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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
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MetaCyc Pathway: folate transformations I

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis Vitamins Biosynthesis Folate Biosynthesis

Some taxa known to possess this pathway include ? : Blautia producta , Clostridium formicaceticum , Escherichia coli K-12 substr. MG1655 , Hyphomicrobium methylovorum GM2 , Hyphomicrobium zavarzinii ZV580 , Lactobacillus casei , Methylobacterium extorquens AM1 , Methylobacterium organophilum , Moorella thermoacetica , Pseudomonas sp. MS

Expected Taxonomic Range: Archaea , Bacteria , Eukaryota

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The various folate coenzymes are essential cofactors that facilitate the transfer of one-carbon units from donor molecules into important biosynthetic pathways leading to methionine, purine, and pyrimidine biosynthesis. They also mediate the interconversion of serine and glycine (EC, glycine hydroxymethyltransferase), and play a role in histidine catabolism [Lucock00].

Tetrahydrofolate (tetrahydropteroylmonoglutamate, H4PteGlu1, THF), is merely the parent structure of this large family of coenzymes. The folate coenzymes differ in the oxidation state of the pteridine ring, the character of the one-carbon substituent at the N5 and N10 positions, and the number of glutamic acid moieties conjugated one to another via a series of γ-glutamyl links to form an oligo-γ-glutamyl tail (see the pathway glutamate removal from folates for more information on this subject). There are numerous enzymes that convert the folates from one form to another, and the important ones are included in this pathway.

Important folate coenzymes include the mono- and polyglutamylated forms of tetrahydrofolate (H4PteGlun), N5-formyl tetrahydrofolate (5-formyl-H4PteGlun), N10-formyl tetrahydrofolate (10-formyl-H4PteGlun), 5,10-methenyl-tetrahydrofolate (5,10-methenyl-H4PteGlun), 5,10-methylene-tetrahydrofolate (5,10-methylene-H4PteGlun), and 5-methyl-tetrahydrofolate (5-methyl-H4PteGlun).

Folate cofactors are particularly important in the methylotrophs - the bacteria that can utilize C1 (single carbon)compounds as their sole carbon and energy source. In the methylotroph Methylobacterium extorquens AM1, formaldehyde that enters the cytoplasm condenses with one of the two pterin cofactors, tetrahydrofolate or tetrahydromethanopterin (H4MPT), and forms the respective methylene derivative (see the pathway formate reduction to 5,10-methylenetetrahydrofolate).

The reaction of formaledehyde with THF is spontaneous [Kallen66, Marx03a], and produces 5,10-methylene-THF, which can be metabolized in two ways: it can enter the serine cycle (see formaldehyde assimilation I (serine pathway)), where the carbon is used for biosysnthesis, or it may be oxidized via 5,10-methenyl-THF to 10-formyl-THF. 10-formyl-THF can be eventually converted back to THF, releasing formate which is oxidized to CO2 (see formate oxidation to CO2) [Goenrich02, Pomper99, Pomper02]. This route is completely reversible, and can flow in both directions; as described above it catalyzes the oxidation of formaldehyde to formate. However, in the other direction, it catalyzes the conversion of formate (which accumulates through the pathway formaldehyde oxidation V (H4MPT pathway)) to methylene-tetrahydrofolate, which feeds the serine cycle, a formaldehyde assimilation cycle (formaldehyde assimilation I (serine pathway)).

Vertebrates are not able to synthesize folates, and are completely dependent on folates in their diet. Dietary folates exist mainly as poly and mono-glutamylated 5-methyl-THF and formyl-THF [Thien77]. Polyglutamyl folates in food are hydrolyzed to folylmonoglutamates by EC, γ-glutamyl hydrolase), and metabolized within the enterocyte into 5-methyl-H4PteGlu1. This monoglutamyl folate is the main form of the vitamin in the plasma [Herbert62, Lucock89], and is transported to peripheral tissues. In the tissues it is demethylated by vitamin B12-dependent EC, methionine synthase, to monoglutamyl tetrahydrofolate (H4PteGlu1). This H4PteGlu1 form is the preferred substrate of EC, tetrahydrofolate synthase, which conjugates glutamate moieties to generate oligo-γ-glutamyl H4PteGlu. The predominant product of this reaction is the hexaglutamyl-HPteGlu form [Cook87]. The conversion of 5- methyl-H44PteGlu1 into H44PteGlu1 by vitamin B12- dependent methionine synthase is thus responsible for the conversion of extracellular 5-methyl-H4PteGlu1 from dietary sources into the form that can be used in the biosynthetic pathways [Green88].

In erythrocites folate is largely present in the forms of 5- methyl-H44PteGlun and formyl-H44PteGlun, mostly containing five or six glutamate residues [Lucock00a, Perry76]. However, the active forms of folate required for nucleotide synthesis are 10-formyl-H4PteGlun and 5,10-methylene-H4PteGlun. 5,10-methylene-H4PteGlun is also required by EC, methylenetetrahydrofolate reductase [NAD(P)H], in the biosynthesis of methionine. Thus, 5,10-methylene-H4PteGlun is at the branch point of three important pathways [Green88].

Variants: 4-aminobenzoate biosynthesis , folate polyglutamylation , folate transformations II , glutamate removal from folates , N10-formyl-tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis and salvage , tetrahydrofolate biosynthesis , tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate

Created 05-Nov-2004 by Caspi R , SRI International


Cook87: Cook JD, Cichowicz DJ, George S, Lawler A, Shane B (1987). "Mammalian folylpoly-gamma-glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis." Biochemistry 26(2);530-9. PMID: 3828323

Goenrich02: Goenrich M, Bursy J, Hubner E, Linder D, Schwartz AC, Vorholt JA (2002). "Purification and characterization of the methylene tetrahydromethanopterin dehydrogenase MtdB and the methylene tetrahydrofolate dehydrogenase FolD from Hyphomicrobium zavarzinii ZV580." Arch Microbiol 177(4);299-303. PMID: 11889483

Green88: Green JM, MacKenzie RE, Matthews RG (1988). "Substrate flux through methylenetetrahydrofolate dehydrogenase: predicted effects of the concentration of methylenetetrahydrofolate on its partitioning into pathways leading to nucleotide biosynthesis or methionine regeneration." Biochemistry 27(21);8014-22. PMID: 3266075

Herbert62: Herbert V, Larrabee AR, Buchanan JM (1962). "Studies on the identification of a folate compound of human serum." J Clin Invest 41;1134-8. PMID: 13906633

Kallen66: Kallen RG, Jencks WP (1966). "The mechanism of the condensation of formaldehyde with tetrahydrofolic acid." J Biol Chem 241(24);5851-63. PMID: 5954363

Lucock00: Lucock M (2000). "Folic acid: nutritional biochemistry, molecular biology, and role in disease processes." Mol Genet Metab 71(1-2);121-38. PMID: 11001804

Lucock00a: Lucock M, Daskalakis I, Briggs D, Yates Z, Levene M (2000). "Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c --> t methylenetetrahydrofolate reductase and 2756a --> g methionine synthase genotypes." Mol Genet Metab 70(1);27-44. PMID: 10833329

Lucock89: Lucock MD, Hartley R, Smithells RW (1989). "A rapid and specific HPLC-electrochemical method for the determination of endogenous 5-methyltetrahydrofolic acid in plasma using solid phase sample preparation with internal standardization." Biomed Chromatogr 3(2);58-63. PMID: 2736319

Marx03a: Marx CJ, Chistoserdova L, Lidstrom ME (2003). "Formaldehyde-detoxifying role of the tetrahydromethanopterin-linked pathway in Methylobacterium extorquens AM1." J Bacteriol 185(24);7160-8. PMID: 14645276

Perry76: Perry J, Lumb M, Laundy M, Reynolds EH, Chanarin I (1976). "Role of vitamin B12 in folate coenzyme synthesis." Br J Haematol 32(2);243-8. PMID: 1247496

Pomper02: Pomper BK, Saurel O, Milon A, Vorholt JA (2002). "Generation of formate by the formyltransferase/hydrolase complex (Fhc) from Methylobacterium extorquens AM1." FEBS Lett 523(1-3);133-7. PMID: 12123819

Pomper99: Pomper BK, Vorholt JA, Chistoserdova L, Lidstrom ME, Thauer RK (1999). "A methenyl tetrahydromethanopterin cyclohydrolase and a methenyl tetrahydrofolate cyclohydrolase in Methylobacterium extorquens AM1." Eur J Biochem 261(2);475-80. PMID: 10215859

Thien77: Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikian V (1977). "Serum folates in man." J Clin Pathol 30(5);438-48. PMID: 405403

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Al12: Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM (2012). "Identity and function of a large gene network underlying mutagenic repair of DNA breaks." Science 338(6112);1344-8. PMID: 23224554

Allison88: Allison N, Williams CH, Guest JR (1988). "Overexpression and mutagenesis of the lipoamide dehydrogenase of Escherichia coli." Biochem J 256(3);741-9. PMID: 3066354

Alwine73: Alwine JC, Russell RM, Murray KN (1973). "Characterization of an Escherichia coli mutant deficient in dihydrolipoyl dehydrogenase activity." J Bacteriol 115(1);1-8. PMID: 4197899

Angelaccio92: Angelaccio S, Pascarella S, Fattori E, Bossa F, Strong W, Schirch V (1992). "Serine hydroxymethyltransferase: origin of substrate specificity." Biochemistry 31(1);155-62. PMID: 1731867

Arifuzzaman06: Arifuzzaman M, Maeda M, Itoh A, Nishikata K, Takita C, Saito R, Ara T, Nakahigashi K, Huang HC, Hirai A, Tsuzuki K, Nakamura S, Altaf-Ul-Amin M, Oshima T, Baba T, Yamamoto N, Kawamura T, Ioka-Nakamichi T, Kitagawa M, Tomita M, Kanaya S, Wada C, Mori H (2006). "Large-scale identification of protein-protein interaction of Escherichia coli K-12." Genome Res 16(5);686-91. PMID: 16606699

Baggott00: Baggott JE (2000). "Hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate at pH 2.5 to 4.5." Biochemistry 39(47);14647-53. PMID: 11087421

Baggott03: Baggott JE, MacKenzie RE (2003). "5,10-methenyltetrahydrofolate cyclohydrolase, rat liver and chemically catalysed formation of 5-formyltetrahydrofolate." Biochem J 374(Pt 3);773-8. PMID: 12793858

Bairoch93: Bairoch A, Boeckmann B (1993). "The SWISS-PROT protein sequence data bank, recent developments." Nucleic Acids Res. 21:3093-3096. PMID: 8332529

Banerjee89: Banerjee RV, Johnston NL, Sobeski JK, Datta P, Matthews RG (1989). "Cloning and sequence analysis of the Escherichia coli metH gene encoding cobalamin-dependent methionine synthase and isolation of a tryptic fragment containing the cobalamin-binding domain." J Biol Chem 1989;264(23);13888-95. PMID: 2668277

Banerjee90: Banerjee RV, Frasca V, Ballou DP, Matthews RG (1990). "Participation of cob(I) alamin in the reaction catalyzed by methionine synthase from Escherichia coli: a steady-state and rapid reaction kinetic analysis." Biochemistry 1990;29(50);11101-9. PMID: 2271698

Banerjee90a: Banerjee RV, Matthews RG (1990). "Cobalamin-dependent methionine synthase." FASEB J 1990;4(5);1450-9. PMID: 2407589

Beckmann97: Beckmann K, Dzuibany C, Biehler K, Fock H, Hell R, Migge A, Becker TW (1997). "Photosynthesis and fluorescence quenching, and the mRNA levels of plastidic glutamine synthetase or of mitochondrial serine hydroxymethyltransferase (SHMT) in the leaves of the wild-type and of the SHMT-deficient stm mutant of Arabidopsis thaliana in relation to the rate of photorespiration." Planta 202(3);379-86. PMID: 9232907

Belfaiza87: Belfaiza J, Guillou Y, Margarita D, Perrin D, Saint Girons I (1987). "Operator-constitutive mutations of the Escherichia coli metF gene." J Bacteriol 1987;169(2);670-4. PMID: 3542965

Blank14: Blank D, Wolf L, Ackermann M, Silander OK (2014). "The predictability of molecular evolution during functional innovation." Proc Natl Acad Sci U S A 111(8);3044-9. PMID: 24516157

Bosl94: Bosl M, Kersten H (1994). "Organization and functions of genes in the upstream region of tyrT of Escherichia coli: phenotypes of mutants with partial deletion of a new gene (tgs)." J Bacteriol 176(1);221-31. PMID: 8282700

BRENDA14: BRENDA team (2014). "Imported from BRENDA version existing on Aug 2014."

Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043

Cai92: Cai XY, Jakubowski H, Redfield B, Zaleski B, Brot N, Weissbach H (1992). "Role of the metF and metJ genes on the vitamin B12 regulation of methionine gene expression: involvement of N5-methyltetrahydrofolic acid." Biochem Biophys Res Commun 1992;182(2);651-8. PMID: 1734876

Cai95: Cai K, Schirch D, Schirch V (1995). "The affinity of pyridoxal 5'-phosphate for folding intermediates of Escherichia coli serine hydroxymethyltransferase." J Biol Chem 270(33);19294-9. PMID: 7642604

Capela01: Capela D, Barloy-Hubler F, Gouzy J, Bothe G, Ampe F, Batut J, Boistard P, Becker A, Boutry M, Cadieu E, Dreano S, Gloux S, Godrie T, Goffeau A, Kahn D, Kiss E, Lelaure V, Masuy D, Pohl T, Portetelle D, Puhler A, Purnelle B, Ramsperger U, Renard C, Thebault P, Vandenbol M, Weidner S, Galibert F (2001). "Analysis of the chromosome sequence of the legume symbiont Sinorhizobium meliloti strain 1021." Proc Natl Acad Sci U S A 98(17);9877-82. PMID: 11481430

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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