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MetaCyc Pathway: tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate

Enzyme View:

This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: folic acid salvage, folate salvage, THF salvage

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

Some taxa known to possess this pathway include ? : Escherichia coli K-12 substr. MG1655 , Homo sapiens , Lactococcus lactis , Saccharomyces cerevisiae

Expected Taxonomic Range: Bacteria , Eukaryota

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].

tetrahydropteroyl mono-L-glutamate (H4PteGlu1) 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

While plants and many microorganisms can synthesize folate coenzymes by the de novo synthesis pathway (see superpathway of tetrahydrofolate biosynthesis), many of them are also capable of salvaging folate from different varieties, such as the 5,10-methenyl form, or the 5- or 10-formyl forms. This pathway describes the conversion of pre-existing 5,10-methylene-tetrahydrofolate and N10-formyl-tetrahydrofolate to tetrahydrofolate.

As vertebrates are not able to synthesize folate in vivo, they are absolutely dependent on nutritional sources, making folate a vitamin. Food folates exist mainly as the polyglutamylated forms N5-methyl-tetrahydrofolate and N10-formyl-tetrahydrofolate (formyl-H4PteGlun) [Thien77]. The polyglutamyl folates are first hydrolyzed to monoglutamate forms by γ-glutamyl hydrolase, and subsequently metabolized into N5-methyl-tetrahydropteroyl mono-L-glutamate. More about that process is found at the pathway glutamate removal from folates.

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]).

Superpathways: superpathway of tetrahydrofolate biosynthesis and salvage

Variants: 4-aminobenzoate biosynthesis , folate polyglutamylation , folate transformations I , folate transformations II , glutamate removal from folates , N10-formyl-tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis , tetrahydrofolate biosynthesis

Created 22-Sep-2010 by Caspi R , 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 birth defects: 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

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. 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

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

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.

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

Allaire98: Allaire M, Li Y, MacKenzie RE, Cygler M (1998). "The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution." Structure 6(2);173-82. PMID: 9519408

Almassy92: Almassy RJ, Janson CA, Kan CC, Hostomska Z (1992). "Structures of apo and complexed Escherichia coli glycinamide ribonucleotide transformylase." Proc Natl Acad Sci U S A 1992;89(13);6114-8. PMID: 1631098

Andersen92a: Andersen PS, Smith JM, Mygind B (1992). "Characterization of the upp gene encoding uracil phosphoribosyltransferase of Escherichia coli K12." Eur J Biochem 1992;204(1);51-6. PMID: 1371255

Beardsley89: Beardsley GP, Moroson BA, Taylor EC, Moran RG (1989). "A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis." J Biol Chem 264(1);328-33. PMID: 2909524

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

Chen92: Chen P, Schulze-Gahmen U, Stura EA, Inglese J, Johnson DL, Marolewski A, Benkovic SJ, Wilson IA (1992). "Crystal structure of glycinamide ribonucleotide transformylase from Escherichia coli at 3.0 A resolution. A target enzyme for chemotherapy." J Mol Biol 227(1);283-92. PMID: 1522592

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

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

Curthoys72: Curthoys NP, Scott JM, Rabinowitz JC (1972). "Folate coenzymes of Clostridium acidi-urici. The isolation of (l)-5,10-methenyltetrahydropteroyltriglutamate, its conversion to (l)-tetrahydropteroyltriglutamate and (l)-10-( 14 C)formyltetrahydropteroyltriglutamate, and the synthesis of (l)-10-formyl-(6,7- 3 H 2 )tetrahydropteroyltriglutamate and (l)-(6,7- 3 H 2 )tetrahydropteroyltriglutamate." J Biol Chem 247(7);1959-64. PMID: 5016637

DAri91: D'Ari L, Rabinowitz JC (1991). "Purification, characterization, cloning, and amino acid sequence of the bifunctional enzyme 5,10-methylenetetrahydrofolate dehydrogenase/5,10-methenyltetrahydrofolate cyclohydrolase from Escherichia coli." J Biol Chem 1991;266(35);23953-8. PMID: 1748668

DeMartino08: DeMartino JK, Hwang I, Connelly S, Wilson IA, Boger DL (2008). "Asymmetric synthesis of inhibitors of glycinamide ribonucleotide transformylase." J Med Chem 51(17);5441-8. PMID: 18686942

Dev78: Dev IK, Harvey RJ (1978). "A complex of N5,N10-methylenetetrahydrofolate dehydrogenase and N5,N10-methenyltetrahydrofolate cyclohydrolase in Escherichia coli. Purification, subunit structure, and allosteric inhibition by N10-formyltetrahydrofolate." J Biol Chem 1978;253(12);4245-53. PMID: 350870

Dev78a: Dev IK, Harvey RJ (1978). "N10-Formyltetrahydrofolate is the formyl donor for glycinamide ribotide transformylase in Escherichia coli." J Biol Chem 253(12);4242-4. PMID: 350869

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

ECOSAL: EcoSal "Escherichia coli and Salmonella: Cellular and Molecular Biology." Online edition.

Gaudet10: Gaudet P, Livstone M, Thomas P (2010). "Annotation inferences using phylogenetic trees." PMID: 19578431

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA01a: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

Showing only 20 references. To show more, press the button "Show all references".

Report Errors or Provide Feedback
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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