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Caulobacter crescentus CB15 Pathway: folate polyglutamylation

Note: a dashed line (without arrowheads) between two compound names is meant to imply that the two names are just different instantiations of the same compound -- i.e. one may be a specific name and the other a general name, or they may both represent the same compound in different stages of a polymerization-type pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Locations of Mapped Genes:

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

Pathway Summary from MetaCyc:
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 6.3.2.17, 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# 6.3.2.12).

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 , formylTHF biosynthesis I , superpathway of tetrahydrofolate biosynthesis , superpathway of tetrahydrofolate biosynthesis and salvage , tetrahydrofolate biosynthesis , tetrahydrofolate salvage from 5,10-methenyltetrahydrofolate

Pathway Evidence Glyph:

Key to pathway glyph edge colors: ?

  An enzyme catalyzing this reaction is present in this organism
  An enzyme catalyzing this reaction was identified in this organism by the Pathway Hole Filler
  No enzyme catalyzing this reaction has been identified in this organism
  The reaction and any enzyme that catalyzes it (if one has been identified) is unique to this pathway
  Represents spontaneous reactions, or lines that do not represent reactions (e.g. in polymerization pathways)

Credits:
Created 02-Nov-2004 by Caspi R , SRI International


References

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

Moran99: Moran RG (1999). "Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview." Semin Oncol 26(2 Suppl 6);24-32. PMID: 10598551

Shane89: Shane B (1989). "Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism." Vitam Horm 45;263-335. PMID: 2688305

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

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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