MetaCyc Pathway: glutamate removal from folates
Inferred from experiment

Enzyme View:

Pathway diagram: glutamate removal from folates

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.

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

Some taxa known to possess this pathway include : Arabidopsis thaliana col, Glycine max, Homo sapiens, Neurospora crassa, Rattus norvegicus

Expected Taxonomic Range: Eukaryota

General Background

Folates are required in a variety of reactions (known as one-carbon metabolism) in both bacterial and mammalian tissues, where they act as carriers of one-carbon units in various oxidation states. These one-carbon units are utilized in the biosynthesis of various cellular components, including glycine, methionine, formylmethionine, thymidylate, pantothenate and purine nucleotides.

During folate biosynthesis the enzyme EC, dihydrofolate synthase, adds an L-glutamate residue to 7,8-dihydropteroate, resulting in 7,8-dihydrofolate monoglutamate, also known as H2PteGlu1. This molecule in turn is reduced by dihydrofolate reductase to tetrahydropteroyl mono-L-glutamate (tetrahydrofolate, H4PteGlu1, or THF) (see superpathway of tetrahydrofolate biosynthesis and salvage). THF can then be converted to several other folate molecules [Sun01] (see folate transformations I).

However, most folate molecules are further modified in cells by successive additions of L-glutamate residues, forming folate polyglutamates (or folylpoly-γ-glutamates) (see folate polyglutamylation). Most of the glutamate residues are added by γ-carboxy-linked polyglutamylation via an amide linkage to the γ-carboxylate group of the folate or folate derivative. Since these isopeptide bonds are different from the more common α-carboxyl-linked amide bonds, they are not hydrolyzed by most peptidases or proteases.

About This Pathway

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 (N5-methyl-H4PteGlun) and N10-formyl-tetrahydrofolate (N10-formyl-H4PteGlun) [Thien77].

In animals, during the absorption of food folates, which are usually polyglutamylated, the folate derivatives are hydrolyzed to a mono-glutamate level prior to transport by the enzyme EC, γ-glutamyl hydrolase. The monoglutamylated forms are then metabolized within the enterocyte into N5-methyl-tetrahydropteroyl mono-L-glutamate. 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 EC, methionine synthase, to monoglutamyl tetrahydrofolate (H4PteGlu1).

γ-Glutamyl hydrolases were characterized from multiple sources, and exhibit either endo- or exopeptidase activity, depending on the organism and tissue of origin [Elsenhans84]. In mammals they are often lysosomal with an acidic pH optimum [Brody90]. The enzyme is often sulfhydryl and zinc dependent [Chandler86, Bhandari90], may be heavily glycosylated [Silink75, Wang93a], and has molecular mass between 50 and 150 kDa.

Created 03-Nov-2004 by Caspi R, SRI International
Revised 22-Sep-2010 by Caspi R, SRI International


Bhandari90: Bhandari SD, Gregory JF, Renuart DR, Merritt AM (1990). "Properties of pteroylpolyglutamate hydrolase in pancreatic juice of the pig." J Nutr 120(5);467-75. PMID: 2341911

Brody90: Brody T, Stokstad EL (1990). "Association of folic acid with rat liver microsomes." Mol Cell Biochem 97(1);67-73. PMID: 2174100

Chandler86: Chandler CJ, Wang TT, Halsted CH (1986). "Pteroylpolyglutamate hydrolase from human jejunal brush borders. Purification and characterization." J Biol Chem 261(2);928-33. PMID: 2867095

Elsenhans84: Elsenhans B, Ahmad O, Rosenberg IH (1984). "Isolation and characterization of pteroylpolyglutamate hydrolase from rat intestinal mucosa." J Biol Chem 259(10);6364-8. PMID: 6547136

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

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

Murata00: Murata T, Bognar AL, Hayashi T, Ohnishi M, Nakayama K, Terawaki Y (2000). "Molecular analysis of the folC gene of Pseudomonas aeruginosa." Microbiol Immunol 44(11);879-86. PMID: 11145267

Silink75: Silink M, Reddel R, Bethel M, Rowe PB (1975). "Gamma-glutamyl hydrolase conjugase. Purification and properties of the bovine hepatic enzyme." J Biol Chem 250(15);5982-94. PMID: 1150668

Sun01: Sun X, Cross JA, Bognar AL, Baker EN, Smith CA (2001). "Folate-binding triggers the activation of folylpolyglutamate synthetase." J Mol Biol 310(5);1067-78. PMID: 11501996

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

Wang93a: Wang Y, Nimec Z, Ryan TJ, Dias JA, Galivan J (1993). "The properties of the secreted gamma-glutamyl hydrolases from H35 hepatoma cells." Biochim Biophys Acta 1164(3);227-35. PMID: 8343522

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

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

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

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

Yao95: Yao R, Rhee MS, Galivan J (1995). "Effects of gamma-glutamyl hydrolase on folyl and antifolylpolyglutamates in cultured H35 hepatoma cells." Mol Pharmacol 48(3);505-11. PMID: 7565632

Yao96: Yao R, Schneider E, Ryan TJ, Galivan J (1996). "Human gamma-glutamyl hydrolase: cloning and characterization of the enzyme expressed in vitro." Proc Natl Acad Sci U S A 93(19);10134-8. PMID: 8816764

Yao96a: Yao R, Nimec Z, Ryan TJ, Galivan J (1996). "Identification, cloning, and sequencing of a cDNA coding for rat gamma-glutamyl hydrolase." J Biol Chem 271(15);8525-8. PMID: 8621474

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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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