2.02012-05-31 10:27:15 -06002015-06-03 15:53:30 -0600ECMDB00528M2MDB0001474,5-Dihydroorotic acid4,5-Dihydroorotic acid is a substrate of the enzyme orotate reductase [EC 1.3.1.14], which is part of the pyrimidine metabolism pathway. (KEGG) Dihydroorotate is oxidized by Dihydroorotate dehydrogenases (DHODs) to orotate. These dehydrogenases use their FMN (flavin mononucleotide) prosthetic group to abstract a hydride equivalent from C6 to deprotonate C5(+)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylate(+)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylic acid(<i>S</i>)-4,5-dihydroorotate(<i>S</i>)-4,5-dihydroorotic acid(<i>S</i>)-4-pyrimidinecarboxylic acid(<i>S</i>)-di-H-orotate(<i>S</i>)-hydroorotic acid(R)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylate(R)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylic acid(S)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylate(S)-2,6-dioxo-hexahydro-pyrimidine-4-carboxylic acid(S)-4,5-Dihydroorotate(S)-4,5-dihydroorotic acid(S)-4-pyrimidinecarboxylate(S)-4-pyrimidinecarboxylic acid(S)-di-H-orotate(S)-di-H-orotic acid(S)-Dihydroorotate(S)-Dihydroorotic acid(S)-hydroorotate(S)-hydroorotic acid2,6-dioxo-hexahydro-pyrimidine-4-carboxylate2,6-dioxo-hexahydro-pyrimidine-4-carboxylic acid4,5-Dihydro-L-orotate4,5-Dihydro-L-orotic acid4,5-Dihydroorotate4,5-Dihydroorotic acid5,6-Dihydroorotate5,6-Dihydroorotic acidDihydro-L-orotateDihydro-L-orotic acidL-4,5-DihydroorotateL-4,5-Dihydroorotic acidL-DihydroorotateL-Dihydroorotic acidL-HydroorotateL-Hydroorotic acidR,S-HydroorotateR,S-Hydroorotic acidC5H6N2O4158.1121158.032756692,6-dioxo-1,3-diazinane-4-carboxylic aciddihydroorotic acid155-54-4OC(=O)C1CC(=O)NC(=O)N1InChI=1S/C5H6N2O4/c8-3-1-2(4(9)10)6-5(11)7-3/h2H,1H2,(H,9,10)(H2,6,7,8,11)UFIVEPVSAGBUSI-UHFFFAOYSA-NSolidCytosollogp-1.70logs-1.10solubility1.27e+01 g/llogp-1.5pka_strongest_acidic3.28pka_strongest_basic-8.2iupac2,6-dioxo-1,3-diazinane-4-carboxylic acidaverage_mass158.1121mono_mass158.03275669smilesOC(=O)C1CC(=O)NC(=O)N1formulaC5H6N2O4inchiInChI=1S/C5H6N2O4/c8-3-1-2(4(9)10)6-5(11)7-3/h2H,1H2,(H,9,10)(H2,6,7,8,11)inchikeyUFIVEPVSAGBUSI-UHFFFAOYSA-Npolar_surface_area95.5refractivity31.58polarizability13.09rotatable_bond_count1acceptor_count4donor_count3physiological_charge-1formal_charge0Pyrimidine metabolismThe metabolism of pyrimidines begins with L-glutamine interacting with water molecule and a hydrogen carbonate through an ATP driven carbamoyl phosphate synthetase resulting in a hydrogen ion, an ADP, a phosphate, an L-glutamic acid and a carbamoyl phosphate. The latter compound interacts with an L-aspartic acid through a aspartate transcarbamylase resulting in a phosphate, a hydrogen ion and a N-carbamoyl-L-aspartate. The latter compound interacts with a hydrogen ion through a dihydroorotase resulting in the release of a water molecule and a 4,5-dihydroorotic acid. This compound interacts with an ubiquinone-1 through a dihydroorotate dehydrogenase, type 2 resulting in a release of an ubiquinol-1 and an orotic acid. The orotic acid then interacts with a phosphoribosyl pyrophosphate through a orotate phosphoribosyltransferase resulting in a pyrophosphate and an orotidylic acid. The latter compound then interacts with a hydrogen ion through an orotidine-5 '-phosphate decarboxylase, resulting in an release of carbon dioxide and an Uridine 5' monophosphate. The Uridine 5' monophosphate process to get phosphorylated by an ATP driven UMP kinase resulting in the release of an ADP and an Uridine 5--diphosphate.
Uridine 5-diphosphate can be metabolized in multiple ways in order to produce a Deoxyuridine triphosphate.
1.-Uridine 5-diphosphate interacts with a reduced thioredoxin through a ribonucleoside diphosphate reductase 1 resulting in the release of a water molecule and an oxidized thioredoxin and an dUDP. The dUDP is then phosphorylated by an ATP through a nucleoside diphosphate kinase resulting in the release of an ADP and a DeoxyUridine triphosphate.
2.-Uridine 5-diphosphate interacts with a reduced NrdH glutaredoxin-like protein through a Ribonucleoside-diphosphate reductase 1 resulting in a release of a water molecule, an oxidized NrdH glutaredoxin-like protein and a dUDP. The dUDP is then phosphorylated by an ATP through a nucleoside diphosphate kinase resulting in the release of an ADP and a DeoxyUridine triphosphate.
3.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate. The latter compound interacts with a reduced flavodoxin through ribonucleoside-triphosphate reductase resulting in the release of an oxidized flavodoxin, a water molecule and a Deoxyuridine triphosphate
4.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate interacts with a reduced flavodoxin through a ribonucleoside-triphosphate reductase resulting in the release of a water molecule, an oxidized flavodoxin and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate.
5.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate then interacts spontaneously with a water molecule resulting in the release of a phosphate, a hydrogen ion and a CDP. The CDP then interacts with a reduced NrdH glutaredoxin-like protein through a ribonucleoside-diphosphate reductase 2 resulting in the release of a water molecule, an oxidized NrdH glutaredoxin-like protein and a dCDP. The dCDP is then phosphorylated through an ATP driven nucleoside diphosphate kinase resulting in an ADP and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate.
6.-Uridine 5-diphosphate is phosphorylated by an ATP-driven nucleoside diphosphate kinase resulting in an ADP and an Uridinetriphosphate The uridine triphosphate interacts with a L-glutamine and a water molecule through an ATP driven CTP synthase resulting in an ADP, a phosphate, a hydrogen ion, an L-glutamic acid and a cytidine triphosphate. The cytidine triphosphate then interacts spontaneously with a water molecule resulting in the release of a phosphate, a hydrogen ion and a CDP. The CDP interacts with a reduced thioredoxin through a ribonucleoside diphosphate reductase 1 resulting in a release of a water molecule, an oxidized thioredoxin and a dCDP. The dCDP is then phosphorylated through an ATP driven nucleoside diphosphate kinase resulting in an ADP and a dCTP. The dCTP interacts with a water molecule and a hydrogen ion through a dCTP deaminase resulting in a release of an ammonium molecule and a Deoxyuridine triphosphate.
The deoxyuridine triphosphate then interacts with a water molecule through a nucleoside triphosphate pyrophosphohydrolase resulting in a release of a hydrogen ion, a phosphate and a dUMP. The dUMP then interacts with a methenyltetrahydrofolate through a thymidylate synthase resulting in a dihydrofolic acid and a 5-thymidylic acid. Then 5-thymidylic acid is then phosphorylated through a nucleoside diphosphate kinase resulting in the release of an ADP and thymidine 5'-triphosphate.PW000942ec00240MetabolicMetabolic pathwayseco01100uridine-5'-phosphate biosynthesisPWY-5686Specdb::CMs3068Specdb::CMs37598Specdb::CMs161353Specdb::CMs1065092Specdb::CMs1065094Specdb::CMs1065096Specdb::CMs1065098Specdb::CMs1065100Specdb::NmrOneD1406Specdb::NmrOneD144210Specdb::NmrOneD144211Specdb::NmrOneD144212Specdb::NmrOneD144213Specdb::NmrOneD144214Specdb::NmrOneD144215Specdb::NmrOneD144216Specdb::NmrOneD144217Specdb::NmrOneD144218Specdb::NmrOneD144219Specdb::NmrOneD144220Specdb::NmrOneD144221Specdb::NmrOneD144222Specdb::NmrOneD144223Specdb::NmrOneD144224Specdb::NmrOneD144225Specdb::NmrOneD144226Specdb::NmrOneD144227Specdb::NmrOneD144228Specdb::NmrOneD144229Specdb::MsMs746Specdb::MsMs747Specdb::MsMs748Specdb::MsMs182814Specdb::MsMs182815Specdb::MsMs182816Specdb::MsMs183162Specdb::MsMs183163Specdb::MsMs183164Specdb::MsMs2837022Specdb::MsMs2837023Specdb::MsMs2837024Specdb::MsMs2868024Specdb::MsMs2868025Specdb::MsMs2868026Specdb::NmrTwoD1350HMDB00528648628C0033730865DI-H-OROTATE4,5-Dihydroorotic acidKeseler, 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-D590.21097882Kanehisa, 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-D114.22080510Bennett, B. D., Kimball, E. H., Gao, M., Osterhout, R., Van Dien, S. J., Rabinowitz, J. D. (2009). "Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli." Nat Chem Biol 5:593-599.19561621Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4.19212411Burger, Klaus; Neuhauser, Horst; Rudolph, Martin. A new, preparatively simple way to dihydroorotic acid, 1-methyl-4,5-dihydroorotic acid and their derivatives. Chemiker-Zeitung (1990), 114(7-8), 251-5. DihydroorotaseP05020PYRC_ECOLIpyrChttp://ecmdb.ca/proteins/P05020.xmlDihydroorotate dehydrogenaseP0A7E1PYRD_ECOLIpyrDhttp://ecmdb.ca/proteins/P0A7E1.xml4,5-Dihydroorotic acid + Ubiquinone-8 > Orotic acid + Ubiquinol-84,5-Dihydroorotic acid + Menaquinone 8 > Menaquinol 8 + Orotic acid4,5-Dihydroorotic acid + Water <> Ureidosuccinic acid + Hydrogen ionR01993DIHYDROOROT-RXN4,5-Dihydroorotic acid + Fumaric acid <> Orotic acid + Succinic acidR018674,5-Dihydroorotic acid + Water <> Ureidosuccinic acidR019934,5-Dihydroorotic acid + a ubiquinone > Orotic acid + a ubiquinolRXN0-64914,5-Dihydroorotic acid + a menaquinone > Orotic acid + a menaquinolRXN0-65544,5-Dihydroorotic acid + Quinone <> Orotic acid + HydroquinoneR01868 N-carbamoyl-L-aspartate + Hydrogen ion > Water + 4,5-Dihydroorotic acid + 4,5-Dihydroorotic acidPW_R0035274,5-Dihydroorotic acid + Ubiquinone-1 + 4,5-Dihydroorotic acid > Ubiquinol-1 + Orotic acidPW_R0035284 4,5-Dihydroorotic acid + Fumaric acid <> Orotic acid + Succinic acid4 4,5-Dihydroorotic acid + Quinone <> Orotic acid + Hydroquinone4 4,5-Dihydroorotic acid + Water <> Ureidosuccinic acid + Hydrogen ion4 4,5-Dihydroorotic acid + Fumaric acid <> Orotic acid + Succinic acidGutnick minimal complete medium (4.7 g/L KH2PO4; 13.5 g/L K2HPO4; 1 g/L K2SO4; 0.1 g/L MgSO4-7H2O; 10 mM NH4Cl) with 4 g/L glucoseShake flask and filter culture11.9uM0.037 oCK12 NCM3722Mid-Log Phase476000Bennett, B. D., Kimball, E. H., Gao, M., Osterhout, R., Van Dien, S. J., Rabinowitz, J. D. (2009). "Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli." Nat Chem Biol 5:593-599.19561621Gutnick minimal complete medium (4.7 g/L KH2PO4; 13.5 g/L K2HPO4; 1 g/L K2SO4; 0.1 g/L MgSO4-7H2O; 10 mM NH4Cl) with 4 g/L glycerolShake flask and filter culture4.58uM0.037 oCK12 NCM3722Mid-Log Phase183200Bennett, B. D., Kimball, E. H., Gao, M., Osterhout, R., Van Dien, S. J., Rabinowitz, J. D. (2009). "Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli." Nat Chem Biol 5:593-599.19561621Gutnick minimal complete medium (4.7 g/L KH2PO4; 13.5 g/L K2HPO4; 1 g/L K2SO4; 0.1 g/L MgSO4-7H2O; 10 mM NH4Cl) with 4 g/L acetateShake flask and filter culture3.59uM0.037 oCK12 NCM3722Mid-Log Phase143600Bennett, B. D., Kimball, E. H., Gao, M., Osterhout, R., Van Dien, S. J., Rabinowitz, J. D. (2009). "Absolute metabolite concentrations and implied enzyme active site occupancy in Escherichia coli." Nat Chem Biol 5:593-599.19561621