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Record Information
Creation Date2005-11-16 15:48:42 UTC
Update Date2016-02-11 01:04:24 UTC
Secondary Accession NumbersNone
Metabolite Identification
Common Name5,10-Methenyltetrahydrofolic acid
DescriptionFolate is important for cells and tissues that rapidly divide. Cancer cells divide rapidly, and drugs that interfere with folate metabolism are used to treat cancer. Methotrexate is a drug often used to treat cancer because it inhibits the production of the active form, tetrahydrofolate. Unfortunately, methotrexate can be toxic, producing side effects such as inflammation in the digestive tract that make it difficult to eat normally. Folinic acid is a form of folate that can help 'rescue' or reverse the toxic effects of methotrexate. Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy. There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients receiving methotrexate cancer chemotherapy. It is important for anyone receiving methotrexate to follow medical advice on the use of folic or folinic acid supplements. Low concentrations of folate, vitamin B12, or vitamin B6 may increase your level of homocysteine, an amino acid normally found in your blood. There is evidence that an elevated homocysteine level is an independent risk factor for heart disease and stroke. The evidence suggests that high levels of homocysteine may damage coronary arteries or make it easier for blood clotting cells called platelets to clump together and form a clot. However, there is currently no evidence available to suggest that lowering homocysteine with vitamins will reduce your risk of heart disease. Clinical intervention trials are needed to determine whether supplementation with folic acid, vitamin B12 or vitamin B6 can lower your risk of developing coronary heart disease. Methylene tetrahydrofolate (CH2FH4) is formed from tetrahydrofolate by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate(CH3FH4) can be made from methylene tetrahydrofolate by reduction of the methylene group, and formyl tetrahydrofolate (CHOFH4, folinic acid) is made by oxidation of methylene tetrahydrofolate. In the form of a series of tetrahydrofolate compounds, folate derivatives are substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2'-deoxythymidine-5'-phosphate) from dUMP (2'-deoxyuridine-5'-phosphate). It helps convert vitamin B12 to one of its coenzyme forms and helps synthesize the DNA required for all rapidly growing cells.
anhydro-Leucovorin aHMDB
Anhydroleucovorin aHMDB
Methenyltetrahydrofolic acidHMDB
Chemical FormulaC20H21N7O6
Average Molecular Weight455.424
Monoisotopic Molecular Weight455.155331439
IUPAC Name(6aR)-3-amino-8-(4-{[(1S)-3-carboxy-1-carboxylatopropyl]carbamoyl}phenyl)-1-oxo-1H,4H,5H,6H,6aH,7H,8H-10λ⁵-imidazo[1,5-f]pteridin-10-ylium
Traditional Name(6aR)-3-amino-8-(4-{[(1S)-3-carboxy-1-carboxylatopropyl]carbamoyl}phenyl)-1-oxo-4H,5H,6H,6aH,7H-10λ⁵-imidazo[1,5-f]pteridin-10-ylium
CAS Registry Number7444-29-3
InChI Identifier
Chemical Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as tetrahydrofolic acids. These are heterocyclic compounds based on the 5,6,7,8-tetrahydropteroic acid skeleton conjugated with at least one L-glutamic acid unit.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPteridines and derivatives
Sub ClassPterins and derivatives
Direct ParentTetrahydrofolic acids
Alternative Parents
  • Tetrahydrofolic acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Hippuric acid
  • Hippuric acid or derivatives
  • Aminobenzoic acid or derivatives
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Benzoic acid or derivatives
  • Benzamide
  • Aminobenzamide
  • Benzoyl
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Benzenoid
  • Pyrimidine
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous amide
  • 2-imidazoline
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Carboxylic acid salt
  • Carboxamide group
  • Azacycle
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Secondary amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Carboxylic acid amidine
  • Amidine
  • Hydrocarbon derivative
  • Organic salt
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Organic zwitterion
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
StatusExpected but not Quantified
  • Endogenous
  • Component of Cyanoamino acid metabolism
  • Component of Glycine, serine and threonine metabolism
  • Component of Glyoxylate and dicarboxylate metabolism
  • Component of Methane metabolism
  • Component of Nitrogen metabolism
  • Component of Pyrimidine metabolism
  • DNA component
ApplicationNot Available
Cellular locations
  • Cytoplasm
  • Mitochondria
Physical Properties
Experimental Properties
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
Water Solubility0.21 mg/mLALOGPS
pKa (Strongest Acidic)3.22ChemAxon
pKa (Strongest Basic)1.27ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area192.29 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity145.01 m3·mol-1ChemAxon
Polarizability43.91 Å3ChemAxon
Number of Rings4ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-0000900000-9a74d30be444557240b0View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a4i-0000900000-87ffec278a0d552070d3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-056r-9210100000-8e44a81962b4227dbc32View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0000900000-6e21d81553cf048dcee3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0udi-2000900000-e3e2170131566f2c34e9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9300100000-8e0fa01b9b99e8b1fea8View in MoNA
Biological Properties
Cellular Locations
  • Cytoplasm
  • Mitochondria
Biofluid LocationsNot Available
Tissue LocationNot Available
Folate malabsorption, hereditarySMP00724Not Available
Folate MetabolismSMP00053map00670
Methotrexate PathwaySMP00432Not Available
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)SMP00543Not Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDNot Available
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB022573
KNApSAcK IDNot Available
Chemspider ID559356
KEGG Compound IDC00445
BioCyc ID5,10-methenyl-thf
BiGG ID34999
Wikipedia LinkNot Available
NuGOwiki LinkHMDB01354
Metagene LinkHMDB01354
PubChem Compound644350
PDB IDNot Available
ChEBI ID15636
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Field MS, Anderson DD, Stover PJ: Mthfs is an Essential Gene in Mice and a Component of the Purinosome. Front Genet. 2011;2:36. doi: 10.3389/fgene.2011.00036. [22303332 ]
  2. Oberpichler I, Pierik AJ, Wesslowski J, Pokorny R, Rosen R, Vugman M, Zhang F, Neubauer O, Ron EZ, Batschauer A, Lamparter T: A photolyase-like protein from Agrobacterium tumefaciens with an iron-sulfur cluster. PLoS One. 2011;6(10):e26775. doi: 10.1371/journal.pone.0026775. Epub 2011 Oct 31. [22066008 ]
  3. Telegina TA, Liudnikova TA, Zemskova IuL, Sviridov EA, Kritskii MS: [Tolerance of 5,10-methenyltetrahydrofolate to ultraviolet radiation]. Prikl Biokhim Mikrobiol. 2005 May-Jun;41(3):315-23. [15977793 ]
  4. Eadsforth TC, Cameron S, Hunter WN: The crystal structure of Leishmania major N(5),N(10)-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target. Mol Biochem Parasitol. 2012 Feb;181(2):178-85. doi: 10.1016/j.molbiopara.2011.11.004. Epub 2011 Nov 15. [22108435 ]
  5. Lin CJ, Wen MJ, Hung YJ, Pei D, Kuo SW, Hsieh CH: The impact of 5,10-methenyltetrahydrofolate synthetase polymorphism on diabetic nephropathy in the Taiwanese population. Genet Test Mol Biomarkers. 2012 Feb;16(2):142-5. doi: 10.1089/gtmb.2011.0050. Epub 2011 Sep 6. [21895484 ]
  6. Field MS, Szebenyi DM, Stover PJ: Regulation of de novo purine biosynthesis by methenyltetrahydrofolate synthetase in neuroblastoma. J Biol Chem. 2006 Feb 17;281(7):4215-21. Epub 2005 Dec 19. [16365037 ]
  7. Kruszyna L, Lianeri M, Rydzanicz M, Gajecka M, Szyfter K, Jagodzinski PP: Polymorphic variants of folate metabolism genes and the risk of laryngeal cancer. Mol Biol Rep. 2010 Jan;37(1):241-7. doi: 10.1007/s11033-009-9643-y. Epub 2009 Aug 1. [19649727 ]
  8. Moldt J, Pokorny R, Orth C, Linne U, Geisselbrecht Y, Marahiel MA, Essen LO, Batschauer A: Photoreduction of the folate cofactor in members of the photolyase family. J Biol Chem. 2009 Aug 7;284(32):21670-83. doi: 10.1074/jbc.M109.018697. Epub 2009 Jun 16. [19531478 ]
  9. Ogwang S, Nguyen HT, Sherman M, Bajaksouzian S, Jacobs MR, Boom WH, Zhang GF, Nguyen L: Bacterial conversion of folinic acid is required for antifolate resistance. J Biol Chem. 2011 Apr 29;286(17):15377-90. doi: 10.1074/jbc.M111.231076. Epub 2011 Mar 3. [21372133 ]
  10. Watkins D, Rosenblatt DS: Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis. 2012 Jul;35(4):665-70. doi: 10.1007/s10545-011-9418-1. Epub 2011 Nov 23. [22108709 ]
  11. Kariluoto S, Edelmann M, Herranen M, Lampi AM, Shmelev A, Salovaara H, Korhola M, Piironen V: Production of folate by bacteria isolated from oat bran. Int J Food Microbiol. 2010 Sep 30;143(1-2):41-7. doi: 10.1016/j.ijfoodmicro.2010.07.026. Epub 2010 Aug 11. [20708290 ]
  12. Selby CP, Sancar A: The second chromophore in Drosophila photolyase/cryptochrome family photoreceptors. Biochemistry. 2012 Jan 10;51(1):167-71. doi: 10.1021/bi201536w. Epub 2011 Dec 27. [22175817 ]
  13. Jahansouz H, Scherubel DM, Himes RH: Formylation of tetrahydrofolate by formyl phosphate. FEBS Lett. 1990 Mar 26;262(2):366-8. [2335221 ]
  14. Tolley M, Bickford L, Clare K, Johann TW: Investigations of amino acids in the ATP binding site of 5,10-methenyltetrahydrofolate synthetase. Protein J. 2012 Aug;31(6):519-28. doi: 10.1007/s10930-012-9428-3. [22773193 ]
  15. Wijaya IM, Zhang Y, Iwata T, Yamamoto J, Hitomi K, Iwai S, Getzoff ED, Kandori H: Detection of distinct alpha-helical rearrangements of cyclobutane pyrimidine dimer photolyase upon substrate binding by Fourier transform infrared spectroscopy. Biochemistry. 2013 Feb 12;52(6):1019-27. doi: 10.1021/bi3016179. Epub 2013 Jan 30. [23331252 ]
  16. Upadhyay V, Demmer U, Warkentin E, Moll J, Shima S, Ermler U: Structure and catalytic mechanism of N(5),N(10)-methenyl-tetrahydromethanopterin cyclohydrolase. Biochemistry. 2012 Oct 23;51(42):8435-43. doi: 10.1021/bi300777k. Epub 2012 Oct 8. [23013430 ]
  17. Kirsch SH, Knapp JP, Herrmann W, Obeid R: Quantification of key folate forms in serum using stable-isotope dilution ultra performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Jan 1;878(1):68-75. doi: 10.1016/j.jchromb.2009.11.021. Epub . [19959403 ]
  18. Knock E, Deng L, Krupenko N, Mohan RD, Wu Q, Leclerc D, Gupta S, Elmore CL, Kruger W, Tini M, Rozen R: Susceptibility to intestinal tumorigenesis in folate-deficient mice may be influenced by variation in one-carbon metabolism and DNA repair. J Nutr Biochem. 2011 Nov;22(11):1022-9. doi: 10.1016/j.jnutbio.2010.07.015. Epub 2010 Dec 28. [21193302 ]


General function:
Involved in catalytic activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
Glycineamideribotide + 5,10-Methenyltetrahydrofolic acid + Water → 5'-Phosphoribosyl-N-formylglycinamide + Tetrahydrofolic aciddetails
General function:
Involved in catalytic activity
Specific function:
Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool. Binds and promotes bundling of vimentin filaments originating from the Golgi (By similarity).
Gene Name:
Uniprot ID:
Molecular weight:
5-Formiminotetrahydrofolic acid → 5,10-Methenyltetrahydrofolic acid + Ammoniadetails
5-Formiminotetrahydrofolic acid + Hydrogen Ion → 5,10-Methenyltetrahydrofolic acid + Ammoniadetails
General function:
Involved in aminomethyltransferase activity
Specific function:
The glycine cleavage system catalyzes the degradation of glycine.
Gene Name:
Uniprot ID:
Molecular weight:
N5-Formyl-THF → 5,10-Methenyltetrahydrofolic acid + Waterdetails
General function:
Involved in catalytic activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
5,10-Methylene-THF + NAD → 5,10-Methenyltetrahydrofolic acid + NADHdetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolatedetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolate + Hydrogen Iondetails
General function:
Involved in formate-tetrahydrofolate ligase activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
5,10-Methylene-THF + NADP → 5,10-Methenyltetrahydrofolic acid + NADPHdetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolatedetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolate + Hydrogen Iondetails
General function:
Involved in ATP binding
Specific function:
Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids.
Gene Name:
Uniprot ID:
Molecular weight:
Adenosine triphosphate + N5-Formyl-THF → ADP + Phosphoric acid + 5,10-Methenyltetrahydrofolic aciddetails
Adenosine triphosphate + N5-Formyl-THF + Hydrogen Ion → ADP + Phosphoric acid + 5,10-Methenyltetrahydrofolic aciddetails
General function:
Involved in catalytic activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
5,10-Methylene-THF + NAD → 5,10-Methenyltetrahydrofolic acid + NADHdetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolatedetails
5,10-Methenyltetrahydrofolic acid + Water → 10-Formyltetrahydrofolate + Hydrogen Iondetails
General function:
Involved in formate-tetrahydrofolate ligase activity
Specific function:
May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism in embryonic an transformed cells complementing thus the enzymatic activities of MTHFD2 (By similarity).
Gene Name:
Uniprot ID:
Molecular weight:
General function:
Involved in catalytic activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight: