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Record Information
StatusDetected and Quantified
Creation Date2006-02-08 11:18:35 UTC
Update Date2020-05-14 21:00:58 UTC
Secondary Accession Numbers
  • HMDB0014264
  • HMDB0062806
  • HMDB01846
  • HMDB14264
  • HMDB62806
Metabolite Identification
Common NameTetrahydrofolic acid
DescriptionTetrahydrofolate is a soluble coenzyme (vitamin B9) that is synthesized de novo by plants and microorganisms, and absorbed from the diet by animals. It is composed of three distinct parts: a pterin ring, a p-ABA (p-aminobenzoic acid) and a polyglutamate chain with a number of residues varying between 1 and 8. Only the tetra-reduced form of the molecule serves as a coenzyme for C1 transfer reactions. In biological systems, the C1-units exist under various oxidation states and the different tetrahydrofolate derivatives constitute a family of related molecules named indistinctly under the generic term folate. (PMID 16042593 ). Folate 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. -- Wikipedia ; Signs of folic acid deficiency are often subtle. Diarrhea, loss of appetite, and weight loss can occur. Additional signs are weakness, sore tongue, headaches, heart palpitations, irritability, and behavioral disorders. Women with folate deficiency who become pregnant are more likely to give birth to low birth weight and premature infants, and infants with neural tube defects. In adults, anemia is a sign of advanced folate deficiency. In infants and children, folate deficiency can slow growth rate. Some of these symptoms can also result from a variety of medical conditions other than folate deficiency. It is important to have a physician evaluate these symptoms so that appropriate medical care can be given. -- Wikipedia ; 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. -- Wikipedia . Low concentrations of folate, vitamin B12, or vitamin B6 may increase the level of homocysteine, an amino acid normally found in 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. -- Wikipedia .
(6S)-Tetrahydrofolic acidHMDB
5,6,7,8-Tetrahydrofolic acidHMDB
Tetrahydropteroyl mono-L-glutamateHMDB
Chemical FormulaC19H23N7O6
Average Molecular Weight445.4292
Monoisotopic Molecular Weight445.170981503
IUPAC Name2-{[4-({[(6S)-2-amino-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)phenyl]formamido}pentanedioic acid
Traditional Name2-{[4-({[(6S)-2-amino-4-oxo-5,6,7,8-tetrahydro-1H-pteridin-6-yl]methyl}amino)phenyl]formamido}pentanedioic acid
CAS Registry Number135-16-0
InChI Identifier
Chemical Taxonomy
Description belongs to the class of organic compounds known as xanthines. These are purine derivatives with a ketone group conjugated at carbons 2 and 6 of the purine moiety.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
Sub ClassPurines and purine derivatives
Direct ParentXanthines
Alternative Parents
  • Xanthine
  • Purinone
  • 6-oxopurine
  • Alkaloid or derivatives
  • Pyrimidone
  • Pyrimidine
  • N-substituted imidazole
  • Heteroaromatic compound
  • Vinylogous amide
  • Imidazole
  • Azole
  • Urea
  • Lactam
  • Azacycle
  • Organic nitrogen compound
  • Organic oxygen compound
  • Organopnictogen compound
  • Organic oxide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors


Biological location:


Naturally occurring process:


Industrial application:

Physical Properties
Experimental Properties
Melting Point250 °CNot Available
Boiling PointNot AvailableNot Available
Water Solubility0.27 g/LNot Available
LogP-2.7Not Available
Predicted Properties
Water Solubility0.27 g/LALOGPS
pKa (Strongest Acidic)3.47ChemAxon
pKa (Strongest Basic)2.8ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count12ChemAxon
Hydrogen Donor Count8ChemAxon
Polar Surface Area207.27 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity121.39 m³·mol⁻¹ChemAxon
Polarizability43.38 ųChemAxon
Number of Rings3ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0uka-4676900000-780e78301e85c240ab73Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-006x-1311190000-af98cc8be4da08f9b782Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-0002-7796610000-0937514a7f23431b726eSpectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-0nor-3269210000-20105ed6a7a6e24e2441Spectrum
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-00kr-1935200000-a9449c19c1ae3b0d70daSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0032-0431900000-ff1f3948e47561161293Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-001i-0952300000-ed9d84bc39d490f6210eSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-001i-0920000000-0d0efcb6c323340d20b9Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0006-0001900000-abb4cec0eb79b0bd2de1Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0v4l-2356900000-2fd17d2f587bbd5e882cSpectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9441000000-8c630c7a3633467d6bb3Spectrum
1D NMR1H NMR SpectrumNot AvailableSpectrum
2D NMR[1H,1H] 2D NMR SpectrumNot AvailableSpectrum
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableSpectrum
Biological Properties
Cellular Locations
  • Extracellular
  • Mitochondria
  • Lysosome
Biospecimen Locations
  • Blood
  • Urine
Tissue Locations
  • Brain
  • Epidermis
  • Erythrocyte
  • Fibroblasts
  • Intestine
  • Kidney
  • Liver
  • Neuron
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Testis
Normal Concentrations
BloodDetected and Quantified0.0025 +/- 0.0044 uMAdult (>18 years old)BothNormal details
BloodExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00116 details
UrineExpected but not QuantifiedNot QuantifiedNot AvailableNot AvailableTaking drug identified by DrugBank entry DB00116 details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDNot Available
Phenol Explorer Compound IDNot Available
FooDB IDFDB022705
KNApSAcK IDNot Available
Chemspider ID82572
KEGG Compound IDC00101
BiGG ID33856
Wikipedia LinkTetrahydrofolic acid
PubChem Compound91443
PDB IDNot Available
ChEBI ID20506
Food Biomarker OntologyNot Available
MarkerDB ID
Synthesis ReferenceNot Available
Material Safety Data Sheet (MSDS)Download (PDF)
General References
  1. Garbis SD, Melse-Boonstra A, West CE, van Breemen RB: Determination of folates in human plasma using hydrophilic interaction chromatography-tandem mass spectrometry. Anal Chem. 2001 Nov 15;73(22):5358-64. [PubMed:11816560 ]
  2. Authors unspecified: Pemetrexed: new drug. Pleural mesothelioma: a first encouraging trial. Prescrire Int. 2005 Dec;14(80):212-4. [PubMed:16400741 ]
  3. Asrar FM, O'Connor DL: Bacterially synthesized folate and supplemental folic acid are absorbed across the large intestine of piglets. J Nutr Biochem. 2005 Oct;16(10):587-93. [PubMed:16081276 ]
  4. Ahmed F, Khan MR, Akhtaruzzaman M, Karim R, Marks GC, Banu CP, Nahar B, Williams G: Efficacy of twice-weekly multiple micronutrient supplementation for improving the hemoglobin and micronutrient status of anemic adolescent schoolgirls in Bangladesh. Am J Clin Nutr. 2005 Oct;82(4):829-35. [PubMed:16210713 ]
  5. Pieniazek D, Kubalska J, Pronicka E, Stecko E: Disturbances in histidine metabolism in children with speech abnormalities. Acta Anthropogenet. 1985;9(1-3):117-21. [PubMed:2887178 ]
  6. Ozer B, Serin E, Gumurdulu Y, Kayaselcuk F, Anarat R, Gur G, Kul K, Guclu M, Boyacioglu S: Helicobacter pylori eradication lowers serum homocysteine level in patients without gastric atrophy. World J Gastroenterol. 2005 May 14;11(18):2764-7. [PubMed:15884118 ]
  7. Greenwald P, Milner JA, Anderson DE, McDonald SS: Micronutrients in cancer chemoprevention. Cancer Metastasis Rev. 2002;21(3-4):217-30. [PubMed:12549762 ]
  8. Siega-Riz AM, Savitz DA, Zeisel SH, Thorp JM, Herring A: Second trimester folate status and preterm birth. Am J Obstet Gynecol. 2004 Dec;191(6):1851-7. [PubMed:15592264 ]
  9. Taber LD, O'Brien P, Bowsher RR, Sportsman JR: Competitive particle concentration fluorescence immunoassay for measuring 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) in serum. Clin Chem. 1991 Feb;37(2):254-60. [PubMed:1993335 ]
  10. Mattson MP: Gene-diet interactions in brain aging and neurodegenerative disorders. Ann Intern Med. 2003 Sep 2;139(5 Pt 2):441-4. [PubMed:12965973 ]
  11. Dietrich M, Brown CJ, Block G: The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States. J Am Coll Nutr. 2005 Aug;24(4):266-74. [PubMed:16093404 ]
  12. Kamen BA, Smith AK: A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev. 2004 Apr 29;56(8):1085-97. [PubMed:15094208 ]
  13. Baggott JE, Johanning GL, Branham KE, Prince CW, Morgan SL, Eto I, Vaughn WH: Cofactor role for 10-formyldihydrofolic acid. Biochem J. 1995 Jun 15;308 ( Pt 3):1031-6. [PubMed:8948466 ]
  14. Makino Y, Nagano M, Tamura K, Kawarabayashi T: Pregnancy complicated with pure red cell aplasia: a case report. J Perinat Med. 2003;31(6):530-4. [PubMed:14711112 ]
  15. Pljesa S: [Possible complications of erythropoietin therapy in patients with chronic renal failure]. Med Pregl. 2004 May-Jun;57(5-6):254-7. [PubMed:15503795 ]
  16. Pufulete M, Al-Ghnaniem R, Khushal A, Appleby P, Harris N, Gout S, Emery PW, Sanders TA: Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut. 2005 May;54(5):648-53. [PubMed:15831910 ]
  17. Wang S, Low PS: Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. J Control Release. 1998 Apr 30;53(1-3):39-48. [PubMed:9741912 ]
  18. Hankey GJ, Eikelboom JW, Loh K, Tang M, Pizzi J, Thom J, Yi Q: Sustained homocysteine-lowering effect over time of folic acid-based multivitamin therapy in stroke patients despite increasing folate status in the population. Cerebrovasc Dis. 2005;19(2):110-6. Epub 2004 Dec 17. [PubMed:15608435 ]
  19. Ramaekers VT, Rothenberg SP, Sequeira JM, Opladen T, Blau N, Quadros EV, Selhub J: Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med. 2005 May 12;352(19):1985-91. [PubMed:15888699 ]
  20. Verwei M, Arkbage K, Mocking H, Havenaar R, Groten J: The binding of folic acid and 5-methyltetrahydrofolate to folate-binding proteins during gastric passage differs in a dynamic in vitro gastrointestinal model. J Nutr. 2004 Jan;134(1):31-7. [PubMed:14704289 ]
  21. Mattson MP: Will caloric restriction and folate protect against AD and PD? Neurology. 2003 Feb 25;60(4):690-5. [PubMed:12601113 ]
  22. Omura Y: Excessive use of Steroid Hormone & beneficial effects of True St. 36 acupuncture on malignant brain tumors--part I; how to estimate non-invasively presence of excess dose of Steroid Hormone in patients, baseball players & other professional athletes from its toxic effects on heart & pancreas, as well as persistent or recurrent infection--part II. Acupunct Electrother Res. 2005;30(1-2):57-102. [PubMed:16231633 ]
  23. Paulionis L, Kane SL, Meckling KA: Vitamin status and cognitive function in a long-term care population. BMC Geriatr. 2005 Dec 13;5:16. [PubMed:16351716 ]
  24. Zhu WY, Alliegro MA, Melera PW: The rate of folate receptor alpha (FR alpha) synthesis in folate depleted CHL cells is regulated by a translational mechanism sensitive to media folate levels, while stable overexpression of its mRNA is mediated by gene amplification and an increase in transcript half-life. J Cell Biochem. 2001 Mar 26;81(2):205-19. [PubMed:11241661 ]
  25. Tchantchou F: Homocysteine metabolism and various consequences of folate deficiency. J Alzheimers Dis. 2006 Aug;9(4):421-7. [PubMed:16917151 ]
  26. Lu S, Chen GL, Ren C, Kwabi-Addo B, Epner DE: Methionine restriction selectively targets thymidylate synthase in prostate cancer cells. Biochem Pharmacol. 2003 Sep 1;66(5):791-800. [PubMed:12948860 ]
  27. Durga J, van Boxtel MP, Schouten EG, Bots ML, Kok FJ, Verhoef P: Folate and the methylenetetrahydrofolate reductase 677C-->T mutation correlate with cognitive performance. Neurobiol Aging. 2006 Feb;27(2):334-43. Epub 2005 Feb 24. [PubMed:16399216 ]
  28. Stuerenburg HJ, Ganzer S, Arlt S, Muller-Thomsen T: The influence of smoking on plasma folate and lipoproteins in Alzheimer disease, mild cognitive impairment and depression. Neuro Endocrinol Lett. 2005 Jun;26(3):261-3. [PubMed:15990733 ]
  29. Smith DE, Kok RM, Teerlink T, Jakobs C, Smulders YM: Quantitative determination of erythrocyte folate vitamer distribution by liquid chromatography-tandem mass spectrometry. Clin Chem Lab Med. 2006;44(4):450-9. [PubMed:16599840 ]
  30. Wolters M, Strohle A, Hahn A: [Age-associated changes in the metabolism of vitamin B(12) and folic acid: prevalence, aetiopathogenesis and pathophysiological consequences]. Z Gerontol Geriatr. 2004 Apr;37(2):109-35. [PubMed:15103481 ]
  31. Sahr T, Ravanel S, Rebeille F: Tetrahydrofolate biosynthesis and distribution in higher plants. Biochem Soc Trans. 2005 Aug;33(Pt 4):758-62. [PubMed:16042593 ]

Only showing the first 10 proteins. There are 25 proteins in total.


General function:
Involved in cobalamin binding
Specific function:
Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity).
Gene Name:
Uniprot ID:
Molecular weight:
5-Methyltetrahydrofolic acid + Homocysteine → Tetrahydrofolic acid + L-Methioninedetails
General function:
Involved in methylenetetrahydrofolate reductase (NADPH) activity
Specific function:
Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine.
Gene Name:
Uniprot ID:
Molecular weight:
General function:
Involved in catalytic activity
Specific function:
Not Available
Gene Name:
Uniprot ID:
Molecular weight:
10-Formyltetrahydrofolate + Glycineamideribotide → Tetrahydrofolic acid + N(2)-formyl-N(1)-(5-phospho-D-ribosyl)glycinamidedetails
10-Formyltetrahydrofolate + Glycineamideribotide → Tetrahydrofolic acid + 5'-Phosphoribosyl-N-formylglycinamidedetails
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 + L-Glutamic acid → Tetrahydrofolic acid + Formiminoglutamic aciddetails
Folinic acid + L-Glutamic acid → Tetrahydrofolic acid + N-Formyl-L-glutamic aciddetails
5-Formiminotetrahydrofolic acid + L-Glutamic acid → Tetrahydrofolic acid + Formiminoglutamic aciddetails
Folinic acid + L-Glutamic acid → Tetrahydrofolic acid + N-Formyl-L-glutamic aciddetails
General function:
Involved in aminomethyltransferase activity
Specific function:
The glycine cleavage system catalyzes the degradation of glycine.
Gene Name:
Uniprot ID:
Molecular weight:
[Protein]-S(8)-aminomethyldihydrolipoyllysine + Tetrahydrofolic acid → [protein]-dihydrolipoyllysine + 5,10-Methylene-THF + Ammoniadetails
Glycine + Tetrahydrofolic acid + NAD → 5,10-Methylene-THF + Ammonia + Carbon dioxide + NADH + Hydrogen Iondetails
S-Aminomethyldihydrolipoylprotein + Tetrahydrofolic acid → Dihydrolipoylprotein + 5,10-Methylene-THF + Ammoniadetails
General function:
Involved in dihydrofolate reductase activity
Specific function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
Uniprot ID:
Molecular weight:
Tetrahydrofolic acid + NADP → Dihydrofolic acid + NADPHdetails
Tetrahydrofolic acid + NAD → Dihydrofolic acid + NADH + Hydrogen Iondetails
Tetrahydrofolic acid + NAD → Folic acid + NADH + Hydrogen Iondetails
Tetrahydrofolic acid + NADP → Dihydrofolic acid + NADPH + Hydrogen Iondetails
Tetrahydrofolic acid + NADP → Folic acid + NADPH + Hydrogen Iondetails
General function:
Involved in catalytic activity
Specific function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Required to prevent uracil accumulation in mtDNA. Interconversion of serine and glycine. Associates with mitochondrial DNA.
Gene Name:
Uniprot ID:
Molecular weight:
5,10-Methylene-THF + Glycine + Water → Tetrahydrofolic acid + L-Serinedetails
General function:
Involved in catalytic activity
Specific function:
Interconversion of serine and glycine.
Gene Name:
Uniprot ID:
Molecular weight:
5,10-Methylene-THF + Glycine + Water → Tetrahydrofolic acid + L-Serinedetails
General function:
Involved in tetrahydrofolylpolyglutamate synthase activity
Specific function:
Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Unsubstitued reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.
Gene Name:
Uniprot ID:
Molecular weight:
Adenosine triphosphate + Tetrahydrofolic acid + L-Glutamic acid → ADP + Phosphate + Tetrahydrofolyl-[Glu](2)details
General function:
Involved in IMP cyclohydrolase activity
Specific function:
Bifunctional enzyme that catalyzes 2 steps in purine biosynthesis.
Gene Name:
Uniprot ID:
Molecular weight:
10-Formyltetrahydrofolate + AICAR → Tetrahydrofolic acid + Phosphoribosyl formamidocarboxamidedetails

Only showing the first 10 proteins. There are 25 proteins in total.