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:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Folate Biosynthesis|
Expected Taxonomic Range: Eukaryota
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 18.104.22.168, 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 22.214.171.124, 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 126.96.36.199, 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, Wang93c], and has molecular mass between 50 and 150 kDa.
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
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
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
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