T3DB: Folic acid

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (8)XML

Targets (8)

Record Information

Version

2.0

Creation Date

2009-07-21 20:26:10 UTC

Update Date

2014-12-24 20:25:49 UTC

Accession Number

T3D2698

Identification

Common Name

Folic acid

Class

Small Molecule

Description

Folic acid is a member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (poaceae). Folic acid, being biochemically inactive, is converted to tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase. These folic acid congeners are transported across cells by receptor-mediated endocytosis where they are needed to maintain normal erythropoiesis, synthesize purine and thymidylate nucleic acids, interconvert amino acids, methylated tRNA, and generate and use formate. Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia.

Compound Type

Amide
Amine
Dietary Supplement
Drug
Ester
Food Toxin
Fungal Toxin
Hematinic
Household Toxin
Metabolite
Micronutrient
Natural Compound
Nutraceutical
Organic Compound
Supplement
Vitamin B Complex

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
Acfol
Acifolic
Cytofol
Dosfolat B activ
Fefol
Folacid
Folacin
Folate
Folbal
Folcidin
Foldine
Folettes
Foliamin
Folicet
Folipac
Folsaeure
Folsan
Folsaure
Folsav
Folvite
Incafolic
Liver Lactobacillus casei factor
Millafol
N-(4-{[(2-Amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid
N-Pteroyl-L-glutamic acid
N-[(4-{[(2-Amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)carbonyl]-L-glutamic acid
N-[4-[[(2-Amino-3,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid
PGA
PteGlu
Pteroyl-L-glutamate
Pteroyl-L-glutamic acid
Pteroyl-L-monoglutamate
Pteroyl-L-monoglutamic acid
Pteroylglutamate
Pteroylglutamic acid
Pteroylmonoglutamic acid
Vitamin B9
Vitamin Bc
Vitamin Be
Vitamin M

Chemical Formula

C₁₉H₁₉N₇O₆

Average Molecular Mass

441.398 g/mol

Monoisotopic Mass

441.140 g/mol

CAS Registry Number

59-30-3

IUPAC Name

(2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid

Traditional Name

folate

SMILES

[H][C@@](CCC(O)=O)(NC(=O)C1=CC=C(NCC2=NC3=C(NC(=N)N=C3O)N=C2)C=C1)C(O)=O

InChI Identifier

InChI=1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1

InChI Key

InChIKey=OVBPIULPVIDEAO-LBPRGKRZSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as methoxyphenols. Methoxyphenols are compounds containing a methoxy group attached to the benzene ring of a phenol moiety.

Kingdom

Super Class

Class

Sub Class

Direct Parent

Alternative Parents

Substituents

Methoxyphenol
Phenoxy compound
Anisole
Methoxybenzene
Phenol ether
1-hydroxy-2-unsubstituted benzenoid
Alkyl aryl ether
Monocyclic benzene moiety
Carboxylic acid derivative
Monocarboxylic acid or derivatives
Ether
Carboxylic acid
Organic oxygen compound
Organooxygen compound
Carbonyl group
Hydrocarbon derivative
Organic oxide
Aromatic homomonocyclic compound

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

monocarboxylic acid (CHEBI:545959 )
phenols (CHEBI:545959 )
monomethoxybenzene (CHEBI:545959 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular

Biofluid Locations

Not Available

Tissue Locations

Brain
Erythrocyte
Kidney
Liver

Pathways

Name	SMPDB Link	KEGG Link
Folate Metabolism	SMP00053	map00670
Pterine Biosynthesis	SMP00005	map00790

Applications

B vitamin

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	250 dec°C
Boiling Point	Not Available
Solubility	1.6 mg/L (at 25°C)
LogP	-2.5

Predicted Properties

Property	Value	Source
Water Solubility	0.076 g/L	ALOGPS
logP	-0.04	ALOGPS
logP	-0.68	ChemAxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	3.37	ChemAxon
pKa (Strongest Basic)	2.09	ChemAxon
Physiological Charge	-2	ChemAxon
Hydrogen Acceptor Count	12	ChemAxon
Hydrogen Donor Count	6	ChemAxon
Polar Surface Area	208.99 Å²	ChemAxon
Rotatable Bond Count	9	ChemAxon
Refractivity	111.01 m³·mol⁻¹	ChemAxon
Polarizability	42.06 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0002-2249100000-5ad16461f6638538ea08	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-00xr-4205390000-4152e24c68306bfe6554	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_4) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_5) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_6) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_3) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_4) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_5) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_6) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_7) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_8) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_9) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_10) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_11) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_12) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_13) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_14) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_15) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_16) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-0006-0000900000-4208ea3c2f5d9026c19f	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-0006-0050900000-2c8ad037dc3b270765c4	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-0007-0090300000-ebdec84cbb7fe5afbc0b	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Negative	splash10-0007-0903600000-e5d91e4f2ab79d130b76	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-qTof , Positive	splash10-002b-0960000000-108d96993dc78f1e4b61	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , negative	splash10-0007-0903600000-e5d91e4f2ab79d130b76	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-002b-0960000000-108d96993dc78f1e4b61	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0002-0090000000-9e9a33bc590d0f801929	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Positive	splash10-0aba-6940000000-f0b6076af9cb59413656	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 0V, Positive	splash10-0005-0090600010-5ef6e95b870cc0ebfeb8	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0002-0190000000-2d1f624dc1d2d929527f	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 90V, Negative	splash10-015c-9700000000-5a0aeec6b1c2bfddfdf1	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0002-0090000000-b750c262ac740994e33a	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 0V, Positive	splash10-0005-0090600000-c0e3753ba3591c41d1db	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 75V, Negative	splash10-001i-3900000000-4d5187e4336ce6be5eb7	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-00b9-0910000000-b3bc3e8ccbba45c85e78	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-0002-0090000010-2c53d9aa251e75638183	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Negative	splash10-0006-0000900000-7370828adb963cbb9246	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Negative	splash10-0006-0000900000-3b979cd5ecd30ae0d2bf	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-00bd-0544900000-aa9a130e2cf3dacfb954	2016-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-004j-0954100000-7be7eac442233b5d3bcf	2016-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-004i-1960000000-1950169762886f41b6ec	2016-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0006-0114900000-bff7f5f3d20dcd6a4494	2016-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-00r7-1249300000-e322ba8675bb922877a9	2016-09-14	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9652000000-8c87fa7172ed19a7eb27	2016-09-14	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0006-9410000000-7cba521e870757539424	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, DMSO-d6, experimental)	Not Available	2014-09-20	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 22.53 MHz, DMSO-d6, experimental)	Not Available	2014-09-23	View Spectrum
1D NMR	¹H NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-16	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum

Toxicity Profile

Route of Exposure

Intravenous, Oral

Mechanism of Toxicity

Folic acid, as it is biochemically inactive, is converted to tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase. These folic acid congeners are transported across cells by receptor-mediated endocytosis where they are needed to maintain normal erythropoiesis, synthesize purine and thymidylate nucleic acids, interconvert amino acids, methylate tRNA, and generate and use formate. Using vitamin B12 as a cofactor, folic acid can normalize high homocysteine levels by remethylation of homocysteine to methionine via methionine synthetase.

Metabolism

Hepatic Route of Elimination: Folic Acid is metabolized in the liver to 7, 8-dihydrofolic acid and eventually to 5,6,7,8-tetrahydrofolic acid with the aid of reduced diphosphopyridine nucleotide (DPNH) and folate reductases. A majority of the metabolic products appeared in the urine after 6 hours; excretion was generally complete within 24 hours. Folic Acid is also excreted in the milk of lactating mothers.

Toxicity Values

LD50: 85 mg/kg (Intraperitoneal, Mouse) (6) LD50: 120 mg/kg (Intravenous, Guinea pig) (6) LD50: 239 mg/kg (Intravenous Mouse) (6) LD50: 500 mg/kg (Intravenous, Rat) (6) LD50: 410 mg/kg (Intravenous, Rabbit) (6)

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

For treatment of folic acid deficiency, megaloblastic anemia and in anemias of nutritional supplements, pregnancy, infancy, or childhood.

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

136610 , 136630 , 229050 , 229100 , 236200 , 236250 , 309548 , 601634 , 601775 , 603174 , 608866

ChEBI ID

27470

BioCyc ID

FOLATE

CTD ID

Not Available

Stitch ID

Folic Acid

PDB ID

FOL

ACToR ID

2649

Wikipedia Link

Folic_Acid

References

Synthesis Reference

Carroll G. Temple, Jr., Robert D. Elliott, Jerry D. Rose, John A. Montgomery, “Preparation of tetrahydrofolic acid from folic acid.” U.S. Patent US4206307, issued April, 1956.

MSDS

Link

General References

Kamen B: Folate and antifolate pharmacology. Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-30-S18-39. [9420019 ]
Fenech M, Aitken C, Rinaldi J: Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis. 1998 Jul;19(7):1163-71. [9683174 ]
Zittoun J: [Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism]. Rev Prat. 1993 Jun 1;43(11):1358-63. [8235383 ]
Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL: Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Adv Data. 1994 Nov 14;(258):1-28. [10138938 ]
Raiten DJ, Fisher KD: Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). J Nutr. 1995 May;125(5):1371S-1398S. [7738698 ]
Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Kopczynska E, Ziolkowski M, Jendryczka-Mackiewicz E, Odrowaz-Sypniewska G, Opozda K, Tyrakowski T: [The concentrations of homocysteine, folic acid and vitamin B12 in alcohol dependent male patients]. Psychiatr Pol. 2004 Sep-Oct;38(5):947-56. [15523939 ]
Gregory JF 3rd, Williamson J, Liao JF, Bailey LB, Toth JP: Kinetic model of folate metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent, turnover of folate pools. J Nutr. 1998 Nov;128(11):1896-906. [9808640 ]
Lin Y, Dueker SR, Follett JR, Fadel JG, Arjomand A, Schneider PD, Miller JW, Green R, Buchholz BA, Vogel JS, Phair RD, Clifford AJ: Quantitation of in vivo human folate metabolism. Am J Clin Nutr. 2004 Sep;80(3):680-91. [15321809 ]
Rodriguez Flores J, Penalvo GC, Mansilla AE, Gomez MJ: Capillary electrophoretic determination of methotrexate, leucovorin and folic acid in human urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 May 5;819(1):141-7. [15797531 ]
Selley ML, Close DR, Stern SE: The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging. 2002 May-Jun;23(3):383-8. [11959400 ]
Litwin M, Abuauba M, Wawer ZT, Grenda R, Kuryl T, Pietraszek E: [Sulphur amino acids, vitamin B12 and folic acid in children with chronic renal failure]. Pol Merkur Lekarski. 2000 Apr;8(46):268-9. [10897644 ]
Gregory JF 3rd, Williamson J, Bailey LB, Toth JP: Urinary excretion of [2H4]folate by nonpregnant women following a single oral dose of [2H4]folic acid is a functional index of folate nutritional status. J Nutr. 1998 Nov;128(11):1907-12. [9808641 ]
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. [16093404 ]
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. [15831910 ]
Clifford AJ, Arjomand A, Dueker SR, Schneider PD, Buchholz BA, Vogel JS: The dynamics of folic acid metabolism in an adult given a small tracer dose of 14C-folic acid. Adv Exp Med Biol. 1998;445:239-51. [9781393 ]
Olthof MR, Bots ML, Katan MB, Verhoef P: Effect of folic acid and betaine supplementation on flow-mediated dilation: a randomized, controlled study in healthy volunteers. PLoS Clin Trials. 2006 Jun;1(2):e10. Epub 2006 Jun 9. [16871332 ]
Stern LL, Bagley PJ, Rosenberg IH, Selhub J: Conversion of 5-formyltetrahydrofolic acid to 5-methyltetrahydrofolic acid is unimpaired in folate-adequate persons homozygous for the C677T mutation in the methylenetetrahydrofolate reductase gene. J Nutr. 2000 Sep;130(9):2238-42. [10958818 ]
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. [15990733 ]
Cahill E, McPartlin J, Gibney MJ: The effects of fasting and refeeding healthy volunteers on serum folate levels. Int J Vitam Nutr Res. 1998;68(2):142-5. [9565830 ]

Gene Regulation

Up-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Down-Regulated Genes

Gene	Gene Symbol	Gene ID	Interaction	Chromosome	Details

Targets

Target Details

1. Folate receptor gamma

General Function:: Folic acid binding
Specific Function:: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells. Isoform Short does not bind folate.
Gene Name:: FOLR3
Uniprot ID:: P41439
Molecular Weight:: 27638.0 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]
Shen F, Ross JF, Wang X, Ratnam M: Identification of a novel folate receptor, a truncated receptor, and receptor type beta in hematopoietic cells: cDNA cloning, expression, immunoreactivity, and tissue specificity. Biochemistry. 1994 Feb 8;33(5):1209-15. [8110752 ]
Shen F, Wu M, Ross JF, Miller D, Ratnam M: Folate receptor type gamma is primarily a secretory protein due to lack of an efficient signal for glycosylphosphatidylinositol modification: protein characterization and cell type specificity. Biochemistry. 1995 Apr 25;34(16):5660-5. [7727426 ]
Prasad PD, Ramamoorthy S, Moe AJ, Smith CH, Leibach FH, Ganapathy V: Selective expression of the high-affinity isoform of the folate receptor (FR-alpha) in the human placental syncytiotrophoblast and choriocarcinoma cells. Biochim Biophys Acta. 1994 Aug 11;1223(1):71-5. [8061055 ]

Target Details

2. Folate receptor beta

General Function:: Methotrexate binding
Specific Function:: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release.
Gene Name:: FOLR2
Uniprot ID:: P14207
Molecular Weight:: 29279.31 Da

References

Dixit V, Van den Bossche J, Sherman DM, Thompson DH, Andres RP: Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells. Bioconjug Chem. 2006 May-Jun;17(3):603-9. [16704197 ]
Wlodarczyk BJ, Cabrera RM, Hill DS, Bozinov D, Zhu H, Finnell RH: Arsenic-induced gene expression changes in the neural tube of folate transport defective mouse embryos. Neurotoxicology. 2006 Jul;27(4):547-57. Epub 2006 Apr 18. [16620997 ]
Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC: Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect. 2006 Oct;114(10):1547-52. [17035141 ]
Wang L, Desmoulin SK, Cherian C, Polin L, White K, Kushner J, Fulterer A, Chang MH, Mitchell-Ryan S, Stout M, Romero MF, Hou Z, Matherly LH, Gangjee A: Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits beta-glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64. doi: 10.1021/jm200739e. Epub 2011 Sep 22. [21879757 ]

Target Details

3. Gamma-glutamyl hydrolase

General Function:: Omega peptidase activity
Specific Function:: Hydrolyzes the polyglutamate sidechains of pteroylpolyglutamates. Progressively removes gamma-glutamyl residues from pteroylpoly-gamma-glutamate to yield pteroyl-alpha-glutamate (folic acid) and free glutamate. May play an important role in the bioavailability of dietary pteroylpolyglutamates and in the metabolism of pteroylpolyglutamates and antifolates.
Gene Name:: GGH
Uniprot ID:: Q92820
Molecular Weight:: 35964.045 Da

References

Schneider E, Ryan TJ: Gamma-glutamyl hydrolase and drug resistance. Clin Chim Acta. 2006 Dec;374(1-2):25-32. Epub 2006 Jun 10. [16859665 ]
Eisele LE, Chave KJ, Lehning AC, Ryan TJ: Characterization of Human gamma-glutamyl hydrolase in solution demonstrates that the enzyme is a non-dissociating homodimer. Biochim Biophys Acta. 2006 Sep;1764(9):1479-86. Epub 2006 Jul 12. [16945597 ]
Chen L, Eitenmiller RR: Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables. J Agric Food Chem. 2007 May 16;55(10):3884-8. Epub 2007 Apr 17. [17439143 ]

Target Details

4. Mitochondrial folate transporter/carrier

General Function:: Folic acid transporter activity
Specific Function:: Transports folate across the inner membranes of mitochondria.
Gene Name:: SLC25A32
Uniprot ID:: Q9H2D1
Molecular Weight:: 35406.83 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [17139284 ]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [17016423 ]

Target Details

5. Proton-coupled folate transporter

General Function:: Methotrexate transporter activity
Specific Function:: Has been shown to act both as an intestinal proton-coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme.
Gene Name:: SLC46A1
Uniprot ID:: Q96NT5
Molecular Weight:: 49770.04 Da

References

Nakai Y, Inoue K, Abe N, Hatakeyama M, Ohta KY, Otagiri M, Hayashi Y, Yuasa H: Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. Epub 2007 May 2. [17475902 ]
Ashokkumar B, Mohammed ZM, Vaziri ND, Said HM: Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr. 2007 Jul;86(1):159-66. [17616776 ]

Target Details

6. Dihydrofolate reductase

General Function:: Nadph binding
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:: DHFR
Uniprot ID:: P00374
Molecular Weight:: 21452.61 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Dissociation	0.81 uM	Not Available	BindingDB 50367343
Dissociation	4.4 uM	Not Available	BindingDB 50367343
Dissociation	4.8 uM	Not Available	BindingDB 50367343

References

Taira K, Benkovic SJ: Evaluation of the importance of hydrophobic interactions in drug binding to dihydrofolate reductase. J Med Chem. 1988 Jan;31(1):129-37. [3275776 ]

Target Details

7. Folate receptor alpha

General Function:: Receptor activity
Specific Function:: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release. Required for normal embryonic development and normal cell proliferation.
Gene Name:: FOLR1
Uniprot ID:: P15328
Molecular Weight:: 29818.94 Da

References

Wang L, Desmoulin SK, Cherian C, Polin L, White K, Kushner J, Fulterer A, Chang MH, Mitchell-Ryan S, Stout M, Romero MF, Hou Z, Matherly LH, Gangjee A: Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits beta-glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64. doi: 10.1021/jm200739e. Epub 2011 Sep 22. [21879757 ]

Target Details

8. Thymidylate synthase

General Function:: Thymidylate synthase activity
Specific Function:: Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
Gene Name:: TYMS
Uniprot ID:: P04818
Molecular Weight:: 35715.65 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
Inhibitory	40 uM	Not Available	BindingDB 50367343
IC50	290 uM	Not Available	BindingDB 50367343

References

Brixner DI, Ueda T, Cheng YC, Hynes JB, Broom AD: Folate analogues as inhibitors of thymidylate synthase. J Med Chem. 1987 Apr;30(4):675-8. [3470522 ]

Folic acid (T3D2698)

Structure for T3D2698: Folic acid

Targets

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Binding/Activity Constants

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Binding/Activity Constants

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