0.80, P = 0.0009, respectively). Since, in addition, a reciprocal linear association exists between Hcy and tetraglutamyl formylfolate (r = -0.41, 99% CI -0.73, 0.05, P = 0.0206), erythrocyte tetraglutamates may be a good reflection of the bodies' active coenzyme pools. Pentaglutamyl formylfolate, the longest oligo-gamma-glutamyl chain form of this coenzyme may be a good indicator of folate depletion. The abundance of this coenzyme both increases with increasing Hcy (r = 0.55, 99% CI 0.13, 0.80, P = 0.0014) and increases as H4PteGlu1, the principle folate congener, decreases (r = -0.59, 99% CI -0.82, -0.20, P = 0.0004). Furthermore, the apparent equilibrium between substrate (5CH3H4PteGlu1) and product (H4PteGlu1) of methionine synthase is significantly associated with the abundance of 5CHOH4PteGlu5 (r = -0.53, 99% CI -0. 79, -0.11, P = 0.0018). This suggests that low methionine synthase activity for whatever reason (metabolic or dietary) may lead to an increase in the relative abundance of 5CHOH4PteGlu5. Like 5CHOH4PteGlu5, evidence is given that 5CH3H4PteGlu6, the longest oligo-gamma-glutamyl chain form of this particular coenzyme pool, may also be a good indicator of folate depletion. This is shown by a change in the relative proportion of erythrocyte methylfolate polyglutamates following supplementation with 400 microg/day PteGlu. Short-chain polyglutamates of methylfolate (5CH3H4PteGlu1--> 5CH3H4PteGlu4) increase in proportion to the total methylfolate pool, while long-chain polyglutamates of methylfolate (5CH3H4PteGlu5 and particularly 5CH3H4PteGlu6) decrease in their relative abundance.
Mol Genet Metab 1999 May
PMID:Folate-homocysteine interrelations: potential new markers of folate status. 1032 20

Periconceptual folate supplementation has been found to prevent the occurrence of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tube defects. Methionine synthase catalyzes the vitamin B(12)-dependent conversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. The observation that homocysteine and vitamin B(12) levels are independent predictors of NTD risk suggested that methionine synthase could be a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association between specific MS alleles and NTDs. We mapped the MS gene to a position between 909 and 913 cR(10000) on chromosome 1 by radiation hybrid mapping. Polymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequilibrium test. A lack of association was also observed for the D1919G missense mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population.
Mol Genet Metab 1999 Aug
PMID:Methionine synthase: high-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects. 1044 43

Methionine synthase reductase (MSR) deficiency is an autosomal recessive disorder of folate/cobalamin metabolism leading to hyperhomocysteinemia, hypo- methioninemia and megaloblastic anemia. Deficiency in MSR activity occurs as the result of a defect in the MSR enzyme, which is required for the reductive activation of methionine synthase (MS). MS itself is responsible for the folate/cobalamin-dependent conversion of homo- cysteine to methionine. We have recently cloned the cDNA corresponding to the MSR protein, a novel member of the ferredoxin-NADP(+)reductase (FNR) family of electron transferases. We have used RT-PCR, heteroduplex, single-strand conformation poly- morphism (SSCP) and DNA sequence analyses to reveal 11 mutations in eight patients from seven families belonging to the cblE complementation group of patients of cobalamin metabolism that is defective in the MSR protein. The mutations include splicing defects leading to large insertions or deletions, as well as a number of smaller deletions and point mutations. Apart from an intronic substitution found in two unrelated patients, the mutations appear singular among individuals. Of the eleven, three are nonsense mutations, allowing for the identification of two patients for whom little if any MSR protein should be produced. The remaining eight involve point mutations or in-frame disruptions of the coding sequence and are distributed throughout the coding region, including proposed FMN, FAD and NADPH binding sites. These data demonstrate a unique requirement for MSR in the reductive activation of MS.
Hum Mol Genet 1999 Oct
PMID:Molecular basis for methionine synthase reductase deficiency in patients belonging to the cblE complementation group of disorders in folate/cobalamin metabolism. 1048 69


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