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Caulobacter crescentus CB15 Pathway: superpathway of tetrahydrofolate biosynthesis and salvage
Inferred by computational analysis

Pathway diagram: superpathway of tetrahydrofolate biosynthesis and salvage

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

Locations of Mapped Genes:

Schematic showing all replicons, marked with selected genes

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

Pathway Summary from MetaCyc:
General Background

Tetrahydrofolate (vitamin B9) and its derivatives, commonly termed folates, 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. Folates also mediate the interconversion of serine and glycine, play a role in histidine catabolism [Lucock00], and in plants are also involved in photorespiration, amino acid metabolism and chloroplastic protein biosynthesis [Hanson02] [Jabrin03].

Folates are abundant in green leaves, and folic acid was initially isolated from a large amount (four tons) of spinach leaves. The name folate is derived from the Latin folium (leaf) [Mitchell41].

Folates are modified by the addition of glutamate moieties conjugated one to another via a series of γ-glutamyl links to form an oligo-γ-glutamyl tail. The polyglutamylated forms are usually preferred by the enzymes that use folates since the turnover rate of those compounds is markedly increased [Cossins97, Scott00, Kirk94]. In addition, in eukaryotic cells the glutamylated forms of folate facilitate the retention of the vitamin within the cell and its subcellular compartments [Appling91].

The product of this pathway, tetrahydropteroyl mono-L-glutamate (tetrahydropteroylmonoglutamate, H4PteGlu1, THF), is merely the parent structure of this large family of coenzymes. Members of the family differ in the oxidation state of the pteridine ring, the character of the one-carbon substituent at the N5 and N10 positions (see folate transformations I), and the number of conjugated glutamate residues (see folate polyglutamylation).

About This Pathway

This pathway for the de novo biosynthesis of folates is found in bacteria, fungi, and plants.

Folates are tripartite molecules and are made up of a pterin, 4-aminobenzoate and L-glutamate moieties. The first two are synthesized from GTP and chorismate, respectively. The first committed step catalyzed by GTP cyclohydrolase I converts GTP into 7,8-dihydroneopterin 3'-triphosphate. The triphosphate motif is removed by a still unknown process, and the resulting 7,8-dihydroneopterin is converted to 6-hydroxymethyl-7,8-dihydropterin by dihydroneopterin aldolase (FolB). The consecutive action of the FolK, FolP, FolC, and FolA enzymes finally produces the final product, tetrahydropteroyl mono-L-glutamate [Illarionova02].

In plants the pterin moiety is formed from GTP in the cytosol, which couples to pABA (synthesized in plastids) in mitochondria followed by subsequent glutamylation and reduction steps which may take place in cytosol, mitochondria and plastids [Hanson02, Ravanel01]. 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.

In addition to the de novo pathway, many organisms also possess a salvage pathway that is used to re-synthesize tetrahydrofolate from breakdown products of folates in the cell, such as 5 or 10-formyl-tetrahydrofolate.

About Folates In Animals

While plants and many microorganisms can synthesize folate coenzymes by the de novo synthesis pathway, vertebrates are absolutely dependent on nutritional sources, making folate a vitamin. Food folates exist mainly as N5-methyl-tetrahydrofolate and N10-formyl-tetrahydrofolate (formyl-H4PteGlun) [Thien77].

Polyglutamyl folates are hydrolyzed to folylmonoglutamates by γ-glutamyl hydrolase, and metabolized within the enterocyte into 5-methyl-H4PteGlu1. This monoglutamyl folate coenzyme is the plasma form of the vitamin [Herbert62, Lucock89], and is transported to peripheral tissues where it is demethylated by the vitamin B12-dependent folylpolyglutamate γ-glutamyl hydrolase to monoglutamyl tetrahydrofolate (H4PteGlu1).

Insufficient supply of the vitamin in vertebrates leads to anemia in adults, and has been shown to cause neural tube malformation in human embryos [Feinleib01]. In addition, folate defficiency has been linked to a number of other birth defects, several types of cancer, dementia, affective disorders, Down's syndrom, and serious conditions affecting pregnancy outcome (for a review, see [Lucock00]).

Subpathways: tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate, superpathway of tetrahydrofolate biosynthesis, tetrahydrofolate biosynthesis, 6-hydroxymethyl-dihydropterin diphosphate biosynthesis I, 4-aminobenzoate biosynthesis

Variants: folate polyglutamylation, formylTHF biosynthesis I

Created in MetaCyc 31-Jan-1995 by Riley M, Marine Biological Laboratory
Revised in MetaCyc 09-Dec-2004 by SRI International
Revised in MetaCyc 22-Sep-2010 by SRI International
Imported from MetaCyc 18-Sep-2013 by Fulcher CA, SRI International


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

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

Feinleib01: Feinleib M, Beresford SA, Bowman BA, Mills JL, Rader JI, Selhub J, Yetley EA (2001). "Folate fortification for the prevention of birthdefects: case study." Am J Epidemiol 154(12 Suppl);S60-9. PMID: 11744531

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

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

Illarionova02: Illarionova V, Eisenreich W, Fischer M, Haussmann C, Romisch W, Richter G, Bacher A (2002). "Biosynthesis of tetrahydrofolate. Stereochemistry of dihydroneopterin aldolase." J Biol Chem 277(32);28841-7. PMID: 12039964

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

Kirk94: Kirk CD, Imeson HC, Zheng LL, Cossins EA, (1994) "The affinity of pea cotyledon 10-formyltetrahydrofolate synthetase for polyglutamate substrates." Phytochemistry (1994), 35(2), 291-296.

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

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

Mitchell41: Mitchell HK, Snell EE, Williams RJ (1941). "The concentration of "folic acid"." Journal of the American Chemical Society, Vol. 63:2284. PMID: 3067148

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

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

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

Green04: Green ML, Karp PD (2004). "A Bayesian method for identifying missing enzymes in predicted metabolic pathway databases." BMC Bioinformatics 5;76. PMID: 15189570

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