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|
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 (as described in superpathway of tetrahydrofolate biosynthesis and salvage) the enzyme EC 18.104.22.168, tetrahydrofolate synthase (encoded in Escherichia coli by folC) adds a glutamate residue to 7,8-dihydropteroate, resulting in 7,8-dihydrofolate, also known as H2PteGlu1. This molecule in turn is reduced by dihydrofolate reductase (FolA) to tetrahydrofolate (H4PteGlu1, or THF). 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 glutamate residues, forming folate polyglutamtes (or folylpoly-γ-glutamates). Most of the glutamates 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 not the normal amide bonds they are not hydrolyzed by peptidases or proteases that are specific for α-carboxyl-linked peptide bonds.
The addition of glutamyl residues probably occurs after the reduction of newly synthesized dihydrofolate to tetrahydrofolate and its conversion to other tetrahydrofolate derivatives.
Apparently, the glutamylation of folate residues serves several goals: it prevents the efflux of folates out of the cell, it increases the binding of folate cofactors to the enzymes of folate interconversion and biosynthesis, and in mammals, it allows the accumulation of folates in the mitochondria, which is required for glycine synthesis [Moran99]. Folylpolyglutamates are generally better substrates for folate-dependent enzymes than their monoglutamyl counterparts. Km values decrease with increasing oligo-γ-glutamyl chain length [Shane89]. At least in one case, the vitamin B12-independent methionine synthetase, there is an absolute requirement for the polyglutamate cofactor [Bognar85].
In addition, many folate enzymes are multifunctional and channel one-carbon units between reactions without achieving equilibrium with the cell medium. Therefore, the conjugated oligo-γ-glutamyl chain can potentially regulate the reaction rates, and allows channeling of the substrate between enzymes in a way which controls biosynthetic pathways [Shane89].
Folylpoly-γ-glutamate synthetase (FPGS), the enzyme that catalyzes the conversion of folates to polyglutamates, has been purified from several organisms, including Escherichia coli [Bognar85]. It is a MgATP-dependent enzyme present in all cells. FPGS forms a complex with MgATP, a folate derivative, and glutamate, in an ordered manner whereby the three substrates are added sequentially [Sun01]. In Escherichia coli, FPGS is a bi-functional enzyme, which also catalyzes the addition of glutamate to 7,8-dihydropteroate, generating 7,8,-dihydrofolate (dihydrofolate synthetase, (E.C# 22.214.171.124).
In exponentially growing cells of Escherichia coli folylpoly-γ- glutamates have short glutamate chain lengths: mono- and triglutamate derivatives are most abundant, with tetra-, penta- and hexaglutamate derivatives also present (in order of decreasing abundance). However, in stationary phase, cells contain longer-chain-length folypolyglutamates, with the predominant chain length containing six or seven glutamyl residues. These longer chains are generated by a second enzyme, which adds glutamate moieties in α-linkage to tetrahydropteroyl- triglutamates [Ferone86]. However, this enzyme has not been purified, nor has the gene encoding it been identified.
Both folylpolyglutamate synthetases can accept several different folate derivatives as substrates. It seems that the preferred substrate for the addition of a second glutamate residue is 10-formyl-THF (10-formyl-H4PteGlu1), while the preferred substrate for the addition of a third glutamate residue is the glutamated form of 5,10-methylene-THF (5,10-methylene-H4PteGlu2).
Variants: 4-aminobenzoate biosynthesis , folate transformations I , folate transformations II , glutamate removal from folates , N10-formyl-tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis and salvage , tetrahydrofolate biosynthesis , tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate
Unification Links: EcoCyc:PWY-2161
Bognar85: Bognar AL, Osborne C, Shane B, Singer SC, Ferone R (1985). "Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product." J Biol Chem 1985;260(9);5625-30. PMID: 2985605
Ferone86: Ferone R, Singer SC, Hunt DF (1986). "In vitro synthesis of alpha-carboxyl-linked folylpolyglutamates by an enzyme preparation from Escherichia coli." J Biol Chem 261(35);16363-71. PMID: 3536926
Beckmann97: Beckmann K, Dzuibany C, Biehler K, Fock H, Hell R, Migge A, Becker TW (1997). "Photosynthesis and fluorescence quenching, and the mRNA levels of plastidic glutamine synthetase or of mitochondrial serine hydroxymethyltransferase (SHMT) in the leaves of the wild-type and of the SHMT-deficient stm mutant of Arabidopsis thaliana in relation to the rate of photorespiration." Planta 202(3);379-86. PMID: 9232907
Bognar87: Bognar AL, Osborne C, Shane B (1987). "Primary structure of the Escherichia coli folC gene and its folylpolyglutamate synthetase-dihydrofolate synthetase product and regulation of expression by an upstream gene." J Biol Chem 262(25);12337-43. PMID: 3040739
Cai95: Cai K, Schirch D, Schirch V (1995). "The affinity of pyridoxal 5'-phosphate for folding intermediates of Escherichia coli serine hydroxymethyltransferase." J Biol Chem 270(33);19294-9. PMID: 7642604
Capela01: Capela D, Barloy-Hubler F, Gouzy J, Bothe G, Ampe F, Batut J, Boistard P, Becker A, Boutry M, Cadieu E, Dreano S, Gloux S, Godrie T, Goffeau A, Kahn D, Kiss E, Lelaure V, Masuy D, Pohl T, Portetelle D, Puhler A, Purnelle B, Ramsperger U, Renard C, Thebault P, Vandenbol M, Weidner S, Galibert F (2001). "Analysis of the chromosome sequence of the legume symbiont Sinorhizobium meliloti strain 1021." Proc Natl Acad Sci U S A 98(17);9877-82. PMID: 11481430
Chen96: Chen L, Qi H, Korenberg J, Garrow TA, Choi YJ, Shane B (1996). "Purification and properties of human cytosolic folylpoly-gamma-glutamate synthetase and organization, localization, and differential splicing of its gene." J Biol Chem 271(22);13077-87. PMID: 8662720
Chistoserdova94b: Chistoserdova LV, Lidstrom ME (1994). "Genetics of the serine cycle in Methylobacterium extorquens AM1: cloning, sequence, mutation, and physiological effect of glyA, the gene for serine hydroxymethyltransferase." J Bacteriol 176(21);6759-62. PMID: 7961431
Contestabile00: Contestabile R, Angelaccio S, Bossa F, Wright HT, Scarsdale N, Kazanina G, Schirch V (2000). "Role of tyrosine 65 in the mechanism of serine hydroxymethyltransferase." Biochemistry 39(25);7492-500. PMID: 10858298
Delle94: Delle Fratte S, Iurescia S, Angelaccio S, Bossa F, Schirch V (1994). "The function of arginine 363 as the substrate carboxyl-binding site in Escherichia coli serine hydroxymethyltransferase." Eur J Biochem 225(1);395-401. PMID: 7925461
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
Fitzpatrick98: Fitzpatrick TB, Malthouse JP (1998). "A substrate-induced change in the stereospecificity of the serine-hydroxymethyltransferase-catalysed exchange of the alpha-protons of amino acids--evidence for a second catalytic site." Eur J Biochem 252(1);113-7. PMID: 9523719
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