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 → Folate Transformations|
Some taxa known to possess this pathway include : Blautia producta, Clostridium formicaceticum, Escherichia coli K-12 substr. MG1655, Hyphomicrobium methylovorum GM2, Hyphomicrobium zavarzinii ZV580, Lactobacillus casei, Methylobacterium extorquens AM1, Methylobacterium organophilum, Moorella thermoacetica, Pseudomonas sp. MS
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The various folate coenzymes 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. They also mediate the interconversion of serine and glycine ( EC 126.96.36.199, glycine hydroxymethyltransferase), and play a role in histidine catabolism [Lucock00].
Tetrahydrofolate (tetrahydropteroylmonoglutamate, H4PteGlu1, THF), is merely the parent structure of this large family of coenzymes. The folate coenzymes differ in the oxidation state of the pteridine ring, the character of the one-carbon substituent at the N5 and N10 positions, and the number of glutamic acid moieties conjugated one to another via a series of γ-glutamyl links to form an oligo-γ-glutamyl tail (see the pathway glutamate removal from folates for more information on this subject). There are numerous enzymes that convert the folates from one form to another, and the important ones are included in this pathway.
Important folate coenzymes include the mono- and polyglutamylated forms of tetrahydrofolate (H4PteGlun), N5-formyl tetrahydrofolate (5-formyl-H4PteGlun), N10-formyl tetrahydrofolate (10-formyl-H4PteGlun), 5,10-methenyl-tetrahydrofolate (5,10-methenyl-H4PteGlun), 5,10-methylene-tetrahydrofolate (5,10-methylene-H4PteGlun), and 5-methyl-tetrahydrofolate (5-methyl-H4PteGlun).
Folate cofactors are particularly important in the methylotrophs - the bacteria that can utilize C1 (single carbon)compounds as their sole carbon and energy source. In the methylotroph Methylobacterium extorquens AM1, formaldehyde that enters the cytoplasm condenses with one of the two pterin cofactors, tetrahydrofolate or tetrahydromethanopterin (H4MPT), and forms the respective methylene derivative (see the pathway formate assimilation into 5,10-methylenetetrahydrofolate).
The reaction of formaledehyde with THF is spontaneous [Kallen66, Marx03], and produces 5,10-methylene-THF, which can be metabolized in two ways: it can enter the serine cycle (see formaldehyde assimilation I (serine pathway)), where the carbon is used for biosysnthesis, or it may be oxidized via 5,10-methenyl-THF to 10-formyl-THF. 10-formyl-THF can be eventually converted back to THF, releasing formate which is oxidized to CO2 (see formate oxidation to CO2) [Goenrich02, Pomper99, Pomper02]. This route is completely reversible, and can flow in both directions; as described above it catalyzes the oxidation of formaldehyde to formate. However, in the other direction, it catalyzes the conversion of formate (which accumulates through the pathway formaldehyde oxidation V (H4MPT pathway)) to methylene-tetrahydrofolate, which feeds the serine cycle, a formaldehyde assimilation cycle ( formaldehyde assimilation I (serine pathway)).
Vertebrates are not able to synthesize folates, and are completely dependent on folates in their diet. Dietary folates exist mainly as poly and mono-glutamylated 5-methyl-THF and formyl-THF [Thien77]. Polyglutamyl folates in food are hydrolyzed to folylmonoglutamates by EC 188.8.131.52, γ-glutamyl hydrolase), and metabolized within the enterocyte into 5-methyl-H4PteGlu1. This monoglutamyl folate is the main form of the vitamin in the plasma [Herbert62, Lucock89], and is transported to peripheral tissues. In the tissues it is demethylated by vitamin B12-dependent EC 184.108.40.206, methionine synthase, to monoglutamyl tetrahydrofolate (H4PteGlu1). This H4PteGlu1 form is the preferred substrate of EC 220.127.116.11, tetrahydrofolate synthase, which conjugates glutamate moieties to generate oligo-γ-glutamyl H4PteGlu. The predominant product of this reaction is the hexaglutamyl-HPteGlu form [Cook87]. The conversion of 5- methyl-H44PteGlu1 into H44PteGlu1 by vitamin B12- dependent methionine synthase is thus responsible for the conversion of extracellular 5-methyl-H4PteGlu1 from dietary sources into the form that can be used in the biosynthetic pathways [Green88].
In erythrocites folate is largely present in the forms of 5- methyl-H44PteGlun and formyl-H44PteGlun, mostly containing five or six glutamate residues [Lucock00a, Perry76]. However, the active forms of folate required for nucleotide synthesis are 10-formyl-H4PteGlun and 5,10-methylene-H4PteGlun. 5,10-methylene-H4PteGlun is also required by EC 18.104.22.168, methylenetetrahydrofolate reductase [NAD(P)H], in the biosynthesis of methionine. Thus, 5,10-methylene-H4PteGlun is at the branch point of three important pathways [Green88].
Variants: folate transformations II
Cook87: Cook JD, Cichowicz DJ, George S, Lawler A, Shane B (1987). "Mammalian folylpoly-gamma-glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis." Biochemistry 26(2);530-9. PMID: 3828323
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Lucock00a: Lucock M, Daskalakis I, Briggs D, Yates Z, Levene M (2000). "Altered folate metabolism and disposition in mothers affected by a spina bifida pregnancy: influence of 677c --> t methylenetetrahydrofolate reductase and 2756a --> g methionine synthase genotypes." Mol Genet Metab 70(1);27-44. PMID: 10833329
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