Providing one-carbon units for biological methylations: mechanistic studies on serine hydroxymethyltransferase, methylenetetrahydrofolate reductase, and methyltetrahydrofolate-homocysteine methyltransferase

1990 ◽  
Vol 90 (7) ◽  
pp. 1275-1290 ◽  
Author(s):  
Rowena G. Matthews ◽  
James T. Drummond
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Serine Hydroxymethyltransferase ◽  
Mechanistic Studies ◽  
Homocysteine Methyltransferase

scholarly journals Regulation of C1 metabolism by l-methionine in Saccharomyces cerevisiae

1972 ◽  
Vol 130 (3) ◽  
pp. 773-783 ◽  
Author(s):  
K. L. Lor ◽  
E. A. Cossins
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Methylenetetrahydrofolate Reductase ◽  
Deae Cellulose ◽  
Serine Hydroxymethyltransferase ◽  
C1 Metabolism ◽  
Formyltetrahydrofolate Synthetase ◽  
Feeding Experiments ◽  
Cellulose Column ◽  
Homocysteine Methyltransferase

1. The concentrations of folate derivatives in aerobic cultures of Saccharomyces cerevisiae (A.T.C.C. 9763) were determined by microbiological assay employing Lactobacillus casei (A.T.C.C. 7469) and Pediococcus cerevisiae (A.T.C.C. 8081). Cells cultured in media lacking l-methionine contained higher concentrations of folate derivatives than cells grown in the same media supplemented with 2.5μmol of l-methionine/ml. The concentrations of highly conjugated derivatives were also decreased by supplementing the growth medium with l-methionine. 2. DEAE-cellulose column chromatography of extracts prepared from cells grown under these conditions revealed that the concentrations of methylated tetrahydrofolates were drastically decreased by the methionine supplement. Smaller decreases were also observed in the concentrations of formylated and unsubstituted derivatives. 3. The concentrations of four enzymes of C1 metabolism were compared after 6h of growth in the presence and in the absence of l-methionine (2.5μmol/ml). The specific activities of formyltetrahydrofolate synthetase, methylenetetrahydrofolate reductase and serine hydroxymethyltransferase were not altered by this treatment but that of 5-methyltetrahydrofolate–homocysteine methyltransferase was decreased by approx. 65% when l-methionine was supplied. The activities of 5-methyltetrahydrofolate–homocysteine methyltransferase, serine hydroxymethyltransferase and formyltetrahydrofolate synthetase were not appreciably altered by l-methionine in vitro. In contrast this amino acid was found to inhibit the activity of methylenetetrahydrofolate reductase. 4. Feeding experiments employing sodium [14C]formate indicated that cells grown in the presence of exogenous methionine, although having less ability to convert formate into methionine, readily incorporated 14C into serine and the adenosyl moiety of S-adenosylmethionine. 5. It is suggested that exogenous l-methionine controls C1 metabolism in Saccharomyces principally by regulation of methyl-group biogenesis within the folate pool.

scholarly journals One-carbon metabolism in Neurospora crassa wild-type and in mutants partially deficient in serine hydroxymethyltransferase

1976 ◽  
Vol 160 (2) ◽  
pp. 305-314 ◽  
Author(s):  
E A Cossins ◽  
P Y Chan ◽  
G Combepine
Keyword(s):  
Neurospora Crassa ◽  
Mutant Strain ◽  
Methylenetetrahydrofolate Reductase ◽  
Serine Hydroxymethyltransferase ◽  
Growth Media ◽  
Wild Type ◽  
Feeding Experiments ◽  
Methylenetetrahydrofolate Dehydrogenase ◽  
In The Wild ◽  
One Carbon Metabolism

1. The concentrations of folate-dependent enzymes in Neurospora crassa Lindegren A wild type (FGSC no. 853), Ser-l mutant, strain H605a (FGSC no. 118), and for mutant, strain C-24 (FGSC no. 9), were compared during exponential growth on defined minimal media. Both mutants were partially lacking in serine hydroxymethyltransferase, but contained higher concentrations of 10-formyltetrahydrofolate synthetase than did the wild type. Mycelia of the mutants contained higher concentrations of these enzymes when growth media were supplemented with 1mM-glycine. In the wild-type, this glycine supplement also increased the specific activities of 5,10-methylenetetrahydrofolate dehydrogenase and 5,10-methylenetetrahydrofolate reductase. 5. During growth, total folate and polyglutamyl folate concentrations were greatest in the wild-type. Methylfolates were not detected in mutant Ser-l, and were only present in the for mutant after growth in glycine-supplemented media. Exogenous glycine increased folate concentration threefold in the wild type, mainly owing to increases in unsubstituted polyglutamyl derivatives. 3. Feeding experiments using 14C-labelled substrates showed that C1 units were generated from formate, glycine and serine in the wild type. Greater incorporation of 14C occurred when mycelia were cultured in glycine-supplemented media. Formate and serine were precursors of C1 units in the mutants, but the ability to cleave glycine was slight or lacking.

Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3786-3791 ◽  
Author(s):  
Christine F. Skibola ◽  
Martyn T. Smith ◽  
Alan Hubbard ◽  
Barry Shane ◽  
Abby C. Roberts ◽  
...  
Keyword(s):  
Thymidylate Synthase ◽  
Acute Lymphocytic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Univariate Analysis ◽  
Mthfr Gene ◽  
Lymphocytic Leukemia ◽  
Serine Hydroxymethyltransferase ◽  
Fold Reduction ◽  
Adult Acute Lymphocytic Leukemia ◽  
Potential Interactions

We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% CI, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% CI: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% CI, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% CI, 0.38-1.7). In addition, potential interactions between theSHMT1 and TS or MS genes were observed. TS 3R3R individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% CI, 0.0067-0.77). Further, MS 2756AG individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% CI, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage in the pathogenesis of ALL, and that genetic interactions involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk.

scholarly journals Pathogenetic Justification for the Use of Folates for the Prevention of Congenital Malformations

2017 ◽  
Vol 23 (2) ◽  
Author(s):  
V Mischenko ◽  
I Rudenko ◽  
M Holubenko ◽  
A Lavrinenko ◽  
K Tumasian
Keyword(s):  
Congenital Malformations ◽  
Methylenetetrahydrofolate Reductase ◽  
Reproductive Age ◽  
Detoxification Enzymes ◽  
Second Phase ◽  
Glutathione S Transferase ◽  
Hereditary Predisposition ◽  
Detoxification System ◽  
Folate Cycle ◽  
Homocysteine Methyltransferase

The frequency and severity of congenital malformations (CMF) do not tend to decline in modern society. CMF for etiologic factors are referred to the pathologies of a multifactorial nature. Among the many causative factors of CMF there is a hereditary predisposition.         The objective of the study was to increase the effectiveness of complex individualized prophylaxis of congenital malformations in women with polymorphic alleles of genes of folate cycle enzymes, the second phase of the detoxification system through the use of diagnostic, preventive, and therapeutic measures.         Materials and methods. 120 women of reproductive age who live in the city of Odessa and the Odessa region were examined. The alleles of the genes of the folate cycle enzymes of methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR), glutathione-S-transferase M1 (GSTM1), folate acid, cyanocobalamin were determined.         Results of the study and their discussion. The determination of the polymorphic alleles of the genes of the folate cycle enzymes of methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate homocysteine methyltransferase reductase (MTRR), glutathione-S-transferase M1 (GSTM1), low folate, cyanocobalamin indicates the presence of a hereditary predisposition to the emergence of CMF, before and during pregnancy. Polymorphism of genes that control the synthesis of GSTM1 may alter the activity of detoxification enzymes. Expression of genes of GSTM1 enzymes begins in the embryonic period. Glutathione-dependent detoxification plays a key role in disinfecting of DNA peroxides. Mistakes of metabolism, functions of the corresponding enzymes are realized by chromosomal abnormalities and the risk of the occurrence of CMF, which requires the use of antioxidant therapy before and during pregnancy.         Conclusions. It was found that a high (about 55%) frequency of the polymorphic alleles of the genes of folate cycle enzymes MTHFR (homozygous – 10.0%, heterozygous – 16.7%), 5 MTRR (homozygous 12.5%, heterozygous – 15.5%) , the second phase of the GSTM1 detoxification system (homozygous – 13.3%, heterozygous – 15.8%), the content below the reference values of folic acid in 26.7%, cyanocobalamin – in 63.4% of observations indicates a hereditary predisposition and may contribute the emergence of CMF, which explains the expediency of timely use of preventive measures including folates, antioxidants.

scholarly journals Polymorphisms in Cytoplasmic Serine Hydroxymethyltransferase and Methylenetetrahydrofolate Reductase Affect the Risk of Cardiovascular Disease in Men

2005 ◽  
Vol 135 (8) ◽  
pp. 1989-1994 ◽  
Author(s):  
Unhee Lim ◽  
Kun Peng ◽  
Barry Shane ◽  
Patrick J. Stover ◽  
Augusto A. Litonjua ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Methylenetetrahydrofolate Reductase ◽  
Serine Hydroxymethyltransferase

scholarly journals Maternal Risk for Down Syndrome Is Modulated by Genes Involved in Folate Metabolism

2012 ◽  
Vol 32 (2) ◽  
pp. 73-81 ◽  
Author(s):  
Bruna Lancia Zampieri ◽  
Joice Matos Biselli ◽  
Eny Maria Goloni-Bertollo ◽  
Hélio Vannucchi ◽  
Valdemir Melechco Carvalho ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Methylenetetrahydrofolate Reductase ◽  
Methylmalonic Acid ◽  
Folate Metabolism ◽  
Serum Folate ◽  
Vitamin B ◽  
Maternal Risk ◽  
Solute Carrier ◽  
The Impact ◽  
Homocysteine Methyltransferase

Studies have shown that the maternal risk for Down syndrome (DS) may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B12status) concentrations. The polymorphismstranscobalamin II (TCN2)c.776C>G,betaine-homocysteine S-methyltransferase (BHMT)c.742A>G,methylenetetrahydrofolate reductase (NAD(P)H) (MTHFR)c.677 C>T and theMTHFR677C-1298A-1317T haplotype modulate DS risk. The polymorphismsMTHFRc.677C>T and solute carrier family19 (folate transporter), member 1 (SLC19A1)c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms.

B-Vitamins, Methylenetetrahydrofolate Reductase (MTHFR) and Hypertension

2011 ◽  
Vol 81 (4) ◽  
pp. 240-244 ◽  
Author(s):  
Mary Ward ◽  
Carol P Wilson ◽  
J J Strain ◽  
Geraldine Horigan ◽  
John M. Scott ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Risk Factor ◽  
Low Dose ◽  
Methylenetetrahydrofolate Reductase ◽  
Genetic Determinant ◽  
Gene Encoding ◽  
Homocysteine Concentration ◽  
Homozygous Mutant ◽  
B Vitamin

Hypertension is a leading risk factor for cardiovascular disease (CVD) and stroke. A common polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), previously identified as the main genetic determinant of elevated homocysteine concentration and also recognized as a risk factor for CVD, appears to be independently associated with hypertension. The B-vitamin riboflavin is required as a cofactor by MTHFR and recent evidence suggests it may have a role in modulating blood pressure, specifically in those with the homozygous mutant MTHFR 677 TT genotype. If studies confirm that this genetic predisposition to hypertension is correctable by low-dose riboflavin, the findings could have important implications for the management of hypertension given that the frequency of this polymorphism ranges from 3 to 32 % worldwide.

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