MetaCyc Pathway: folate transformations II
Inferred from experimentTraceable author statement to experimental support

Pathway diagram: folate transformations II

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

Superclasses: BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisVitamins BiosynthesisFolate BiosynthesisFolate Transformations

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Glycine max, Pisum sativum, Solanum lycopersicum, Solanum tuberosum, Spinacia oleracea

Expected Taxonomic Range: Viridiplantae

General Background

The formation of the formyl and methyl derivatives of tetrahydrofolate (vitamin B9) directly involved in or representing sidesteps of the biosynthesis of this vital cofactors [Cossins97] [Hanson00] is displayed in this pathway. Folates are involved in a wide range of key metabolic functions in plants [Hanson02] [Jabrin03] mediating fluxes through C1-pathways with a high demand for methylated compounds such as secondary metabolites [Hanson01].

Plants prefer the polyglutamylated forms of folates (compare folate polyglutamylation, glutamate removal from folates) since the turnover rate of those compounds is markedly increased [Cossins97] [Scott00] and meets the high demands for folates as observed in plants [Hanson02]. In addition the conjugated forms of folate facilitate the retention of the vitamin within the cell and its subcellular compartments [Appling91]. The plant enzymes involved in this pathway, although essentially catalyzing the same steps, have been found to differ in many regards from their bacterial counterparts [Cossins97] [Basset04a] [Basset04].

Special information

Folates are tripartite molecules and are made up of pterin, p-aminobenzoate (pPABA) and glutamate moieties. The one-carbon units are either attached to the N-5 of the pterin moietie, to the N-10 of the pPAPA moiety or are brigded in between those two (e.g. 5,10-methenyl or methylene-THF) [Basset05]. The different forms of folates are jointly connected and easily convertible into each other through a tight network of reactions ( folate transformations I). Most of the enzymes have been identified in plants but some of them such as the formyltetrahydrofolate deformylase, presumably involved in the mutual conversion of tetrahydrofolate and its 10-formyl derivative remain to be demonstrated.

Among the many folates N5-formyl-tetrahydrofolate is the most enigmatic compound involved in the folate biosynthesis. N5-formyl-tetrahydrofolate is the only folate derivative that does not serve as a cofactor in the C1-metabolism, but it is the most frequent and stable form of folates found in plants [Stover93]. Moreover, N5-formyl-tetrahydrofolate is known to inhibit most of the folate dependent enzymes at physiological concentrations. The biological role of this compound is still poorly understood but it has been discussed as factor involved in the regulation of essential biosynthetic steps such as the formation of serine during photorespiration [Goyer05, Roje02].

The complete set of folate enzymes is only present in mitochondria. However, the recent discovery that folylpolyglutamate synthases are present in cytosol, mitochondria and plastids with each of them encoded by a different gene in Arabidopsis thaliana [Ravanel01] points to the fact that at least parts of the pathway can be carried out independently in those compartments. Interestingly, the enzyme hydrolyzing the polyglutamylated folates (γ-glutamyl hydrolase) has been found to be an extracellular enzyme in plants [Huangpu96]. Consequently, the transport and exact conversion of folates and their derivatives within the different cell compartments and their regulation pattern remains to be clarified before successfully attempting the endeavor to genetically engineer this pathway.

Variants: folate transformations I

Unification Links: AraCyc:PWY-3841

Created 14-Jun-2005 by Foerster H, TAIR


Appling91: Appling DR (1991). "Compartmentation of folate-mediated one-carbon metabolism in eukaryotes." FASEB J 5(12);2645-51. PMID: 1916088

Basset04: Basset GJ, Ravanel S, Quinlivan EP, White R, Giovannoni JJ, Rebeille F, Nichols BP, Shinozaki K, Seki M, Gregory JF, Hanson AD (2004). "Folate synthesis in plants: the last step of the p-aminobenzoate branch is catalyzed by a plastidial aminodeoxychorismate lyase." Plant J 40(4);453-61. PMID: 15500462

Basset04a: Basset GJ, Quinlivan EP, Ravanel S, Rebeille F, Nichols BP, Shinozaki K, Seki M, Adams-Phillips LC, Giovannoni JJ, Gregory JF, Hanson AD (2004). "Folate synthesis in plants: the p-aminobenzoate branch is initiated by a bifunctional PabA-PabB protein that is targeted to plastids." Proc Natl Acad Sci U S A 101(6);1496-501. PMID: 14745019

Basset05: Basset GJC, Quinlivan EP, Gregory III JF, Hanson AD (2005). "Folate Synthesis and Metabolism in Plants and Prospects For Biofortification." Crop Sci. 45; 449-453.

Cossins97: Cossins EA, Chen L (1997). "Folates and one-carbon metabolism in plants and fungi." Phytochemistry 45(3);437-52. PMID: 9190084

Goyer05: Goyer A, Collakova E, Diaz de la Garza R, Quinlivan EP, Williamson J, Gregory JF, Shachar-Hill Y, Hanson AD (2005). "5-Formyltetrahydrofolate is an inhibitory but well tolerated metabolite in Arabidopsis leaves." J Biol Chem 280(28);26137-42. PMID: 15888445

Hanson00: Hanson AD, Gage DA, Shachar-Hill Y (2000). "Plant one-carbon metabolism and its engineering." Trends Plant Sci 5(5);206-13. PMID: 10785666

Hanson01: Hanson AD, Roje S (2001). "One-carbon metabolism in higher plants." Annu Rev Plant Physiol Plant Mol Biol 52;119-137. PMID: 11337394

Hanson02: Hanson AD, Gregory JF (2002). "Synthesis and turnover of folates in plants." Curr Opin Plant Biol 5(3);244-9. PMID: 11960743

Huangpu96: Huangpu J, Pak JH, Graham MC, Rickle SA, Graham JS (1996). "Purification and molecular analysis of an extracellular gamma-glutamyl hydrolase present in young tissues of the soybean plant." Biochem Biophys Res Commun 228(1);1-6. PMID: 8912628

Jabrin03: Jabrin S, Ravanel S, Gambonnet B, Douce R, Rebeille F (2003). "One-carbon metabolism in plants. Regulation of tetrahydrofolate synthesis during germination and seedling development." Plant Physiol 131(3);1431-9. PMID: 12644692

Ravanel01: Ravanel S, Cherest H, Jabrin S, Grunwald D, Surdin-Kerjan Y, Douce R, Rebeille F (2001). "Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana." Proc Natl Acad Sci U S A 98(26);15360-5. PMID: 11752472

Roje02: Roje S, Janave MT, Ziemak MJ, Hanson AD (2002). "Cloning and characterization of mitochondrial 5-formyltetrahydrofolate cycloligase from higher plants." J Biol Chem 277(45);42748-54. PMID: 12207015

Scott00: Scott J, Rebeille F, Fletcher J (2000). "Folic acid and folates: the feasibility for nutritional enhancement in plant foods." J Sci Food Agric 80; 795-824.

Stover93: Stover P, Schirch V (1993). "The metabolic role of leucovorin." Trends Biochem Sci 18(3);102-6. PMID: 8480361

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

Anderson11: Anderson DD, Quintero CM, Stover PJ (2011). "Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria." Proc Natl Acad Sci U S A 108(37);15163-8. PMID: 21876188

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

Baccanari75: Baccanari D, Phillips A, Smith S, Sinski D, Burchall J (1975). "Purification and properties of Escherichia coli dihydrofolate reductase." Biochemistry 1975;14(24);5267-73. PMID: 46

Baccanari82: Baccanari DP, Daluge S, King RW (1982). "Inhibition of dihydrofolate reductase: effect of reduced nicotinamide adenine dinucleotide phosphate on the selectivity and affinity of diaminobenzylpyrimidines." Biochemistry 1982;21(20);5068-75. PMID: 6814484

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

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

Batruch10: Batruch I, Javasky E, Brown ED, Organ MG, Johnson PE (2010). "Thermodynamic and NMR analysis of inhibitor binding to dihydrofolate reductase." Bioorg Med Chem 18(24);8485-92. PMID: 21084197

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

Bowden89: Bowden K, Hall AD, Birdsall B, Feeney J, Roberts GC (1989). "Interactions between inhibitors of dihydrofolate reductase." Biochem J 1989;258(2);335-42. PMID: 2495789

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

Burchall65: Burchall JJ, Hitchings GH (1965). "Inhibitor binding analysis of dihydrofolate reductases from various species." Mol Pharmacol 1965;1(2);126-36. PMID: 4378654

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

Chen97: Chen L, Chan SY, Cossins EA (1997). "Distribution of Folate Derivatives and Enzymes for Synthesis of 10-Formyltetrahydrofolate in Cytosolic and Mitochondrial Fractions of Pea Leaves." Plant Physiol 115(1);299-309. PMID: 12223808

Chen97a: Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B (1997). "Human methionine synthase. cDNA cloning, gene localization, and expression." J Biol Chem 272(6);3628-34. PMID: 9013615

Chen99: Chen L, Nargang FE, Cossins EA, (1999) "Isolation and sequencing of a plant cDNA encoding a bifunctional methylenetetrahydrofolate dehydrogenase:methenyltetrahydrofolate cyclohydrolase protein." Pteridines (1999), 10, 171-177.

Cheung97: Cheung E, D'Ari L, Rabinowitz JC, Dyer DH, Huang JY, Stoddard BL (1997). "Purification, crystallization, and preliminary x-ray studies of a bifunctional 5,10-methenyl/methylene-tetrahydrofolate cyclohydrolase/dehydrogenase from Escherichia coli." Proteins 27(2);322-4. PMID: 9061797

Chistoserdova94: Chistoserdova LV, Lidstrom ME (1994). "Genetics of the serine cycle in Methylobacterium extorquens AM1: cloning, sequence, mutation, and physiological effect of glyA, the gene for serine hydroxymethyltransferase." J Bacteriol 176(21);6759-62. PMID: 7961431

Contestabile00: Contestabile R, Angelaccio S, Bossa F, Wright HT, Scarsdale N, Kazanina G, Schirch V (2000). "Role of tyrosine 65 in the mechanism of serine hydroxymethyltransferase." Biochemistry 39(25);7492-500. PMID: 10858298

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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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