2.0 2012-05-31 09:57:42 -0600 2015-09-13 12:56:06 -0600 ECMDB00121 M2MDB000044 Folic acid Folic acid is a member of the vitamin B family. 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, synthesize purine and thymidylate nucleic acids, interconvert amino acids, methylated tRNA, and generate and use formate. Acifolic Cytofol Dosfolat B activ Folacid Folacin Folate Folbal Folcidin Foldine Folettes Foliamin Folic acid Folicet Folipac 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-glutamate N-(4-{[(2-Amino-4-oxo-3,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid N-Pteroyl-L-glutamate N-Pteroyl-L-glutamic acid N-[(4-{[(2-Amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)carbonyl]-L-glutamate 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-glutamate 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 Pteroylmonoglutamate Pteroylmonoglutamic acid Vitamin Bc Vitamin Be Vitamin M C19H19N7O6 441.3975 441.139681375 (2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid folate 59-30-3 NC1=NC(=O)C2=NC(CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CN=C2N1 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 OVBPIULPVIDEAO-LBPRGKRZSA-N Solid Cytoplasm Periplasm logp -0.04 ALOGPS logs -3.76 ALOGPS solubility 7.61e-02 g/l ALOGPS melting_point 250 oC logp -0.68 ChemAxon pka_strongest_acidic 3.37 ChemAxon pka_strongest_basic 2.09 ChemAxon iupac (2S)-2-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)formamido]pentanedioic acid ChemAxon average_mass 441.3975 ChemAxon mono_mass 441.139681375 ChemAxon smiles NC1=NC(=O)C2=NC(CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)=CN=C2N1 ChemAxon formula C19H19N7O6 ChemAxon inchi 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 ChemAxon inchikey OVBPIULPVIDEAO-LBPRGKRZSA-N ChemAxon polar_surface_area 208.99 ChemAxon refractivity 111.01 ChemAxon polarizability 42.06 ChemAxon rotatable_bond_count 9 ChemAxon acceptor_count 12 ChemAxon donor_count 6 ChemAxon physiological_charge -2 ChemAxon formal_charge 0 ChemAxon Folate biosynthesis The biosynthesis of folic acid begins with a product of purine nucleotides de novo biosynthesis pathway, GTP. This compound is involved in a reaction with water through a GTP cyclohydrolase 1 protein complex, resulting in a hydrogen ion, formic acid and 7,8-dihydroneopterin 3-triphosphate. The latter compound is dephosphatased through a dihydroneopterin triphosphate pyrophosphohydrolase resulting in the release of a pyrophosphate, hydrogen ion and 7,8-dihydroneopterin 3-phosphate. The latter compound reacts with water spontaneously resulting in the release of a phosphate and a 7,8 -dihydroneopterin. This compound reacts with a dihydroneopterin aldolase, releasing a glycoaldehyde and 6-hydroxymethyl-7,9-dihydropterin. The latter compound is phosphorylated with a ATP-driven 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase resulting in a (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate. Chorismate is metabolized by reacting with L-glutamine through a 4-amino-4-deoxychorismate synthase resulting in L-glutamic acid and 4-amino-4-deoxychorismate. The latter compound then reacts through an aminodeoxychorismate lyase resulting in pyruvic acid,hydrogen ion and p-aminobenzoic acid. (2-amino-4-hydroxy-7,8-dihydropteridin-6-yl)methyl diphosphate and p-aminobenzoic acid react through a dihydropteroate synthase resulting in pyrophosphate and 7,8-dihydropteroic acid. This compound reacts with L-glutamic acid through an ATP driven bifunctional folylpolyglutamate synthetase / dihydrofolate synthetase resulting in a 7,8-dihydrofolate monoglutamate. This compound is reduced through an NADPH mediated dihydrofolate reductase resulting in a tetrahydrofate. This product goes on to a one carbon pool by folate pathway. PW000908 ec00790 Metabolic One carbon pool by folate Dihydrofolic acid, a product of the folate biosynthesis pathway, can be metabolized by multiple enzymes. Dihydrofolic acid can be reduced by a NADP-driven dihydrofolate reductase resulting in a NADPH, hydrogen ion and folic acid. Dihydrofolic acid can also be reduced by an NADPH-driven dihydrofolate reductase resulting in a NADP and a tetrahydrofolic acid. Folic acid can also produce a tetrahydrofolic acid through a NADPH-driven dihydrofolate reductase. Dihydrofolic acid also interacts with 5-thymidylic acid through a thymidylate synthase resulting in the release of dUMP and 5,10-methylene-THF Tetrahydrofolic acid can be converted into 5,10-methylene-THF through two different reversible reactions. Tetrahydrofolic acid interacts with a S-Aminomethyldihydrolipoylprotein through a aminomethyltransferase resulting in the release of ammonia, a dihydrolipoylprotein and 5,10-Methylene-THF Tetrahydrofolic acid interacts with L-serine through a glycine hydroxymethyltransferase resulting in a glycine, water and 5,10-Methylene-THF. The compound 5,10-methylene-THF reacts with an NADPH dependent methylenetetrahydrofolate reductase [NAD(P)H] resulting in NADP and 5-Methyltetrahydrofolic acid. This compound interacts with homocysteine through a methionine synthase resulting in L-methionine and tetrahydrofolic acid. Tetrahydrofolic acid can be metabolized into 10-formyltetrahydrofolate through 4 different enzymes: 1.- Tetrahydrofolic acid interacts with FAICAR through a phosphoribosylaminoimidazolecarboxamide formyltransferase resulting in a 1-(5'-Phosphoribosyl)-5-amino-4-imidazolecarboxamide and a 10-formyltetrahydrofolate 2.-Tetrahydrofolic acid interacts with 5'-Phosphoribosyl-N-formylglycinamide through a phosphoribosylglycinamide formyltransferase 2 resulting in a Glycineamideribotide and a 10-formyltetrahydrofolate 3.-Tetrahydrofolic acid interacts with Formic acid through a formyltetrahydrofolate hydrolase resulting in water and a 10-formyltetrahydrofolate 4.-Tetrahydrofolic acid interacts with N-formylmethionyl-tRNA(fMet) through a 10-formyltetrahydrofolate:L-methionyl-tRNA(fMet) N-formyltransferase resulting in a L-methionyl-tRNA(Met) and a 10-formyltetrahydrofolate 10-formyltetrahydrofolate can interact with a hydrogen ion through a bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in water and 5,10-methenyltetrahydrofolic acid. Tetrahydrofolic acid can be metabolized into 5,10-methenyltetrahydrofolic acid by reacting with a 5'-phosphoribosyl-a-N-formylglycineamidine through a phosphoribosylglycinamide formyltransferase 2 resulting in water, glycineamideribotide and 5,10-methenyltetrahydrofolic acid. The latter compound can either interact with water through an aminomethyltransferase resulting in a N5-Formyl-THF, or it can interact with a NADPH driven bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in a NADP and 5,10-Methylene THF. PW000773 ec00670 Metabolic One Carbon Pool by Folate I Dihydrofolic acid, a product of the folate biosynthesis pathway, can be metabolized by multiple enzymes. Dihydrofolic acid can be reduced by a NADP-driven dihydrofolate reductase resulting in a NADPH, hydrogen ion and folic acid. Dihydrofolic acid can also be reduced by an NADPH-driven dihydrofolate reductase resulting in a NADP and a tetrahydrofolic acid. Folic acid can also produce a tetrahydrofolic acid through a NADPH-driven dihydrofolate reductase. Dihydrofolic acid also interacts with 5-thymidylic acid through a thymidylate synthase resulting in the release of dUMP and 5,10-methylene-THF Tetrahydrofolic acid can be converted into 5,10-methylene-THF through two different reversible reactions. Tetrahydrofolic acid interacts with a S-Aminomethyldihydrolipoylprotein through a aminomethyltransferase resulting in the release of ammonia, a dihydrolipoylprotein and 5,10-Methylene-THF Tetrahydrofolic acid interacts with L-serine through a glycine hydroxymethyltransferase resulting in a glycine, water and 5,10-Methylene-THF. The compound 5,10-methylene-THF reacts with an NADPH dependent methylenetetrahydrofolate reductase [NAD(P)H] resulting in NADP and 5-Methyltetrahydrofolic acid. This compound interacts with homocysteine through a methionine synthase resulting in L-methionine and tetrahydrofolic acid. Tetrahydrofolic acid can be metabolized into 10-formyltetrahydrofolate through 4 different enzymes: 1.- Tetrahydrofolic acid interacts with FAICAR through a phosphoribosylaminoimidazolecarboxamide formyltransferase resulting in a 1-(5'-Phosphoribosyl)-5-amino-4-imidazolecarboxamide and a 10-formyltetrahydrofolate 2.-Tetrahydrofolic acid interacts with 5'-Phosphoribosyl-N-formylglycinamide through a phosphoribosylglycinamide formyltransferase 2 resulting in a Glycineamideribotide and a 10-formyltetrahydrofolate 3.-Tetrahydrofolic acid interacts with Formic acid through a formyltetrahydrofolate hydrolase resulting in water and a 10-formyltetrahydrofolate 4.-Tetrahydrofolic acid interacts with N-formylmethionyl-tRNA(fMet) through a 10-formyltetrahydrofolate:L-methionyl-tRNA(fMet) N-formyltransferase resulting in a L-methionyl-tRNA(Met) and a 10-formyltetrahydrofolate 10-formyltetrahydrofolate can interact with a hydrogen ion through a bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in water and 5,10-methenyltetrahydrofolic acid. Tetrahydrofolic acid can be metabolized into 5,10-methenyltetrahydrofolic acid by reacting with a 5'-phosphoribosyl-a-N-formylglycineamidine through a phosphoribosylglycinamide formyltransferase 2 resulting in water, glycineamideribotide and 5,10-methenyltetrahydrofolic acid. The latter compound can either interact with water through an aminomethyltransferase resulting in a N5-Formyl-THF, or it can interact with a NADPH driven bifunctional 5,10-methylene-tetrahydrofolate dehydrogenase resulting in a NADP and 5,10-Methylene THF. PW001735 Metabolic Specdb::CMs 22269 Specdb::CMs 37303 Specdb::CMs 165078 Specdb::CMs 1050360 Specdb::CMs 1050362 Specdb::CMs 1050364 Specdb::CMs 1050366 Specdb::CMs 1050367 Specdb::CMs 1050369 Specdb::CMs 1050371 Specdb::CMs 1050373 Specdb::CMs 1050375 Specdb::CMs 1050377 Specdb::CMs 1050379 Specdb::CMs 1050381 Specdb::CMs 1050382 Specdb::CMs 1050384 Specdb::CMs 1050386 Specdb::CMs 1050388 Specdb::CMs 1050390 Specdb::CMs 1050392 Specdb::CMs 1050394 Specdb::CMs 1050395 Specdb::CMs 1050397 Specdb::CMs 1050399 Specdb::EiMs 344 Specdb::NmrOneD 1092 Specdb::NmrOneD 2513 Specdb::NmrOneD 3211 Specdb::NmrOneD 5134 Specdb::NmrOneD 5135 Specdb::NmrOneD 5772 Specdb::NmrOneD 5773 Specdb::NmrOneD 5774 Specdb::NmrOneD 5775 Specdb::NmrOneD 5776 Specdb::NmrOneD 5777 Specdb::NmrOneD 5778 Specdb::NmrOneD 5779 Specdb::NmrOneD 5780 Specdb::NmrOneD 5781 Specdb::NmrOneD 5782 Specdb::NmrOneD 5783 Specdb::NmrOneD 5784 Specdb::NmrOneD 5785 Specdb::NmrOneD 5786 Specdb::NmrOneD 5787 Specdb::NmrOneD 5788 Specdb::NmrOneD 5789 Specdb::NmrOneD 5790 Specdb::NmrOneD 5791 Specdb::MsMs 174 Specdb::MsMs 175 Specdb::MsMs 176 Specdb::MsMs 2912 Specdb::MsMs 182913 Specdb::MsMs 182914 Specdb::MsMs 182915 Specdb::MsMs 183261 Specdb::MsMs 183262 Specdb::MsMs 183263 Specdb::MsMs 374579 Specdb::MsMs 439273 Specdb::MsMs 451198 Specdb::MsMs 2226655 Specdb::MsMs 2226878 Specdb::MsMs 2227812 Specdb::MsMs 2228083 Specdb::MsMs 2229178 Specdb::MsMs 2229235 Specdb::MsMs 2230246 Specdb::MsMs 2230263 Specdb::MsMs 2231457 Specdb::MsMs 2231502 Specdb::MsMs 2231600 Specdb::MsMs 2232575 Specdb::NmrTwoD 1150 HMDB00121 6037 5815 C00504 27470 CPD-12826 FOL Folic acid Keseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590. 21097882 Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114. 22080510 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 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 Zittoun J: [Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism]. Rev Prat. 1993 Jun 1;43(11):1358-63. 8235383 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 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 Piper, James R.; McCaleb, George S.; Montgomery, John A. Synthesis of 10-propargylfolic acid from 2-amino-6-(bromomethyl)-4(1H)-pteridinone. Journal of Heterocyclic Chemistry (1987), 24(1), 279-82. http://hmdb.ca/system/metabolites/msds/000/000/082/original/HMDB00121.pdf?1358894364 Dihydrofolate reductase P0ABQ4 DYR_ECOLI folA http://ecmdb.ca/proteins/P0ABQ4.xml Tetrahydrofolic acid + 2 NAD <> Folic acid +2 NADH +2 Hydrogen ion R00937 Tetrahydrofolic acid + 2 NADP <> Folic acid +2 NADPH +2 Hydrogen ion R00940 Dihydrofolic acid + NAD <> Folic acid + NADH + Hydrogen ion R02235 Dihydrofolic acid + NADP <> Folic acid + NADPH + Hydrogen ion R02236 Dihydrofolic acid + NADP + Dihydrofolic acid > Folic acid + NADPH + Hydrogen ion + NADPH PW_R002537 Folic acid + 2 NADPH + 2 Hydrogen ion + 2 NADPH > Tetrahydrofolic acid +2 NADP + Tetrahydrofolic acid PW_R004674