2.02012-05-31 09:55:28 -06002015-09-13 12:56:05 -0600ECMDB00026M2MDB000006Ureidopropionic acidUreidopropionic acid is an intermediate in the metabolism of uracil. More specifically it is a breakdown product of dihydrouracil and is produced by the enzyme dihydropyrimidase. It is further decomposed to beta-alanine via the enzyme beta-ureidopropionase. Ureidopropionic acid is essentially a urea derivative of beta-alanine. High levels of Ureidopropionic acid are found in individuals with beta-ureidopropionase (UP) deficiency [PMID: 11675655]. Enzyme deficiencies in pyrimidine metabolism are associated with a risk for severe toxicity against the antineoplastic agent 5-fluorouracil.β-ureidopropionateβ-ureidopropionic acid3-(Carbamoylamino)propanoate3-(Carbamoylamino)propanoic acid3-Ureido-propionate3-Ureido-propionic acid3-Ureidopropanoate3-Ureidopropanoic acid3-Ureidopropionate3-Ureidopropionic acid<i>N</i>-carbamoyl-β-alanineb-Ureidopropionateb-Ureidopropionic acidBeta-UreidopropionateBeta-Ureidopropionic acidCarbamoyl-b-Ala-OHCarbamoyl-beta-Ala-OHCarbamoyl-β-ala-OHN-(Aminocarbonyl)-'b-AlanineN-(Aminocarbonyl)-b-alanineN-(Aminocarbonyl)-beta-AlanineN-(Aminocarbonyl)-β-alaninen-Carbamoyl-β-alanineN-Carbamoyl-b-alanineN-Carbamoyl-beta-alanineN-Carbamoyl-β-alanineN-Carbamyl-b-alanineN-Carbamyl-beta-alanineN-Carbamyl-β-alanineUreidopropionateUreidopropionic acidβ-Ureidopropionateβ-Ureidopropionic acidC4H8N2O3132.1179132.0534921323-(carbamoylamino)propanoic acidureidopropionic acid462-88-4NC(=O)NCCC(O)=OInChI=1S/C4H8N2O3/c5-4(9)6-2-1-3(7)8/h1-2H2,(H,7,8)(H3,5,6,9)JSJWCHRYRHKBBW-UHFFFAOYSA-NSolidCytoplasmPeriplasmlogp-0.98logs-0.40solubility5.27e+01 g/lmelting_point170 oClogp-1.4pka_strongest_acidic4.23pka_strongest_basic-2iupac3-(carbamoylamino)propanoic acidaverage_mass132.1179mono_mass132.053492132smilesNC(=O)NCCC(O)=OformulaC4H8N2O3inchiInChI=1S/C4H8N2O3/c5-4(9)6-2-1-3(7)8/h1-2H2,(H,7,8)(H3,5,6,9)inchikeyJSJWCHRYRHKBBW-UHFFFAOYSA-Npolar_surface_area92.42refractivity28.82polarizability12.07rotatable_bond_count3acceptor_count3donor_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.PW000942ec00240MetabolicPantothenate and CoA biosynthesisThe CoA biosynthesis requires compounds from two other pathways: aspartate metabolism and valine biosynthesis. It requires a Beta-Alanine and R-pantoate.
The compound (R)-pantoate is generated in two reactions, as shown by the interaction of alpha-ketoisovaleric acid, 5,10 methylene-THF and water through a 3-methyl-2-oxobutanoate hydroxymethyltransferase resulting in a tetrahydrofolic acid and a 2-dehydropantoate. This compound interacts with hydrogen through a NADPH driven acetohydroxy acid isomeroreductase resulting in the release of NADP and R-pantoate.
On the other hand L-aspartic acid interacts with a hydrogen ion and gets decarboxylated through an Aspartate 1- decarboxylase resulting in a carbon dioxide and a Beta-alanine.
Beta-alanine and R-pantoate interact with an ATP driven pantothenate synthetase resulting in pyrophosphate, AMP, hydrogen ion and pantothenic acid.
Pantothenic acid is phosphorylated through a ATP-driven pantothenate kinase resulting in a ADP, a hydrogen ion and D-4'-Phosphopantothenate. This compound interacts with a CTP and a L-cysteine resulting in a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a hydrogen ion, a pyrophosphate, a CMP and 4-phosphopantothenoylcysteine.
The latter compound interacts with a hydrogen ion through a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a carbon dioxide release and a 4-phosphopantetheine. This compound interacts with an ATP, hydrogen ion and an phosphopantetheine adenylyltransferase resulting in a release of pyrophosphate, and dephospho-CoA.
Dephospho-CoA reacts with an ATP driven dephospho-CoA kinase resulting in a ADP , a hydrogen ion and a Coenzyme A.
. The latter is converted into (R)-4'-phosphopantothenate is two steps, involving a β-alanine ligase and a kinase. In most organsims the ligase acts before the kinase (EC 6.3.2.1, pantoate—β-alanine ligase (AMP-forming) followed by EC 2.7.1.33, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 2.7.1.169, pantoate kinase acts before EC 6.3.2.36, 4-phosphopantoate—β-alanine ligase, as described in phosphopantothenate biosynthesis III.
The kinases are feedback inhibited by CoA itself, accounting for the primary regulatory mechanism of CoA biosynthesis. The addition of L-cysteine to (R)-4'-phosphopantothenate, resulting in the formation of R-4'-phosphopantothenoyl-L-cysteine (PPC), is followed by decarboxylation of PPC to 4'-phosphopantetheine. The ultimate reaction is catalyzed by EC 2.7.1.24, dephospho-CoA kinase, which converts 4'-phosphopantetheine to CoA. All enzymes of this pathway are essential for growth.
The reactions in the biosynthetic route towards CoA are identical in most organisms, although there are differences in the functionality of the involved enzymes. In plants every step is catalyzed by single monofunctional enzymes, whereas in bacteria and mammals bifunctional enzymes are often employed [Rubio06].PW000828ec00770MetabolicDrug metabolism - other enzymesec00983beta-Alanine metabolismThe Beta-Alanine Metabolism starts with a product of Aspartate metabolism. Aspartate is decarboxylated by aspartate 1-decarboxylase, releasing carbon dioxide and Beta-alanine. Beta alanine is then metabolized through a pantothenate synthetase resulting in Pantothenic acid undergoes phosphorylation through a ATP driven pantothenate kinase, resulting in D-4-phosphopantothenate.
Pantothenate (vitamin B5) is the universal precursor for the synthesis of the 4'-phosphopantetheine moiety of coenzyme A and acyl carrier protein. Only plants and microorganismscan synthesize pantothenate de novo - animals require a dietary supplement. The enzymes of this pathway are therefore considered to be antimicrobial drug targets.PW000896ec00410MetabolicMetabolic pathwayseco01100Specdb::CMs1106Specdb::CMs1271Specdb::CMs1302Specdb::CMs1334Specdb::CMs10368Specdb::CMs30959Specdb::CMs30960Specdb::CMs30961Specdb::CMs30962Specdb::CMs32121Specdb::CMs32122Specdb::CMs37252Specdb::CMs137989Specdb::CMs145723Specdb::CMs1047064Specdb::CMs1047066Specdb::CMs1047068Specdb::CMs1047069Specdb::CMs1047071Specdb::NmrOneD1038Specdb::NmrOneD141930Specdb::NmrOneD141931Specdb::NmrOneD141932Specdb::NmrOneD141933Specdb::NmrOneD141934Specdb::NmrOneD141935Specdb::NmrOneD141936Specdb::NmrOneD141937Specdb::NmrOneD141938Specdb::NmrOneD141939Specdb::NmrOneD141940Specdb::NmrOneD141941Specdb::NmrOneD141942Specdb::NmrOneD141943Specdb::NmrOneD141944Specdb::NmrOneD141945Specdb::NmrOneD141946Specdb::NmrOneD141947Specdb::NmrOneD141948Specdb::NmrOneD141949Specdb::MsMs45Specdb::MsMs46Specdb::MsMs47Specdb::MsMs288871Specdb::MsMs288872Specdb::MsMs288873Specdb::MsMs328132Specdb::MsMs328133Specdb::MsMs328134Specdb::MsMs451947Specdb::MsMs1472316Specdb::MsMs1472317Specdb::MsMs1472318Specdb::MsMs1472319Specdb::MsMs1472320Specdb::MsMs1472321Specdb::MsMs1472322Specdb::MsMs1472323Specdb::MsMs1472324Specdb::MsMs1472325Specdb::MsMs1472326Specdb::MsMs1472327Specdb::MsMs1472328Specdb::MsMs1472329Specdb::MsMs1472330Specdb::NmrTwoD931HMDB00026111109C02642182613-UREIDO-PROPIONATEURPKanehisa, 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-D114.22080510Simaga S, Kos E. 1978. "Uracil catabolism by Escherichia coli K12S." Z Naturforsch C 33(11-12):1006-8154218Patel BN, West TP. 1987. "Degradation of the pyrimidine bases uracil and thymine by Escherichia coli B." Microbios 49(199):107-133553866Moolenaar, S. H., Gohlich-Ratmann, G., Engelke, U. F., Spraul, M., Humpfer, E., Dvortsak, P., Voit, T., Hoffmann, G. F., Brautigam, C., van Kuilenburg, A. B., van Gennip, A., Vreken, P., Wevers, R. A. (2001). "beta-Ureidopropionase deficiency: a novel inborn error of metabolism discovered using NMR spectroscopy on urine." Magn Reson Med 46:1014-1017.11675655Sparidans RW, Bosch TM, Jorger M, Schellens JH, Beijnen JH: Liquid chromatography-tandem mass spectrometric assay for the analysis of uracil, 5,6-dihydrouracil and beta-ureidopropionic acid in urine for the measurement of the activities of the pyrimidine catabolic enzymes. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jul 24;839(1-2):45-53. Epub 2006 Feb 28.16513432Ito S, Kawamura T, Inada M, Inoue Y, Hirao Y, Koga T, Kunizaki J, Shimizu T, Sato H: Physiologically based pharmacokinetic modelling of the three-step metabolism of pyrimidine using C-uracil as an in vivo probe. Br J Clin Pharmacol. 2005 Dec;60(6):584-93.16305582Hofmann U, Schwab M, Seefried S, Marx C, Zanger UM, Eichelbaum M, Murdter TE: Sensitive method for the quantification of urinary pyrimidine metabolites in healthy adults by gas chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Jul 5;791(1-2):371-80.12798197Malet-Martino MC, Armand JP, Lopez A, Bernadou J, Beteille JP, Bon M, Martino R: Evidence for the importance of 5'-deoxy-5-fluorouridine catabolism in humans from 19F nuclear magnetic resonance spectrometry. Cancer Res. 1986 Apr;46(4 Pt 2):2105-12.2936452Desmoulin F, Gilard V, Malet-Martino M, Martino R: Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos. 2002 Nov;30(11):1221-9.12386128w-Ureido carboxylic acids. (1962), 3 pp. GB 913713 19621228 CAN 58:72975 AN 1963:72975 http://hmdb.ca/system/metabolites/msds/000/000/018/original/HMDB00026.pdf?1358463400D-phenylhydantoinaseQ46806PHYDA_ECOLIhyuAhttp://ecmdb.ca/proteins/Q46806.xmlUncharacterized oxidoreductase yeiTP76440YEIT_ECOLIyeiThttp://ecmdb.ca/proteins/P76440.xmlDihydrouracil + Water <> Ureidopropionic acidR02269