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Record Information
Creation Date2005-11-16 15:48:42 UTC
Update Date2016-02-11 01:04:55 UTC
Secondary Accession Numbers
  • HMDB06206
Metabolite Identification
Common NameN5-Formyl-THF
DescriptionThe active metabolite of folic acid. Leucovorin is used principally as its calcium salt as an antidote to folic acid antagonists which block the conversion of folic acid to folinic acid.
L(-)-5-Formyl-5,6,7,8-tetrahydrofolic acidKegg
10-Formyl-7,8-dihydrofolic acidHMDB
5-Formyl-5,6,7,8-tetrahydrofolic acidHMDB
5-Formyltetrahydrofolic acidHMDB
5-Formyltetrahydropteroylglutamic acidHMDB
Folinic acidHMDB
Folinic acid-SFHMDB
L-N-[P-[[(2-amino-5-Formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl)methyl]amino]benzoyl]-glutamic acidHMDB
N5-Formyl-5,6,7,8-tetrahydrofolic acidHMDB
N5-Formyltetrahydrofolic acidHMDB
Chemical FormulaC20H23N7O7
Average Molecular Weight473.4393
Monoisotopic Molecular Weight473.165896125
IUPAC Name2-[(4-{[(2-amino-5-formyl-4-oxo-3,4,5,6,7,8-hexahydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
Traditional Name2-[(4-{[(2-amino-5-formyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
CAS Registry Number58-05-9
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
  • Phenylalkylamine
  • Substituted aniline
  • Benzoyl
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Aniline
  • Amino fatty acid
  • Fatty acyl
  • Imidolactam
  • Benzenoid
  • Pyrimidine
  • Primary aromatic amine
  • Dicarboxylic acid or derivatives
  • Monocyclic benzene moiety
  • Heteroaromatic compound
  • Vinylogous amide
  • Tertiary carboxylic acid amide
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
StatusDetected and Quantified
  • Endogenous
BiofunctionNot Available
ApplicationNot Available
Cellular locations
  • Extracellular
Physical Properties
Experimental Properties
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
Water Solubility0.3 mg/mLALOGPS
pKa (Strongest Acidic)3.18ChemAxon
pKa (Strongest Basic)4.33ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area215.55 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity126.66 m3·mol-1ChemAxon
Polarizability46.59 Å3ChemAxon
Number of Rings3ChemAxon
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-0031900000-31498c227b611f3360eaView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a6r-0393400000-f81606ae4f4b27aadbacView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0a4i-1591000000-825bc8196995ef0bc1e3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-00di-0000900000-203ae236b032df3233d7View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0umj-1131900000-5174748fd5288f6523fdView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0007-9674000000-192da85bfca095ec870eView in MoNA
Biological Properties
Cellular Locations
  • Extracellular
Biofluid Locations
  • Blood
Tissue Location
  • Bladder
  • Fibroblasts
  • Pancreas
  • Testes
Folate malabsorption, hereditarySMP00724Not Available
Folate MetabolismSMP00053map00670
Methotrexate PathwaySMP00432Not Available
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)SMP00543Not Available
Normal Concentrations
BloodDetected and Quantified0.0025 +/- 0.0036 uMAdult (>18 years old)BothNormal details
Abnormal Concentrations
Not Available
Associated Disorders and Diseases
Disease ReferencesNone
Associated OMIM IDsNone
DrugBank IDDB00650
DrugBank Metabolite IDNot Available
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB022689
KNApSAcK IDNot Available
Chemspider ID140
KEGG Compound IDC03479
BiGG ID41929
Wikipedia Linkfolinate
NuGOwiki LinkHMDB01562
Metagene LinkHMDB01562
PubChem Compound143
ChEBI ID209153
Synthesis ReferenceZakrzewski, Sigmund F.; Sansone, Annette M. Preparation of folinic acid (N5-formyltetrahydro folic acid). Methods Enzymol. (1971), 18(Pt. B), 731-3.
Material Safety Data Sheet (MSDS)Not Available
General References
  1. Perry TL, Applegarth DA, Evans ME, Hansen S, Jellum E: Metabolic studies of a family with massive formiminoglutamic aciduria. Pediatr Res. 1975 Mar;9(3):117-22. [235753 ]
  2. 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. [11816560 ]
  3. Straw JA, Szapary D, Wynn WT: Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984 Jul;44(7):3114-9. [6609768 ]
  4. Micke O, Bruns F, Schafer U, Kurowski R, Horst E, Willich N: CA 19-9 in the therapy monitoring and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy. Anticancer Res. 2003 Mar-Apr;23(2A):835-40. [12820309 ]
  5. Pfeiffer CM, Fazili Z, McCoy L, Zhang M, Gunter EW: Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay. Clin Chem. 2004 Feb;50(2):423-32. Epub 2003 Dec 11. [14670827 ]
  6. Karakayali FY, Bayar S, Hazinedaroglu S, Sahin F, Karayalcin K: Does folinic acid have a choleretic effect on humans? Turk J Gastroenterol. 2003 Jun;14(2):102-5. [14614635 ]
  7. Pineda M, Ormazabal A, Lopez-Gallardo E, Nascimento A, Solano A, Herrero MD, Vilaseca MA, Briones P, Ibanez L, Montoya J, Artuch R: Cerebral folate deficiency and leukoencephalopathy caused by a mitochondrial DNA deletion. Ann Neurol. 2006 Feb;59(2):394-8. [16365882 ]
  8. Birmingham BK, Greene DS: Analysis of folinic acid in human serum using high-performance liquid chromatography with amperometric detection. J Pharm Sci. 1983 Nov;72(11):1306-9. [6606033 ]
  9. Sengelov L, von der Maase H, Lundbeck F, Barlebo H, Colstrup H, Engelholm SA, Krarup T, Madsen EL, Meyhoff HH, Mommsen S, Nielsen OS, Pedersen D, Steven K, Sorensen B: Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncol. 2002;41(5):447-56. [12442921 ]
  10. Bunni MA, Priest DG: Human red blood cell-mediated metabolism of leucovorin [(R,S)5-formyltetrahydrofolate] Arch Biochem Biophys. 1991 May 1;286(2):633-7. [1897982 ]
  11. Ramaekers VT, Hausler M, Opladen T, Heimann G, Blau N: Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics. 2002 Dec;33(6):301-8. [12571785 ]
  12. 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. [11241661 ]
  13. Jansman FG, Coenen JL, De Graaf JC, Tobi H, Sleijfer DT, Brouwers JR: Relationship between pharmacokinetics of 5-FU in plasma and in saliva, and toxicity of 5-fluorouracil/folinic acid. Anticancer Res. 2002 Nov-Dec;22(6B):3449-55. [12552938 ]
  14. Vimercati A, Greco P, D'Apolito A, Angelici MC, Possenti A, Carbonara S, Selvaggi L: [Risk assessment of vertical transmission of Toxoplasma infections] Acta Biomed Ateneo Parmense. 2000;71 Suppl 1:537-40. [11424802 ]
  15. Joulia JM, Pinguet F, Ychou M, Duffour J, Astre C, Bressolle F: Plasma and salivary pharmacokinetics of 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer receiving 5-FU bolus plus continuous infusion with high-dose folinic acid. Eur J Cancer. 1999 Feb;35(2):296-301. [10448274 ]
  16. Polyzos A, Kouraklis G, Giannopoulos A, Bramis J, Delladetsima JK, Sfikakis PP: Irinotecan as salvage chemotherapy for advanced small bowel adenocarcinoma: a series of three patients. J Chemother. 2003 Oct;15(5):503-6. [14598944 ]
  17. Micke O, Hesselmann S, Bruns F, Horst E, Devries A, Schuller P, Willich N, Schafer U: Results and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy. Anticancer Res. 2005 May-Jun;25(3A):1523-30. [16033054 ]
  18. Bentivoglio G, Melica F, Cristoforoni P: Folinic acid in the treatment of human male infertility. Fertil Steril. 1993 Oct;60(4):698-701. [8405528 ]
  19. Kajiyama Y, Tsurumaru M, Udagawa H, Tsutsumi K, Kinoshita Y, Akiyama H: Relief of jaundice by 5-fluorouracil and folinic acid in patients with recurrent gastric cancer. Surg Oncol. 1996 Aug;5(4):177-81. [9067566 ]
  20. Jardine LF, Ingram LC, Bleyer WA: Intrathecal leucovorin after intrathecal methotrexate overdose. J Pediatr Hematol Oncol. 1996 Aug;18(3):302-4. [8689347 ]


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:
N5-Formyl-THF + L-Glutamic acid → Tetrahydrofolic acid + N-Formyl-L-glutamic aciddetails
N5-Formyl-THF + 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:
N5-Formyl-THF → 5,10-Methenyltetrahydrofolic acid + Waterdetails
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 thymidylate synthase activity
Specific function:
Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:
Uniprot ID:
Molecular weight:
  1. Aschele C, Debernardis D, Bandelloni R, Cascinu S, Catalano V, Giordani P, Barni S, Turci D, Drudi G, Lonardi S, Gallo L, Maley F, Monfardini S: Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil. Ann Oncol. 2002 Dec;13(12):1882-92. [12453856 ]
  2. Zhu AX, Puchalski TA, Stanton VP Jr, Ryan DP, Clark JW, Nesbitt S, Charlat O, Kelly P, Kreconus E, Chabner BA, Supko JG: Dihydropyrimidine dehydrogenase and thymidylate synthase polymorphisms and their association with 5-fluorouracil/leucovorin chemotherapy in colorectal cancer. Clin Colorectal Cancer. 2004 Feb;3(4):225-34. [15025795 ]
  3. Smorenburg CH, Peters GJ, van Groeningen CJ, Noordhuis P, Smid K, van Riel AM, Dercksen W, Pinedo HM, Giaccone G: Phase II study of tailored chemotherapy for advanced colorectal cancer with either 5-fluouracil and leucovorin or oxaliplatin and irinotecan based on the expression of thymidylate synthase and dihydropyrimidine dehydrogenase. Ann Oncol. 2006 Jan;17(1):35-42. Epub 2005 Oct 26. [16251201 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]


General function:
Involved in ATP binding
Specific function:
Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter
Gene Name:
Uniprot ID:
Molecular weight:
  1. Horikawa M, Kato Y, Tyson CA, Sugiyama Y: The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab Pharmacokinet. 2002;17(1):23-33. [15618649 ]
  2. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. [12874005 ]
General function:
Involved in ATP binding
Specific function:
May act as an inducible transporter in the biliary and intestinal excretion of organic anions. Acts as an alternative route for the export of bile acids and glucuronides from cholestatic hepatocytes
Gene Name:
Uniprot ID:
Molecular weight:
  1. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. [11585759 ]
  2. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. [12874005 ]
General function:
Involved in ATP binding
Specific function:
May be an organic anion pump relevant to cellular detoxification
Gene Name:
Uniprot ID:
Molecular weight:
  1. Chen ZS, Lee K, Walther S, Raftogianis RB, Kuwano M, Zeng H, Kruh GD: Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144-50. [12036927 ]