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:
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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 220.127.116.11, 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 reduction to 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 18.104.22.168, 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 22.214.171.124, methionine synthase, to monoglutamyl tetrahydrofolate (H4PteGlu1). This H4PteGlu1 form is the preferred substrate of EC 126.96.36.199, 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 [Green88a].
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 188.8.131.52, methylenetetrahydrofolate reductase [NAD(P)H], in the biosynthesis of methionine. Thus, 5,10-methylene-H4PteGlun is at the branch point of three important pathways [Green88a].
Variants: 4-aminobenzoate biosynthesis , folate polyglutamylation , 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
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
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
Goenrich02: Goenrich M, Bursy J, Hubner E, Linder D, Schwartz AC, Vorholt JA (2002). "Purification and characterization of the methylene tetrahydromethanopterin dehydrogenase MtdB and the methylene tetrahydrofolate dehydrogenase FolD from Hyphomicrobium zavarzinii ZV580." Arch Microbiol 177(4);299-303. PMID: 11889483
Green88a: Green JM, MacKenzie RE, Matthews RG (1988). "Substrate flux through methylenetetrahydrofolate dehydrogenase: predicted effects of the concentration of methylenetetrahydrofolate on its partitioning into pathways leading to nucleotide biosynthesis or methionine regeneration." Biochemistry 27(21);8014-22. PMID: 3266075
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
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
Marx03: Marx CJ, Chistoserdova L, Lidstrom ME (2003). "Formaldehyde-detoxifying role of the tetrahydromethanopterin-linked pathway in Methylobacterium extorquens AM1." J Bacteriol 185(24);7160-8. PMID: 14645276
Pomper02: Pomper BK, Saurel O, Milon A, Vorholt JA (2002). "Generation of formate by the formyltransferase/hydrolase complex (Fhc) from Methylobacterium extorquens AM1." FEBS Lett 523(1-3);133-7. PMID: 12123819
Pomper99: Pomper BK, Vorholt JA, Chistoserdova L, Lidstrom ME, Thauer RK (1999). "A methenyl tetrahydromethanopterin cyclohydrolase and a methenyl tetrahydrofolate cyclohydrolase in Methylobacterium extorquens AM1." Eur J Biochem 261(2);475-80. PMID: 10215859
Howard06: Howard EC, Henriksen JR, Buchan A, Reisch CR, Burgmann H, Welsh R, Ye W, Gonzalez JM, Mace K, Joye SB, Kiene RP, Whitman WB, Moran MA (2006). "Bacterial taxa that limit sulfur flux from the ocean." Science 314(5799);649-52. PMID: 17068264
Park06: Park YJ, Yoo CB, Choi SY, Lee HB (2006). "Purifications and characterizations of a ferredoxin and its related 2-oxoacid:ferredoxin oxidoreductase from the hyperthermophilic archaeon, Sulfolobus solfataricus P1." J Biochem Mol Biol 39(1);46-54. PMID: 16466637
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