Tetrahydrofolate

11 Key excerpts on "Tetrahydrofolate"

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  B Vitamins and Folate

  Chemistry, Analysis, Function and Effects

  • Victor R Preedy(Author)
  • 2012(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  In: Barness, L., and Oski, F. (ed.) Advances in Pediatrics . Medical Book Publishers, Chicago, IL, USA, pp. 1–21. Wolffe, A., 1998. Chromatin , 3th edition. Academic Press, San Diego, CA, USA, pp. 1–447. Zempleni, J., Wijeratne, S.S., and Hassan, Y.I., 2009. Biotin. BioFactors . 35: 36–46. Zempleni, J., Li, Y., Xue, J., and Cordonier, E.L., 2011. The role of holo-carboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. Epigenetics . 6: 892–894. 157 Biochemistry of Biotin CHAPTER 11 The Chemistry of Folate ABALO CHANGO Institut Polytechnique Lasalle Beauvais, 19 rue Pierre Waguet, F-60026 Beauvais Cedex, France Email: [email protected] 11.1 Introduction A nutritional factor in yeast that both prevented and cured macrocytic anaemia in pregnant women was first described by Lucy Wills in 1931. Folic acid received its name in 1941 when isolated from spinach as a growth factor for Streptococcus lactis (Mitchell et al. 1941). Various investigators investigating this growth factor also referred to it as vitamin M, vitamin B 9 , vitamin Bc, folic acid or folate (Whiteley 1971). The word ‘folate’ comes from the Latin word folium , which means leaf. Folate refers to all pteroylglutamates possessing vitamin activity. ‘Folic acid’ and ‘folate’ are the preferred synonyms for pter-oylglutamic acid (PteGlu) and pteroylglutamate, respectively. The biochemical functions of folate were first determined with bacteria. Folate plays a major role in carrying one-carbon units within cells. In the brush border of mucosal cells, the polyglutamyl chain is removed by the enzyme folate conjugase and folate monoglutamate is subsequently absorbed. Folate acts as both a donor and receiver of one-carbon moieties in a variety of reactions. The chemistry and biochemistry of folate have been extensively discussed in several excellent reviews.

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  Oxidative Stress and Age-Related Neurodegeneration

  • Yuan Luo, Lester Packer, Enrique Cadenas(Authors)
  • 2005(Publication Date)
  • CRC Press

    (Publisher)

  5-methylTetrahydrofolate (5-MTHF), which is involved in HCY metabolism, and methylidyneTetrahydrofolate, involved in purine synthesis and in the generation of thymine side chains for incorporation into DNA. 5,12,13 . With relevance to the transmethylation pathway, methylene THF produces 5-MTHF in a reaction catalyzed by methylene Tetrahydrofolate reductase (MTHFR) (Figure 25.1, Reaction 4). Variations in the gene encoding for that enzyme can result in decreased folate metabolism, which increases HCY levels and the risk of neural tube defects. Patients with congenital MTHFR deficiency have reduced levels of several important Interaction between Dietary and Genetic Deficiencies 445 NADPH + H + NADP + Diet intake (Circulating folate) Folate Cystathionine Cysteine 5, 10 Methylene SAM SAH 5-MeTHF PPi + Pi ATP CH 3 CH 3 -Ac Adenosyl -KB GSH GS-SG 2H 2 O GR; Rx-13 GS; Rx-11 GPx; Rx-12 CBS/Vit B6; Rx-9 MS/Vit B12; Rx-5 MTHFR; Rx-4 MAT; Rx-6 SAHH; Rx-8 SAMT; Rx-7 GSH-E-CDNB GsT(E); Rx-14 CDNB E + P Serine NADPH + H + NADP + FR; Rx-1 Dihydrofolate THF NADPH + H + NADP + DR; Rx-2 Serine Glycine HMT; Rx-3 Homocysteine C L; Rx-10 H 2 O 2 Choline Betaine Acetylcholine Acetyl-CoA Methionine ChaT,Rx15 FIGURE 25.1 Pathway regulating homocysteine elimination and glutathione metabolism in the brain. biological metabolites, such as methionine and S -adenosylmethionine (SAM), in the cerebrospinal fluid (CSF), and show demyelination in the brain, which might be due to decreased methylation. 13 Polymorphisms in 5,10-MTHFR that exhibit decreased activity are present in as much as 20% of some populations. 14 Diminished activity of this enzyme also reduces production of THF (required for DNA synthesis) and reduced adenosylmethionine (required for DNA methylation; 15 ). Notably, a 36% increase in MTHFR polymorphisms has recently been reported among young peo-ple.

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  Advanced Nutrition

  Micronutrients

  • (Author)
  • 2014(Publication Date)
  • Library Press

    (Publisher)

  It must be noted that NTDs occur early in pregnancy (first month), therefore women must have abundant folate upon conception. Folate is required to make red blood cells and white blood cells and folate deficiency may lead to anemia, which further leads to fatigue and weakness and inability to concentrate. Biochemistry of DNA base and amino acid production Metabolism of folic acid to produce methyl-vitamin B 12 In the form of a series of Tetrahydrofolate (THF) compounds, folate derivatives are substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′ -deoxythymidine-5′ -phosphate) from dUMP (2′ -deoxyuridine-5′ -phosphate). It is a substrate for an important reaction that involves vitamin B 12 and it is necessary for the synthesis of DNA, and so required for all dividing cells. The pathway leading to the formation of Tetrahydrofolate (FH 4 ) begins when folate (F) is reduced to dihydrofolate (DHF) (FH 2 ), which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B 3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. Methylene-THF (CH 2 FH 4 ) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahy-drofolate (CH 3 -THF) can be made from methylene-THF by reduction of the methylene group with NADPH. It is important to note that Vitamin B 12 is the only acceptor of ________________________ WORLD TECHNOLOGIES ________________________ methyl-THF. There is also only one acceptor for methyl-B 12 , which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is important because a defect in homocysteine methyltransferase or a deficiency of B 12 can lead to a methyl-trap of THF and a subsequent deficiency. Thus, a deficiency in B 12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.

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  Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System

  Proceedings of an International Round Table on Adenosylmethionine and the Central Nervous System, Naples, Italy, May 1978

  • Vincenzo Zappia, Earl Usdin, Francesco Salvatore, Vincenzo Zappia, Earl Usdin, Francesco Salvatore(Authors)
  • 2013(Publication Date)
  • Pergamon

    (Publisher)

  The Relation Between Folate and Adenosylmethionine Metabolism in Brain Anthony J. Turner, Andrew G. M. Pearson and Robert J. Mason Department of Biochemistry, University of Leeds, 9 Hyde Terrace, Leeds LS2 9LS. England Adenosyl methionine is the sole methyl donor in all methyl transfer reactions, except those resulting in the biosynthe-sis of methionine. Giulio Cantoni, 1952 The addition or removal of a non-carbon group from biological compounds is a common metabolic occurrence and, of the groups involved in such transfer reactions, carbon dioxide is the species most often used. However, where the transfer of one-carbon groups at different oxidation states is required, the intracellular pool of folates is called into play. Derivatives of Tetrahydrofolate (FH4) function as cofactors in a variety of biologically important transformations including nucleotide metab-olism, amino acid metabolism and the biosynthesis of methyl groups. The question posed in this review is whether N^-methyl FH4 (CH3FH4) functions only in the pro-vision of methyl groups for methionine biosynthesis or whether it may act directly in neurotransmitter methylation processes in brain. ENZYMOLOGY OF FOLATE METABOLISM IN BRAIN The folic acid molecule is composed of a pterin moiety linked via a £-aminobenzoyl group to one or more glutamate residues (Fig.l). Naturally occuring folates may differ from one another in three major respects: the nature and position of one-carbon substituents, the state of oxidation of the pterin nucleus and the number of glutamate residues present in the molecule. Folic acid itself is reduced via 7,8-dihydrofolic acid to the active form of the vitamin (5,6,7,8-Tetrahydrofolate) in a reaction catalysed by dihydrofolate reductase. Dihydrofolic acid is also formed as a result of the thymidylate synthase reaction, and must likewise be re-converted to Tetrahydrofolate by the action of dihydrofolate reductase.

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  An Evidence-based Approach to Vitamins and Minerals

  Health Benefits and Intake Recommendations

  • Jane Higdon, Victoria J. Drake(Authors)
  • 2011(Publication Date)
  • Thieme

    (Publisher)

  7 2 Folic Acid The terms folic acid and folate are often used in-terchangeably for this water-soluble B-complex vitamin. Folic acid, the more stable form, occurs rarely in foods or the human body but is the form most often used in vitamin supplements and for-tified foods. Naturally occurring folates exist in many chemical forms. They are found in foods as well as in metabolically active forms in the hu-man body. 1 In the following discussion, forms found in food or the body are referred to as fo-lates , whereas the form found in supplements or fortified foods is referred to as folic acid . Function One-carbon Metabolism The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units. 2 Folate coenzymes act as ac-ceptors and donors of one-carbon units in a vari-ety of reactions critical to the metabolism of nu-cleic acids and amino acids. 3 Nucleic acid metabolism. Folate coenzymes play a vital role in DNA metabolism through two dif-ferent pathways ( Fig. 2.1 ): 1. The synthesis of DNA from its precursors (thy-midine and purines) is dependent on folate coenzymes. 2. A folate coenzyme is required for the synthe-sis of methionine, and methionine is required for the synthesis of S -adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA. Methylation of DNA may be important in cancer prevention. Fig. 2.1 Folate and nucleic acid metabolism: 5,10-methy-lene Tetrahydrofolate (THF) is required for the synthesis of nucleic acids, and 5-methyl THF is required for the forma-tion of methionine from homocysteine. methionine, in the form of S -adenosylmethionine, is required for many biological methylation reactions, including dNA methyla-tion. Methylene TH-folate reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methy-lene THF to 5-methyl THF.

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  Present Knowledge in Nutrition

  Basic Nutrition and Metabolism

  • Bernadette P. Marriott, Diane F. Birt, Virginia A. Stalling, Allison A. Yates(Authors)
  • 2020(Publication Date)
  • Academic Press

    (Publisher)

  Fig. 14.2 ).

  F. Regulation of the Biosynthetic Pathways

  The folate-mediated biosynthetic cycles are interconnected, and factors that regulate any one cycle of 1-C metabolism will influence folate availability for the other cycles or pathways. Studies in animals and human cells suggest that folate cofactors are preferentially partitioned toward the nuclear compartment (at the expense of homocysteine remethylation) under conditions of folate deficiency, thereby ensuring proper functioning of the de novo thymidylate synthesis pathway.

  32

  The partitioning of MTHFD1 from the cytosol to the nucleus appears to mediate this provision of 1-C units for thymidylate biosynthesis.

  29

  Additional enzymes with regulatory functions include formylTHF dehydrogenase that regulates the supply of formate for folate-mediated nucleotide biosynthesis by depleting 10-formylTHF pools

  33

  (Fig. 14.3 , reaction 5); MTHFR that mediates the flow of 1-C units between thymidylate biosynthesis and methylation reactions (Fig. 14.2 , reaction 9); and cSHMT that preferentially partitions cSHMT-derived 5,10-methyleneTHF toward thymidylate biosynthesis at the expense of methylation reactions (Fig. 14.2 , reaction 6).

  34

  Several important metabolic regulators also exist within the biosynthetic cycles. For example, SAM and SAH are the major regulators of the use of methyl groups in the methionine cycle and exert control at several regulatory points. Surplus SAM binds to the regulatory domain of MTHFR and inhibits enzyme activity thereby reducing the production of 5-methyTHF, which is required for the recycling of homocysteine through the methionine synthase reaction. Diminished production of 5-methyTHF by MTHFR also yields an active GNMT, which is normally inhibited by 5-methyTHF. GNMT catalyzes the SAM-dependent methylation of glycine to sarcosine thereby metabolizing excess SAM. Sarcosine is converted back to glycine and 5,10 methyleneTHF via sarcosine dehydrogenase following its transport into the mitochondria (Fig. 14.3 , reaction 8), which allows for the conservation of 1-C units. SAM also activates CBS (Fig. 14.2

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  Handbook of Vitamins

  • Janos Zempleni, John W. Suttie, Jesse F. Gregory III, Patrick J. Stover, Janos Zempleni, John W. Suttie, Jesse F. Gregory III, Patrick J. Stover(Authors)
  • 2013(Publication Date)
  • CRC Press

    (Publisher)

  The folate coenzymes are enclosed in rectangles. The correspond-ing enzymes for each reaction number are noted in Table 11.3 and in the text. S -adenosylmethionine (SAM) is a potent allosteric activator (+) of cystathionine Beta-symbol -synthase (reaction 8) and inhibitor (–) of 5,10-methyleneTetrahydrofolate reductase (reaction 3). Most methyltransferases (reaction 6) are inhibited by S -adenosylhomocysteine (SAH). –CH =, methenyl; –CH 2 –, methylene; –CH 3 , methyl; –CHO, formate; DHF, dihydrofolate; dTMP, 2-deoxythymidine 5 ′ -monophosphate; dUMP, 2-deoxyuridine 5 ′ -monophosphate; FIGLU, formiminoglutamic acid; NH = CH–, formimino; THF, Tetrahydrofolate; X, methyl group acceptor. 431 Folate 11.8.2.3 Homocysteine Remethylation Methionine synthase is a vitamin B 12 –dependent enzyme that sequentially transfers a methyl group from 5-methylTHF to the cobalamin coenzyme and to homocysteine, thus forming methionine and regenerating THF (Figure 11.2, Reaction 4). The methionine synthase reaction is the only reaction in which the methyl group of 5-methylTHF can be metabolized in mammalian tissues. The role of this enzyme is vitally important for both the folate cycle (i.e., the regeneration of THF) and for the production of methionine, which is required for SAM-dependent transmethylation reactions. 5-MethylTHF is the primary form of folate found in circulation and is thus the major form trans-ported into most tissues. In order to be retained within the cell, 5-methylTHF must be converted to THF via the methionine synthase reaction because 5-methylTHF is a poor substrate for polyglutam-ination, a step that is required for cellular folate retention (Shane 2009). For the methionine synthase enzyme to be active, the cobalamin cofactor must be reduced, which is accomplished enzymatically by methionine synthase reductase (MTRR). The methyl-trap hypothesis was proposed to explain why a vitamin B 12 deficiency results in a secondary folate deficiency (Herbert and Zalusky 1962).

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  Vitamins in the prevention of human diseases

  • Wolfgang Herrmann, Rima Obeid, Wolfgang Herrmann, Rima Obeid(Authors)
  • 2011(Publication Date)
  • De Gruyter

    (Publisher)

  Folic acid is a synthetic derivative of folate which is more resilient against oxidation than naturally occurring folates. Folic acid enters the folate cycle by reduction into dihydrofolate by dihydrofolatereductase (DHFR) (Fig 6.4). By means of the intertwined folate-and methionine-cycle ( Fig. 6.4), folates are predominantly utilized in one-carbon metabolism for the synthesis of three out of four DNA-nucleotides (adenine, guanine and thymine) and metabolism of the amino acids, methionine, serine, glycine and cysteine. Many enzymes involved in folate metabolism require cofactors for normal functioning. Methionine synthase is a zinc protein and requires vitamin B12 (cobalamin) as a cofactor and vitamin B6 (pyridoxine) is an important cofactor for the trans-sulfuration pathway. Furthermore, vitamin B2 is needed for adequate synthesis of 5,10-methylene-Tetrahydrofolate-reductase (MTHFR) and zinc is also necessary for adequate uptake of folates from the jejunum (Rawlings and Barrett, 1997; Ulrey, 2005). Humans do not have the ability to endogenously synthesize folates. The demand for folates therefore has to be met entirely by dietary intake. Green leafy vegetables, beans or liver are important natural sources of folates. Alternatively, in several countries grain, cereal and bread products are increasingly often fortified with folic acid, making these products a rich source of folic acid. Natural folate is present in food as 5-methyl-Tetrahydrofolate (5-mTHF) with a polyglutamate tail. In the jejunum,5-methyl-THF-polyglutamate is hydro-lyzed to 5-methyl-THF-monoglutamate by glutamate carboxypeptidase II. Because of its low pH optimum, the proton-coupled folate transporter favors folate transport into the entero-cytes of the jejunum. Within the enterocytes, 5-methyl-THF-monoglutamate is converted into 5-mTHF and thereafter released into the circulation (Zhao, 2009). In peripheral tissue, several mechanisms for 5-mTHF uptake exist.

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  Vitamins

  Their Role in the Human Body

  • George F. M. Ball(Author)
  • 2008(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  These reduced forms can be substituted with a cova-lently bonded one-carbon adduct attached to nitrogen positions 5 or 10 or bridged across both positions. The following substituted forms of THF are important intermediates in folate metabolism: 10-formyl-THF, 5-methyl-THF, 5-formimino-THF, 5,10-methylene-THF and 5,10-methenyl-THF (see Fig. 17.1). An important structural aspect of the 5,6,7,8-tet-rahydrofolates is the stereochemical orientation at the C-6 asymmetric carbon of the pteridine ring. Of the two stereoisomers, 6 S and 6 R (formerly called 6 l and 6 d ), only the 6 S is biologically active and occurs in nature. Methods of chemical synthesis of tetrahydro-folates, whether by catalytic hydrogenation or chemi-cal reduction, yield a racemic product (i.e. a mixture of both stereoisomers). All folate compounds exist predominantly as poly-glutamates, containing typically from five to seven glutamate residues in γ -peptide linkage. The γ -pep-tide bond is unique in mammalian biochemistry. Folate conjugates are abbreviated to PteGlu n deriva-tives, where n is the number of glutamate residues; for example, 5-CH 3 -H 4 PteGlu 3 refers to triglutamyl-5-methyltetrahydrofolic acid. Methotrexate (4-amino-10-methylfolic acid; Fig. 17.2) is a folate antagonist which is used as an anti-cancer drug. 17.3 Dietary sources and bioavailability 17.3.1 Dietary sources Polyglutamyl folate is an essential biochemical con-stituent of living cells, and most foods contribute some folate. The folates generally exist in nature bound to proteins (Baugh & Krumdieck, 1971) and they are also bound to storage polysaccharides (various types of starch and glycogen) in foods (C erná & Káš, 1983). In the United States, dried beans, eggs, greens, orange juice, sweet corn, peas and peanut products are good sources of folate that are inexpensive and available all the year round.

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  Netter's Essential Biochemistry E-Book

  Netter's Essential Biochemistry E-Book

  • Peter Ronner(Author)
  • 2016(Publication Date)
  • Elsevier

    (Publisher)

  Chapter 37 ).

  A Tetrahydrofolate synthase (also called folylpoly­glutamate synthase ) adds glutamate residues to THF monoglutamate. Compared with folylmono glutamates, folylpoly glutamates are less likely lost from cells by diffusion (owing to increased charge), less likely transported out of the cell by membrane transporters, and have a greater affinity to many of the enzymes that are involved in folate metabolism.

  Folates are stored in the liver and the kidneys.

  Several drugs have an adverse effect on folate uptake or cellular folate content. The antifolate methotrexate , which is used in the treatment of rheumatoid arthritis and moderate to severe psoriasis, traps cellular folates as dihydrofolates (see Chapter 37 ). The antibiotic trimethoprim and the antimalarial pyrimethamine inhibit the dihydrofolate reductase of humans less than that of bacteria, plasmodia, or Toxoplasma gondii. These drugs are contraindicated in patients who are anemic due to a folate deficiency, and they are used cautiously in patients who are at risk of folate deficiency. Many antiepileptic drugs (e.g., phenytoin , phenobarbital ) lead to low folate status, and patients treated with these drugs often need supplemental folate. Supplementation is especially important in women of child-bearing age (see neural tube defects in Section 8.1 ).

  2 Loading Tetrahydrofolates With One-Carbon Groups

  Serine and glycine are the main sources of one-carbon groups that are added to THF, giving rise to N5 ,N10 -methylene-THF. N5 ,N10 -methylene-THF in turn can give rise to other one-carbon THFs. The detoxification of methanol yields formate (HCOO– ), which is toxic and must form N10 -formyl-THF before it can be disposed of as CO2 . N5

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  Phytonutrients

  • Andrew Salter, Helen Wiseman, Gregory Tucker, Andrew Salter, Helen Wiseman, Gregory Tucker(Authors)
  • 2012(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  This is the only reaction in C1 metabolism in which the folate substrate is oxidised during single-unit transfer, with the electrons being used to reduce the C1-unit to the methyl level. It is therefore necessary to regenerate the fully reduced form of folate for a sustained synthesis of DNA. This reduction of dihydrofolate into THF is achieved by dihydrofolate reductase (DHFR), a ubiquitous enzyme which is also involved in de novo synthesis of THF in folate-autotrophs (Figure 6.4). TS and DHFR are monofunctional enzymes in most species except protozoa and plants where they exist as a bifunctional enzyme (Nzila et al. 2005a; Rébeillé et al. 2006; Blancquaert et al. 2010). Thymidylate synthesis was thought to be restricted to the cytosol in animals but recent evidence indicates a folate-mediated synthesis of dTMP in the nucleus (Tibbets and Appling 2010). This synthesis may be cell-specific and involves translocation into the nucleus during the S and G2/M phases of TS, DHFR and the cytoplasmic SHMT following modification by sumoylation (Woeller et al. 2007). In plants, the probable existence of bifunctional DHFR-TS isoforms in mitochondria, plastids and the cytosol also suggests a multi-compartmented synthesis of thymidylate (Rébeillé et al. 2006; Blancquaert et al. 2010) (Figure 6.3). Figure 6.4 Tetrahydrofolate biosynthetic pathway in plants. The enzymes involved in the synthesis of THF polyglutamate are: 1 : GTP cyclohydrolase I; 2 : dihydroneopterin triphosphate pyrophosphatase; 3 : dihydroneopterin aldolase; 4 : aminodeoxychorismate (ADC) synthase; 5 : ADC lyase; 6 : hydroxymethyldihydropterin pyrophosphokinase; 7 : dihydropteroate synthase; 8 : dihydrofolate synthetase; 9 : dihydrofolate reductase; 10 : folylpolyglutamate synthetase. pABA, para-aminobenzoate. Pantothenate synthesis Pantothenate is a water-soluble vitamin (B5) that is synthesised de novo by plants and micro-organisms but obtained through the diet by animals

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