You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Human Metabolome Database.
Record Information
StatusDetected and Quantified
Creation Date2005-11-16 15:48:42 UTC
Update Date2018-02-21 20:56:02 UTC
Secondary Accession Numbers
  • HMDB01396
Metabolite Identification
Common Name5-Methyltetrahydrofolic acid
Description5 methyltetrahydrofolic acid (5-MTHF) is the most biologically active form of the B-vitamin known as folic acid, also known generically as folate. 5-MTHF functions, in concert with vitamin B12, as a methyl-group donor involved in the conversion of the amino acid homocysteine to methionine. Methyl (CH3) group donation is vital to many bodily processes, including serotonin, melatonin, and DNA synthesis. Therapeutically, 5-MTHF is instrumental in reducing homocysteine levels, preventing neural tube defects, and improving vascular endothelial function. Research on folate supplementation suggests it plays a key role in preventing cervical dysplasia and protecting against neoplasia in ulcerative colitis. Folic acid also shows promise as part of a nutritional protocol to treat vitiligo, and may reduce inflammation of the gingiva. Furthermore, certain neurological, cognitive, and psychiatric presentations may be secondary to folate deficiency. Such presentations include depression, peripheral neuropathy, myelopathy, restless legs syndrome, insomnia, dementia, forgetfulness, irritability, endogenous depression, organic psychosis, and schizophrenia-like syndromes. After ingestion, the process of conversion of folic acid to the metabolically active coenzyme forms is relatively complex. Synthesis of the active forms of folic acid requires several enzymes, adequate liver and intestinal function, and adequate supplies of riboflavin (B2), niacin (B3), pyridoxine (B6), zinc, vitamin C, and serine. After formation of the coenzyme forms of the vitamin in the liver, these metabolically active compounds are secreted into the small intestine with bile (the folate enterohepatic cycle), where they are reabsorbed and distributed to tissues throughout the body. Human pharmacokinetic studies indicate folic acid has high bioavailability, with large oral doses of folic acid substantially raising plasma levels in healthy subjects in a time and dose dependent manner. Red blood cells (RBCs) appear to be the storage depot for folic acid, as RBC levels remain elevated for periods in excess of 40 days following discontinuation of supplementation. Folic acid is poorly transported to the brain and rapidly cleared from the central nervous system. The primary methods of elimination of absorbed folic acid are fecal (through bile) and urinary. Despite the biochemical complexity of this process, evidence suggests oral supplementation with folic acid increases the body's pool of 5-MTHF in healthy individuals. However, enzyme defects, mal-absorption, digestive system pathology, and liver disease can result in impaired ability to activate folic acid. In fact, some individuals have a severe congenital deficiency of the enzyme Methyl tetrahydrofolate reductase (5-MTHFR), which is needed to convert folic acid to 5-MTHF. Milder forms of this enzyme defect likely interact with dietary folate status to determine risk for some disease conditions. In individuals with a genetic defect of this enzyme (whether mild or severe), supplementation with 5- MTHF might be preferable to folic acid supplementation. (PMID: 17176169 ).
5-Methyl tetrahydrofolateHMDB
Methyl folateHMDB
N( 5)-MethyltetrahydrofolateHMDB
N-(4-(((2-amino-1,4,5,6,7,8-hexahydro-5-Methyl-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-L-glutamic acidHMDB
N-(5-Methyl-5,6,7,8-tetrahydropteroyl)-L-glutamic acidHMDB
N5-Methyl-tetrahydrofolic acidHMDB
N5-Methyltetrahydropteroyl mono-L-glutamateHMDB
5-Methyltetrahydrofolate, (DL-glu)-isomerMeSH
5-Methyltetrahydrofolate, (L-glu)-(R)-isomerMeSH
5-Methyltetrahydrofolate, (L-glu)-(S)-isomerMeSH
5-Methyltetrahydrofolate, calcium salt (1:1), (L-glu)-isomerMeSH
5-Methyltetrahydrofolate, methyl-(14)C-labeled, (DL-glu)-isomerMeSH
5-Methyltetrahydrofolate, methyl-(14)C-labeled, (L-glu)-isomerMeSH
L-Methyl folateMeSH
N(5)-Methyltetrahydrofolic acidMeSH
Prefolic aMeSH
Chemical FormulaC20H25N7O6
Average Molecular Weight459.4558
Monoisotopic Molecular Weight459.186631567
IUPAC Name(2R)-2-[(4-{[(2-amino-5-methyl-4-oxo-3,4,5,6,7,8-hexahydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
Traditional Name(2R)-2-[(4-{[(2-amino-5-methyl-4-oxo-3,6,7,8-tetrahydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid
CAS Registry Number134-35-0
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
  • Glutamic acid or derivatives
  • Hippuric acid or derivatives
  • Hippuric acid
  • N-acyl-alpha-amino acid
  • N-acyl-alpha amino acid or derivatives
  • Alpha-amino acid or derivatives
  • Aminobenzamide
  • Aminobenzoic acid or derivatives
  • Benzoic acid or derivatives
  • Benzamide
  • Benzoyl
  • Phenylalkylamine
  • Tertiary aliphatic/aromatic amine
  • Aniline or substituted anilines
  • Dialkylarylamine
  • Secondary aliphatic/aromatic amine
  • Pyrimidone
  • Aminopyrimidine
  • Dicarboxylic acid or derivatives
  • Benzenoid
  • Pyrimidine
  • Monocyclic benzene moiety
  • Vinylogous amide
  • Heteroaromatic compound
  • Secondary carboxylic acid amide
  • Tertiary amine
  • Amino acid or derivatives
  • Amino acid
  • Carboxamide group
  • Secondary amine
  • Carboxylic acid
  • Carboxylic acid derivative
  • Azacycle
  • Organic nitrogen compound
  • Carbonyl group
  • Organonitrogen compound
  • Organooxygen compound
  • Primary amine
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Organic oxygen compound
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Physiological effect

Health effect:

  Health condition:


Biological location:

  Cell and elements:

  Biofluid and excreta:

  Tissue and substructures:

  Organ and components:



Naturally occurring process:

  Biological process:

    Biochemical pathway:


Biological role:

Physical Properties
Experimental Properties
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
Water Solubility0.35 g/LALOGPS
pKa (Strongest Acidic)3.22ChemAxon
pKa (Strongest Basic)4.64ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area198.48 ŲChemAxon
Rotatable Bond Count9ChemAxon
Refractivity126.88 m³·mol⁻¹ChemAxon
Polarizability46.13 ųChemAxon
Number of Rings3ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-03di-2645900000-0472550b7df0d95d4718View in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-059i-4532290000-8e3b1526c05a0a70d971View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-03dl-0313900000-d4f9d7f9d8c65a2e0428View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01ox-0924300000-2f133db2f48bd5b14a8dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000f-0920000000-298e8f3cd55b0fe42badView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0001900000-b1b1292a418283f61ea9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0900-1256900000-32c1cf48970dead32f60View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0006-9641100000-b5468bf27455b7e5ee39View in MoNA
Biological Properties
Cellular Locations
  • Extracellular
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
  • Urine
Tissue Location
  • Kidney
  • Liver
  • Placenta
Betaine MetabolismThumbThumb?image type=greyscaleThumb?image type=simpleMap00260
Cystathionine Beta-Synthase DeficiencyThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Folate MetabolismThumbThumb?image type=greyscaleThumb?image type=simpleMap00670
Folate malabsorption, hereditaryThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Glycine N-methyltransferase DeficiencyThumbThumb?image type=greyscaleThumb?image type=simpleNot Available
Normal Concentrations
BloodDetected and Quantified0.3 (0.094-0.7) uMAdult (>18 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified0.12 (0.04-0.20) uMAdult (>18 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified0.0400-0.128 uMChildren (1-13 years old)BothNormal details
Cerebrospinal Fluid (CSF)Detected and Quantified0.075 (0.045 - 0.13) uMAdult (>18 years old)Not SpecifiedNormal details
UrineExpected but not Quantified Not AvailableNot AvailableNormal
    Abnormal Concentrations
    Cerebrospinal Fluid (CSF)Detected and Quantified0.00700-0.0110 uMChildren (1-13 years old)BothCerebral folate transport deficiency details
    Cerebrospinal Fluid (CSF)Detected and Quantified0.053 (0.02 - 0.09) uMAdult (>18 years old)Not SpecifiedRett syndrome details
    Cerebrospinal Fluid (CSF)Detected and Quantified0.026 +/- 0.007 uMChildren (1-13 years old)Not Specified
    Associated Disorders and Diseases
    Disease References
    1. Surtees R, Hyland K, Smith I: Central-nervous-system methyl-group metabolism in children with neurological complications of HIV infection. Lancet. 1990 Mar 17;335(8690):619-21. [PubMed:1969014 ]
    Cerebral folate transport deficiency
    1. Al-Baradie RS, Chaudhary MW: Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures. Neurosciences (Riyadh). 2014 Oct;19(4):312-6. [PubMed:25274592 ]
    Associated OMIM IDs
    • 613068 (Cerebral folate transport deficiency)
    DrugBank IDNot Available
    Phenol Explorer Compound IDNot Available
    FoodDB IDFDB022600
    KNApSAcK IDNot Available
    Chemspider ID388371
    KEGG Compound IDC00440
    BiGG ID34988
    Wikipedia LinkLevomefolic acid
    METLIN ID6215
    PubChem Compound439234
    PDB IDNot Available
    ChEBI ID15641
    Synthesis ReferenceGennari, Federico. Process for producing 5-methyltetrahydrofolic acid and its salts. U.S. (1992), 6 pp.
    Material Safety Data Sheet (MSDS)Not Available
    General References
    1. Van Hove JL, Lazeyras F, Zeisel SH, Bottiglieri T, Hyland K, Charles HC, Gray L, Jaeken J, Kahler SG: One-methyl group metabolism in non-ketotic hyperglycinaemia: mildly elevated cerebrospinal fluid homocysteine levels. J Inherit Metab Dis. 1998 Dec;21(8):799-811. [PubMed:9870205 ]
    2. Kane MA, Roth E, Raptis G, Schreiber C, Waxman S: Effect of intracellular folate concentration on the modulation of 5-fluorouracil cytotoxicity by the elevation of phosphoribosylpyrophosphate in cultured human KB cells. Cancer Res. 1987 Dec 15;47(24 Pt 1):6444-50. [PubMed:2445472 ]
    3. 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 ]
    4. Ormazabal A, Artuch R, Vilaseca MA, Aracil A, Pineda M: Cerebrospinal fluid concentrations of folate, biogenic amines and pterins in Rett syndrome: treatment with folinic acid. Neuropediatrics. 2005 Dec;36(6):380-5. [PubMed:16429378 ]
    5. Chladek J, Sispera L, Martinkova J: High-performance liquid chromatographic assay for the determination of 5-methyltetrahydrofolate in human plasma. J Chromatogr B Biomed Sci Appl. 2000 Jul 21;744(2):307-13. [PubMed:10993519 ]
    6. Prasad PD, Mahesh VB, Leibach FH, Ganapathy V: Functional coupling between a bafilomycin A1-sensitive proton pump and a probenecid-sensitive folate transporter in human placental choriocarcinoma cells. Biochim Biophys Acta. 1994 Jun 30;1222(2):309-14. [PubMed:8031869 ]
    7. Kim TH, Yang J, Darling PB, O'Connor DL: A large pool of available folate exists in the large intestine of human infants and piglets. J Nutr. 2004 Jun;134(6):1389-94. [PubMed:15173401 ]
    8. Camilo E, Zimmerman J, Mason JB, Golner B, Russell R, Selhub J, Rosenberg IH: Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology. 1996 Apr;110(4):991-8. [PubMed:8613033 ]
    9. 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 ]
    10. Surtees R, Leonard J, Austin S: Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet. 1991 Dec 21-28;338(8782-8783):1550-4. [PubMed:1683972 ]
    11. Surtees R, Hyland K, Smith I: Central-nervous-system methyl-group metabolism in children with neurological complications of HIV infection. Lancet. 1990 Mar 17;335(8690):619-21. [PubMed:1969014 ]
    12. Evans MI, Duquette DA, Rinaldo P, Bawle E, Rosenblatt DS, Whitty J, Quintero RA, Johnson MP: Modulation of B12 dosage and response in fetal treatment of methylmalonic aciduria (MMA): titration of treatment dose to serum and urine MMA. Fetal Diagn Ther. 1997 Jan-Feb;12(1):21-3. [PubMed:9101216 ]
    13. Irizarry MC: Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004 Apr;1(2):226-34. [PubMed:15717023 ]
    14. 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. [PubMed:6609768 ]
    15. Authors unspecified: 5-methyltetrahydrofolate. Monograph. Altern Med Rev. 2006 Dec;11(4):330-7. [PubMed:17176169 ]


    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:
    5-Methyltetrahydrofolic acid + NAD(P)(+) → 5,10-Methylene-THF + NAD(P)Hdetails
    5-Methyltetrahydrofolic acid + NADP → 5,10-Methylene-THF + NADPH + Hydrogen Iondetails
    5-Methyltetrahydrofolic acid + NAD → 5,10-Methylene-THF + NADH + Hydrogen Iondetails
    General function:
    Not Available
    Specific function:
    N5-glutamine methyltransferase responsible for the methylation of the GGQ triplet of the mitochondrial translation release factor MTRF1L.
    Gene Name:
    Uniprot ID:
    Molecular weight:
    Not Available
    Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
    General function:
    Not Available
    Specific function:
    Probable methyltransferase (By similarity).
    Gene Name:
    Uniprot ID:
    Molecular weight:
    Not Available
    Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
    General function:
    Not Available
    Specific function:
    Probable methyltransferase (By similarity).
    Gene Name:
    Uniprot ID:
    Molecular weight:
    Not Available
    Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
    General function:
    Not Available
    Specific function:
    Methyltransferase that may act on DNA.
    Gene Name:
    Uniprot ID:
    Molecular weight:
    Not Available
    Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails