Kinetic profile of overall elimination of 5-methyltetrahydropteroylglutamate in rats. (1/526)
The in vivo biliary and urinary excretion kinetics of 5-methyltetrahydropteroylglutamate (5-CH3-H4PteGlu) were studied in rats. During infusion at various rates (48-965 nmol. h-1. kg-1), the total body clearance (CLtotal) of 5-CH3-H4PteGlu could be attributed almost entirely to the sum of the biliary and urinary (CLurine,p) excretion clearances. After a 4-h infusion at the highest rate, the 5-CH3-H4PteGlu in the liver was 10 times higher than the endogenous level, whereas its polyglutamate form did not increase, suggesting that most of the infused 5-CH3-H4PteGlu is not incorporated in the polyglutamate pool but is eliminated by excretion. The parallel increase in CLtotal and CLurine,p with the increase in infusion rate might result from saturation of reabsorption at the renal proximal tubules, since the urinary excretion clearance, defined with respect to the kidney concentration, also increased while the biliary excretion clearance, defined with respect to the liver concentration, remained almost constant. We conclude that the hepatobiliary excretion is a relatively low-affinity process with a constant clearance, whereas the renal tubular reabsorption is saturated at higher plasma 5-CH3-H4PteGlu concentration ( approximately 0.5 microM). Urinary excretion becomes the predominant elimination route for any excess 5-CH3-H4PteGlu in the body. (+info)Control of expression of one-carbon metabolism genes of Saccharomyces cerevisiae is mediated by a tetrahydrofolate-responsive protein binding to a glycine regulatory region including a core 5'-CTTCTT-3' motif. (2/526)
Expression of yeast genes involved in one-carbon metabolism is controlled by glycine, by L-methionine, and by nitrogen sources. Here we report a novel control element containing a core CTTCTT motif mediating the glycine response, demonstrating that a protein binds this element, that binding is modulated by tetrahydrofolate, and that folate is required for the in vivo glycine response. In an heterologous CYC1 promoter the region needed for the glycine response of GCV2 (encoding the P-subunit of glycine decarboxylase) mediated repression that was relieved by glycine. It was also responsible for L-methionine control but not nitrogen repression. GCV1 and GCV3 have an homologous region in their promoters. The GCV1 region conferred a glycine response on an heterologous promoter acting as a repressor or activator depending on promoter context. A protein was identified that bound to the glycine regulatory regions of GCV1 and GCV2 only if the CTTCTT motif was intact. This protein protected a 17-base pair CATCN7CTTCTT region of GCV2 that is conserved between GCV1 and GCV2. Protein binding was increased by tetrahydrofolate, and use of a fol1 deletion mutant indicated the involvement of a folate in the in vivo glycine response. Tetrahydrofolate or a derivative may act as a ligand for the transcription factor controlling expression of one-carbon metabolism genes. (+info)The energy conserving methyltetrahydromethanopterin:coenzyme M methyltransferase complex from methanogenic archaea: function of the subunit MtrH. (3/526)
In methanogenic archaea the transfer of the methyl group of N5-methyltetrahydromethanopterin to coenzyme M is coupled with energy conservation. The reaction is catalyzed by a membrane associated multienzyme complex composed of eight different subunits MtrA-H. The 23 kDa subunit MtrA harbors a corrinoid prosthetic group which is methylated and demethylated in the catalytic cycle. We report here that the 34 kDa subunit MtrH catalyzes the methylation reaction. MtrH was purified and shown to exhibit methyltetrahydromethanopterin:cob(I)alamin methyltransferase activity. Sequence comparison revealed similarity of MtrH with MetH from Escherichia coli and AcsE from Clostridium thermoaceticum: both enzymes exhibit methyltetrahydrofolate:cob(I)alamin methyltransferase activity. (+info)Folate and homocysteine metabolism in copper-deficient rats. (4/526)
To investigate the effect of copper deficiency on folate and homocysteine metabolism, we measured plasma, red-cell and hepatic folate, plasma homocysteine and vitamin B-12 concentrations, and hepatic methionine synthase activities in rats. Two groups of male Sprague-Dawley rats were fed semi-purified diets containing either 0. 1 mg (copper-deficient group) or 9.2 mg (control group) of copper per kg. After 6 weeks of dietary treatment, copper deficiency was established as evidenced by markedly decreased plasma and hepatic copper concentrations in rats fed the low-copper diet. Plasma, red-cell, hepatic folate, and plasma vitamin B-12 concentrations were similar in both groups, whereas plasma homocysteine concentrations in the copper-deficient group were significantly higher than in the control group (P<0.05). Copper deficiency resulted in a 21% reduction in hepatic methionine synthase activity as compared to the control group (P<0.01). This change most likely caused the increased hepatic 5-methyltetrahydrofolate and plasma homocysteine concentrations in the copper-deficient group. Our results indicate that hepatic methionine synthase may be a cuproenzyme, and plasma homocysteine concentrations are influenced by copper nutriture in rats. These data support the concept that copper deficiency can be a risk factor for cardiovascular disease. (+info)The crystal structure of a bacterial, bifunctional 5,10 methylene-tetrahydrofolate dehydrogenase/cyclohydrolase. (5/526)
The structure of a bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase/cyclohydrolase from Escherichia coli has been determined at 2.5 A resolution in the absence of bound substrates and compared to the NADP-bound structure of the homologous enzyme domains from a trifunctional human synthetase enzyme. Superposition of these structures allows the identification of a highly conserved cluster of basic residues that are appropriately positioned to serve as a binding site for the poly-gamma-glutamyl tail of the tetrahydrofolate substrate. Modeling studies and molecular dynamic simulations of bound methylene-tetrahydrofolate and NADP shows that this binding site would allow interaction of the nicotinamide and pterin rings in the dehydrogenase active site. Comparison of these enzymes also indicates differences between their active sites that might allow the development of inhibitors specific to the bacterial target. (+info)The amino-terminal region of the Escherichia coli T-protein of the glycine cleavage system is essential for proper association with H-protein. (6/526)
T-protein is a component of the glycine cleavage system and catalyzes the tetrahydrofolate-dependent reaction. Our previous work on Escherichia coli T-protein (ET) showed that the lack of the N-terminal 16 residues caused a loss of catalytic activity [Okamura-Ikeda, K., Ohmura, Y., Fujiwara, K. and Motokawa, Y. (1993) Eur. J. Biochem. 216, 539-548]. To define the role of the N-terminal region of ET, a series of deletion mutants were constructed by site-directed mutagenesis and expressed in E. coli. Deletions of the N-terminal 4, 7 and 11 residues led to reduction in the activity to 42, 9 and 4%, respectively, relative to the wild-type enzyme (wtET). The mutant with 7-residue deletion (ETDelta7) was purified and analyzed. ETDelta7 exhibited a marked increase in Km (25-fold) for E. coli H-protein (EH) accompanied by a 10-fold decrease in kcat compared with wtET, indicating the importance of the N-terminal region in the interaction with EH. The role of this region in the ET-EH interaction was investigated by cross-linking of wtET-EH or ETDelta7-EH complex with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, a zero-length cross-linker, in the presence of folate substrates. The resulting tripartite cross-linked products were cleaved with lysylendopeptidase and V8 protease. After purification by reversed-phase HPLC, the cross-linked peptides were subjected to Edman sequencing. An intramolecular cross-linking between Asp34 and Lys216 of wtET which was not observed in wtET alone and an intermolecular cross-linking between Lys288 of wtET and Asp-43 of EH were identified. In contrast, no such cross-linking was detected from the cross-linked product of ETDelta7. These results suggest that EH, when it interacts with ET, causes a change in conformation of ET and that the N-terminal region of ET is essential for the conformational change leading to the proper interaction with EH. (+info)Bioactivity of orally administered unnatural isomers, [6R]-5-formyltetrahydrofolate and [6S]-5,10-methenyltetrahydrofolate, in humans. (7/526)
It has been assumed that humans cannot utilize 5,6,7,8-tetrahydrofolates with the unnatural configuration at carbon 6, since these folates are enzymatically and microbiologically inactive. We hypothesized that orally administered unnatural [6R]-5-formyltetrahydrofolate or [6S]-5,10-methenyltetrahydrofolate is bioactive in humans. Subjects were given independent oral doses of these unnatural folates and of a natural [6S]-5-formyltetrahydrofolate. Plasma, before and after the dose for 4 h, and 2 h urine were collected. Areas under the curve for the change in plasma folate concentrations were measured microbiologically and urinary folates were measured using HPLC. Based on findings of plasma and urinary folates, the unnatural folates were estimated to be 14-50% active as compared to [6S]-5-formyltetrahydrofolate. The major plasma and urinary folate was [6S]-5-methyltetrahydrofolate in all experiments. In urine, a [6S]-5-formyltetrahydrofolate peak was observed only after a [6S]-5-HCO-H4folate dose and peaks of unnatural [6S]-10-formyltetrahydrofolate and 5-formyltetrahydrofolate were identified after a [6R]-5-formyltetrahydrofolate dose. A possible pathway that explains our findings is discussed. This pathway includes the oxidation of the unnatural [6S]-10-formyltetrahydrofolate to 10-formyl-7,8-dihydrofolate which can be further metabolized by 5-amino-4-imidazolecarboxamide-ribotide transformylase producing dihydrofolate. Dihydrofolate can then be metabolized to [6S]-5-methyltetrahydrofolate by well-established metabolism. (+info)Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. (8/526)
Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. BACKGROUND: Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients. METHODS: In a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin. RESULTS: Folinic acid and pyridoxine i.v. supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse effects attributable to folinic acid treatment were observed during this time. CONCLUSIONS: Intravenous folinic acid therapy (50 mg) once per week associated with pyridoxine supplementation appears to be an effective and safe strategy to normalize plasma tHcy levels in the majority of chronic HD patients. (+info)Tetrahydrofolates (THFs) are a type of folate, which is a form of vitamin B9. Folate is essential for the production and maintenance of new cells, especially in DNA synthesis and methylation. THFs are the active forms of folate in the body and are involved in various metabolic processes, including:
1. The conversion of homocysteine to methionine, an amino acid required for protein synthesis and the formation of S-adenosylmethionine (SAM), a major methyl donor in the body.
2. The transfer of one-carbon units in various metabolic reactions, such as the synthesis of purines and pyrimidines, which are essential components of DNA and RNA.
3. The remethylation of homocysteine to methionine, a process that helps maintain normal homocysteine levels in the body. Elevated homocysteine levels have been linked to an increased risk of cardiovascular disease.
THFs can be obtained from dietary sources, such as leafy green vegetables, legumes, and fortified cereals. They can also be synthesized endogenously in the body through the action of the enzyme dihydrofolate reductase (DHFR), which reduces dihydrofolate (DHF) to THF using NADPH as a cofactor.
Deficiencies in folate or impaired THF metabolism can lead to various health issues, including megaloblastic anemia, neural tube defects during fetal development, and an increased risk of cardiovascular disease due to elevated homocysteine levels.
Tetrahydrofolate riboswitch
Tetrahydrofolate synthase
Formate-tetrahydrofolate ligase
Trimethylsulfonium-tetrahydrofolate N-methyltransferase
Dihydrofolate reductase
Methionine synthase
Levomefolic acid
MTHFD1L
Methylenetetrahydrofolate reductase
Glutamate formimidoyltransferase
Immunosuppressive drug
Riboswitch
Fluorodeoxyuridylate
MTHFD2L
Vitamin B12 deficiency
Tetrahydrofolic acid
Aminopterin
Pfl RNA motif
Methotrexate
MTHFD2
MTHFD1
Folate
FolE RNA motif
Chemotherapy
Formyltetrahydrofolate dehydrogenase
Vitamer
Serine hydroxymethyltransferase
Proguanil
Cyclodeaminase domain
Epigenetics of autism
Tetrahydrofolate riboswitch - Wikipedia
4QPD: Crystal structure of the hydrolase domain of 10-formyltetrahydrofolate dehydrogenase (wild-type) complex with...
6SJS: Methyltransferase of the MtgA N227A mutant from Desulfitobacterium hafniense in complex with methyl-tetrahydrofolate
FOLFMS E
4033-27-6 | Tetrahydrofolate Impurity F - Anax Laboratories
Leucovorin Injection: MedlinePlus Drug Information
Thiaville2016 - Folate pathway model (PanB overexpression) | BioModels
Thrombophilias in Pregnancy: Practice Essentials, Pathophysiology, Epidemiology
Fungal methionine synthase Met6p transfers a methyl group from 5-methyl-tetrahydrofolate to - Proteases & Other Enzymes Pathways
Quercetin Increases Hepatic Homocysteine Remethylation and Transsulfuration in Rats Fed a Methionine-Enriched Diet
Methylene tetrahydrofolate Reductase Enzyme Level and Antioxidant Activity in Women with Gestational Hypertension and Pre...
Genes | Free Full-Text | Impacts of the Type I Toxin-Antitoxin System, SprG1/SprF1, on Staphylococcus aureus Gene Expression
Rate and extent of interconversion of tetrahydrofolate cofactors to dihydrofolate after cessation of dihydrofolate reductase...
Genetic Variability of Methyl-Tetrahydrofolate-Reductase Modifies eNOS Coupling in Human Arteries and Veins: Effects on...
5-Methyl-tetrahydrofolate acid improves endothelial function and decreases superoxide production by improving eNOS coupling and...
Sp1 trans-activation of cell cycle regulated promoters is selectively repressed by Sp3
Frontiers | The influence of early environment and micronutrient availability on developmental epigenetic programming: lessons...
Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised...
Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis? |...
Advanced Search Results - Public Health Image Library(PHIL)
KEGG PATHWAY: One carbon pool by folate - Streptomyces avermitilis
Gyromitra Mushroom Toxicity Treatment & Management: Prehospital Care, Emergency Department Care, Consultations
KEGG GENOME: Enterobacter hormaechei subsp. hoffmannii ECR091
L-(+)-glutamine | C5H10N2O3 | ChemSpider
Biochem Exam 3, part 2 Flashcards
BJOC - Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in...
SCOP 1.71: Species: Human (Homo sapiens)
Evidence for Two Molecular Species of Dihydrofolate Reductase in Amethopterin Resistant and Sensitive Cells of the Mouse...
CATH Domain 1jbvA02
Monther Abu-Remaileh | Stanford Medicine
Folate8
- The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). (nih.gov)
- Methylene-tetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. (nih.gov)
- 5-formyl tetrahydrofolate, aka Folinic Acid, is the natural, active coenzyme form of folate. (lifeseasons.com)
- Both 5- methyl tetrahydrofolate (5-MTHF) and 5- formyl tetrahydrofolate (5-FTHF) are considered the metabolically active forms of folate. (lifeseasons.com)
- Five folate forms, 5-methyltetrahydrofolate, folic acid, tetrahydrofolate, 5-formyltetrahydrofolate, 5,10-methenyltetrahydrofolate, and an oxidation product of 5-methyltetrahydrofolate called MeFox (pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyltetrahydrofolate) are measured by isotope-dilution high performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) (Fazili, et al. (cdc.gov)
- 4. Molecular genetic analysis of Saccharomyces cerevisiae C1-tetrahydrofolate synthase mutants reveals a noncatalytic function of the ADE3 gene product and an additional folate-dependent enzyme. (nih.gov)
- However, the folate-dependent cleavage of serine can be described by either the same retroaldol mechanism with formaldehyde as an enzyme-bound intermediate or by a nucleophilic displacement mechanism in which N5 of tetrahydrofolate displaces the C3 hydroxyl of serine, forming a covalent intermediate. (rcsb.org)
- The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate. (cathdb.info)
Coenzyme2
- DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. (nih.gov)
- These results indicated that C-3 of glyphosate was at some point metabolized to a C-1 compound whose ultimate fate could be both oxidation to CO2 and distribution to amino acids and nucleic acid bases that receive a C-1 group from the C-1-donating coenzyme tetrahydrofolate. (nih.gov)
Dehydrogenase1
- The tetrahydrofolate cycle was reconstructed by utilizing Methylobacterium extorquens formate-THF ligase, methenyl-THF cyclohydrolase, and methylene-THF dehydrogenase. (phys.org)
Dihydrofolate to tetrahydrofolate2
- Methotrexate is an allosteric inhibititor of dihydrofolate reductase (DHFR), the enzyme that catalyzes the conversion of dihydrofolate to tetrahydrofolate. (sigmaaldrich.com)
- Trimethoprim (TMP) prevents reduction of dihydrofolate to tetrahydrofolate. (msdmanuals.com)
Methylenetetrahydrofolate2
- DMGDH binds tetrahydrofolate (THF) in vivo, which serves as an acceptor of formaldehyde and in the cell the product of the reaction is 5,10-methylenetetrahydrofolate instead of formaldehyde. (nih.gov)
- A one-carbon group transferase that transfers lipoamide-linked methylamine groups to tetrahydrofolate (TETRAHYDROFOLATES) to form methylenetetrahydrofolate and AMMONIA. (ucdenver.edu)
Leucovorin1
- Levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF) and are able to bypass DHFR reduction to act as a cellular replacement for the co-factor THF. (rcsb.org)
Folic2
- L5744] In order to function within the body, folic acid must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). (rcsb.org)
- ThorneVet's Basic B Complex contains the entire B-complex, including the activated forms of vitamin B2 (riboflavin 5'-phosphate), vitamin B6 (pyridoxal 5'-phosphate), folic acid (folinic acid and L-5-methyl-tetrahydrofolate), and vitamin B12 (adenosylcobalamin and methylcobalamin), as well as 80 mg choline citrate. (onlynaturalpet.com)
Glycine4
- 20. 13C nuclear magnetic resonance detection of interactions of serine hydroxymethyltransferase with C1-tetrahydrofolate synthase and glycine decarboxylase complex activities in Arabidopsis. (nih.gov)
- Serine hydroxymethyltransferase (SHMT) catalyzes the reversible interconversion of serine and glycine with tetrahydrofolate serving as the one-carbon carrier. (rcsb.org)
- As the first step, N5 of tetrahydrofolate makes a nucleophilic attack on C3 of serine, breaking the C2-C3 bond to form N5-hydroxymethylenetetrahydrofolate and an enzyme-bound glycine anion. (rcsb.org)
- The metabolic pathway that efficiently converts formic acid and CO 2 into pyruvate was constructed by the combined use of the tetrahydrofolate cycle and reverse glycine cleavage reaction. (phys.org)
Reductase1
- Polymorphisms of methylene-tetrahydrofolate reductase and risk of lung cancer: a case-control study. (nih.gov)
Putative1
- 2. Site-directed mutagenesis of a highly conserved aspartate in the putative 10-formyl-tetrahydrofolate binding site of yeast C1-tetrahydrofolate synthase. (nih.gov)
Inhibition1
- It demonstrates synergy with sulfonamides, potentiating inhibition of bacterial tetrahydrofolate production. (medscape.com)
Enzymes involved1
- 8. A general method for generation and analysis of defined mutations in enzymes involved in a tetrahydrofolate-interconversion pathway. (nih.gov)
Metabolic1
- 18. Whole-cell detection by 13C NMR of metabolic flux through the C1-tetrahydrofolate synthase/serine hydroxymethyltransferase enzyme system and effect of antifolate exposure in Saccharomyces cerevisiae. (nih.gov)
Metabolism3
- 12. Regulation of expression of the ADE3 gene for yeast C1-tetrahydrofolate synthase, a trifunctional enzyme involved in one-carbon metabolism. (nih.gov)
- tetrahydrofolate) and stopping one carbon metabolism needed for the synthesis of DNA in rapidly dividing cells. (cdc.gov)
- Expression of Formate-Tetrahydrofolate Ligase Did Not Improve Growth but Interferes With Nitrogen and Carbon Metabolism of Synechocystissp. (mpg.de)
Reduces1
- 13. Nitrous oxide exposure reduces hepatic C1-tetrahydrofolate synthase expression in rats. (nih.gov)
Expression1
- 9. Characterization of the rat cytoplasmic C1-tetrahydrofolate synthase gene and analysis of its expression in liver regeneration and fetal development. (nih.gov)
Active1
- 5. Site-directed mutagenesis of yeast C1-tetrahydrofolate synthase: analysis of an overlapping active site in a multifunctional enzyme. (nih.gov)
Function1
- 3. Function of yeast cytoplasmic C1-tetrahydrofolate synthase. (nih.gov)
Supports1
- 11. Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos. (nih.gov)
Human3
- 6. Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase. (nih.gov)
- 7. Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. (nih.gov)
- 16. Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform. (nih.gov)