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Caulobacter crescentus CB15 Pathway: tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate

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

Locations of Mapped Genes:

Synonyms: folic acid salvage, folate salvage, THF salvage

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

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 , formylTHF biosynthesis I , superpathway of tetrahydrofolate biosynthesis , tetrahydrofolate biosynthesis

Pathway Evidence Glyph:

Key to pathway glyph edge colors: ?

  An enzyme catalyzing this reaction is present in this organism
  The reaction and any enzyme that catalyzes it (if one has been identified) is unique to this pathway


References

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 (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

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 (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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