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. 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.
Synonyms: folic acid biosynthesis, folate biosynthesis, THF biosynthesis
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Vitamins Biosynthesis → Folate Biosynthesis|
Some taxa known to possess this pathway include : Arabidopsis thaliana col, Escherichia coli K-12 substr. MG1655, Glycine max, Lactococcus lactis, Pisum sativum, Saccharomyces cerevisiae, Solanum lycopersicum
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].
The product of this pathway, tetrahydropteroyl mono-L-glutamate (tetrahydropteroylmonoglutamate, H4PteGlu1, THF), 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
This pathway for the de novo biosynthesis of folates is found in bacteria, fungi, and plants. Folates are tripartite molecules and are made up of a pterin, 4-aminobenzoate and L-glutamate moieties. The first two are synthesized from GTP and chorismate, respectively (see pathway 6-hydroxymethyl-dihydropterin diphosphate biosynthesis I for the biosynthesis of the former). The consecutive action of the FolK, FolP, FolC, and FolA enzymes finally produces the final product, tetrahydropteroyl mono-L-glutamate [Illarionova02].
In plants the pterin moiety is formed from GTP in the cytosol, which couples to pABA (synthesized in plastids) in mitochondria followed by subsequent glutamylation and reduction steps which may take place in cytosol, mitochondria and plastids [Hanson02, Ravanel01]. The recent discovery that folylpolyglutamate synthases are present in cytosol, mitochondria and plastids with each of them encoded by a different gene in Arabidopsis thaliana [Ravanel01] points to the fact that at least parts of the pathway can be carried out independently in those compartments.
In addition to the de novo pathway, many organisms also possess salvage pathways that are used to re-synthesize tetrahydrofolate from breakdown products of folates in the cell, such as 5 or 10-formyl-tetrahydrofolate.
About Folates In Animals
While plants and many microorganisms can synthesize folate coenzymes by the de novo synthesis pathway, vertebrates are absolutely dependent on nutritional sources, making folate a vitamin. Food folates exist mainly as N5-methyl-tetrahydropteroyl mono-L-glutamate (5-methyl-H4PteGlun) and 10-formyl-tetrahydrofolate mono-L-glutamate (formyl-H4PteGlun) [Thien77].
Polyglutamyl folates are hydrolyzed to folylmonoglutamates by γ-glutamyl hydrolase, and metabolized within the enterocyte into 5-methyl-H4PteGlu1. 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 folylpolyglutamate γ-glutamyl hydrolase to monoglutamyl tetrahydrofolate (H4PteGlu1).
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]).
Unification Links: EcoCyc:PWY-6614
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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
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