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Record Information
Version3.6
Creation Date2005-11-16 15:48:42 UTC
Update Date2013-05-29 19:31:25 UTC
HMDB IDHMDB01396
Secondary Accession NumbersNone
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 ).
Structure
Thumb
Synonyms
  1. 5-Methyl tetrahydrofolate
  2. 5-Methyl-5,6,7,8-tetrahydrofolate
  3. 5-Methyl-tetrahydrofolate
  4. 5-Methyltetrahydrofolate
  5. 5-Methyltetrahydropteroylglutamate
  6. Methyl folate
  7. Methyl-tetrahydrofolate
  8. N( 5)-Methyltetrahydrofolate
  9. N-(4-(((2-Amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-L-Glutamate
  10. N-(4-(((2-Amino-1,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-L-Glutamic acid
  11. N-(5-Methyl-5,6,7,8-tetrahydropteroyl)-L-glutamate
  12. N-(5-Methyl-5,6,7,8-tetrahydropteroyl)-L-glutamic acid
  13. N5-Methyl-tetrahydrofolate
  14. N5-Methyl-tetrahydrofolic acid
  15. N5-methyltetrahydrofolate
  16. N5-methyltetrahydropteroyl mono-L-glutamate
  17. [(6S)-5-methyl-5,6,7,8-tetrahydropteroyl]glutamate
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 IUPAC 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
SMILES
CN1C(CNC2=CC=C(C=C2)C(=O)N[C@H](CCC(O)=O)C(O)=O)CNC2=C1C(=O)NC(N)=N2
InChI Identifier
InChI=1S/C20H25N7O6/c1-27-12(9-23-16-15(27)18(31)26-20(21)25-16)8-22-11-4-2-10(3-5-11)17(30)24-13(19(32)33)6-7-14(28)29/h2-5,12-13,22H,6-9H2,1H3,(H,24,30)(H,28,29)(H,32,33)(H4,21,23,25,26,31)/t12?,13-/m1/s1
InChI KeyZNOVTXRBGFNYRX-ZGTCLIOFSA-N
Chemical Taxonomy
KingdomOrganic Compounds
Super ClassAromatic Heteropolycyclic Compounds
ClassPteridines and Derivatives
Sub ClassPterins and Derivatives
Other Descriptors
  • Aromatic Heteropolycyclic Compounds
Substituents
  • Alpha Amino Acid Or Derivative
  • Aminobenzamide
  • Aminopyrimidine
  • Benzamide
  • Benzoyl
  • Carboxamide Group
  • Carboxylic Acid
  • Dicarboxylic Acid Derivative
  • Hippurate
  • N Acyl Alpha Amino Acid
  • N Substituted Alpha Amino Acid
  • Polyamine
  • Pteroic Acid Derivative
  • Pyrimidine
  • Pyrimidone
  • Secondary Carboxylic Acid Amide
Direct ParentFolic Acid Derivatives
Ontology
StatusDetected and Quantified
Origin
  • Drug metabolite
  • Endogenous
Biofunction
  • Component of Methionine metabolism
  • Waste products
ApplicationNot Available
Cellular locations
  • Extracellular
Physical Properties
StateSolid
Experimental Properties
PropertyValueReference
Melting PointNot AvailableNot Available
Boiling PointNot AvailableNot Available
Water SolubilityNot AvailableNot Available
LogPNot AvailableNot Available
Predicted Properties
PropertyValueSource
water solubility0.35 g/LALOGPS
logP-1.3ALOGPS
logP-2.8ChemAxon
logS-3.1ALOGPS
pKa (strongest acidic)3.22ChemAxon
pKa (strongest basic)4.64ChemAxon
physiological charge-2ChemAxon
hydrogen acceptor count11ChemAxon
hydrogen donor count7ChemAxon
polar surface area198.48ChemAxon
rotatable bond count9ChemAxon
refractivity126.88ChemAxon
polarizability46.13ChemAxon
Spectra
SpectraNot Available
Biological Properties
Cellular Locations
  • Extracellular
Biofluid Locations
  • Blood
  • Cerebrospinal Fluid (CSF)
  • Urine
Tissue Location
  • Kidney
  • Liver
  • Placenta
Pathways
NameSMPDB LinkKEGG Link
Betaine MetabolismSMP00123map00260
Folate MetabolismSMP00053map00670
Methionine MetabolismSMP00033map00270
Normal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
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 Quantified0.075 (0.045 - 0.13) uMAdult (>18 years old)Not SpecifiedNormal details
UrineExpected but not QuantifiedNot ApplicableNot AvailableNot AvailableNormal
  • Not Applicable
details
Abnormal Concentrations
BiofluidStatusValueAgeSexConditionReferenceDetails
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
AIDS
details
Associated Disorders and Diseases
Disease References
AIDS
  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
Rett syndrome
  1. 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
Associated OMIM IDs
DrugBank IDNot Available
DrugBank Metabolite IDDBMET00528
Phenol Explorer Compound IDNot Available
Phenol Explorer Metabolite IDNot Available
FoodDB IDFDB022600
KNApSAcK IDNot Available
Chemspider ID388371
KEGG Compound IDC00440
BioCyc ID5-METHYL-THF
BiGG ID34988
Wikipedia Link5-Methyltetrahydrofolate
NuGOwiki LinkHMDB01396
Metagene LinkHMDB01396
METLIN ID6215
PubChem Compound439234
PDB IDNot Available
ChEBI ID15641
References
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. 5-methyltetrahydrofolate. Monograph. Altern Med Rev. 2006 Dec;11(4):330-7. Pubmed: 17176169

Enzymes

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:
MTR
Uniprot ID:
Q99707
Molecular weight:
140525.91
Reactions
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:
MTHFR
Uniprot ID:
P42898
Molecular weight:
74595.895
Reactions
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:
HEMK1
Uniprot ID:
Q9Y5R4
Molecular weight:
Not Available
Reactions
Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
General function:
Not Available
Specific function:
Probable methyltransferase (By similarity).
Gene Name:
METTL2B
Uniprot ID:
Q6P1Q9
Molecular weight:
Not Available
Reactions
Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
General function:
Not Available
Specific function:
Probable methyltransferase (By similarity).
Gene Name:
METTL6
Uniprot ID:
Q8TCB7
Molecular weight:
Not Available
Reactions
Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails
General function:
Not Available
Specific function:
Methyltransferase that may act on DNA.
Gene Name:
WBSCR22
Uniprot ID:
O43709
Molecular weight:
Not Available
Reactions
Serotonin + 5-Methyltetrahydrofolic acid → 5-Methoxytryptamine + Tetrahydrofolic aciddetails