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Human Metabolome Database Version 3.5

Showing metabocard for Dihydrouracil (HMDB00076)

• Identification
• Taxonomy
• Ontology
• Physical properties
• Spectra
• Biological properties
• Concentrations
• Links
• References

enzymes (2)

• Blood
• Urine

Record Information
Version	3.5
Creation Date	2005-11-16 08:48:42 -0700
Update Date	2013-02-08 17:07:51 -0700
HMDB ID	HMDB00076
Secondary Accession Numbers	None
Metabolite Identification
Common Name	Dihydrouracil
Description	Dihydrouracil is an intermediate breakdown product of uracil. Dihydropyrimidine dehydrogenase catalyzes the reduction of uracil to 5, 6-dihydrouracil then dihydropyrimidinase hydrolyzes 5, 6-dihydrouracil to N-carbamyl-b-alanine. Finally, beta-ureidopropionase catalyzes the conversion of N-carbamyl-b-alanine to beta-alanine. Patients with dihydropyrimidinase deficiency (DPYS; also called 5, 6-dihydropyrimidine amidohydrolase, or DHP; EC 3.5.2.2) exhibit highly increased concentrations of 5, 6-dihydrouracil in urine. The direct measurement of the activity of DHP in patients had been hampered by the fact that the enzyme is expressed almost exclusively in liver tissue. Various neurological abnormalities have been described in this group of patients. (OMIM 222748 ).
Structure	Download: MOL | SDF | SMILES | InChI Display: 2D Structure | 3D Structure
Synonyms	5,6-Dihydro-2,4(1H,3H)-pyrimidinedione 5,6-Dihydro-2,4-dihydroxypyrimidine 5,6-Dihydrouracil Dihydro-2,4(1H,3H)-pyrimidinedione Dihydro-pyrimidine-2,4-dione Dihydrouracil Dihydrouracile Hydrouracil
Chemical Formula	C4H6N2O2
Average Molecular Weight	114.1026
Monoisotopic Molecular Weight	114.042927446
IUPAC Name	1,3-diazinane-2,4-dione
Traditional IUPAC Name	3,4-dihydrouracil
CAS Registry Number	504-07-4
SMILES	O=C1CCNC(=O)N1
InChI Identifier	InChI=1S/C4H6N2O2/c7-3-1-2-5-4(8)6-3/h1-2H2,(H2,5,6,7,8)
InChI Key	OIVLITBTBDPEFK-UHFFFAOYSA-N
Chemical Taxonomy
Kingdom	Organic Compounds
Super Class	Aliphatic Heteromonocyclic Compounds
Class	Diazines
Sub Class	Pyrimidines and Pyrimidine Derivatives
Other Descriptors	Aliphatic Heteromonocyclic Compounds Pyrimidines and Pyrimidine Derivatives Ureides a base derivative(Cyc) a pyrimidine-related compound(Cyc) pyrimidone(ChEBI)
Substituents	Carboxamide Group Carboxylic Acid Imide, N Unsubstituted Urea
Direct Parent	Pyrimidones
Ontology
Status	Detected and Quantified
Origin	Endogenous
Biofunction	Component of Pantothenate and CoA biosynthesis Component of Pyrimidine metabolism Component of beta-Alanine metabolism
Application	Not Available
Cellular locations	Cytoplasm Nucleus
Physical Properties
State	Solid
Experimental Properties	Property Value Reference Melting Point 279 - 281 °C Not Available Boiling Point Not Available Not Available Water Solubility Not Available Not Available LogP Not Available Not Available
Predicted Properties	Property Value Source Water Solubility 25.9 g/L ALOGPS LogP -1.28 ALOGPS LogP -1.2 ChemAxon LogS -0.64 ALOGPS pKa (strongest acidic) 11.73 ChemAxon pKa (strongest basic) -7.6 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 58.2 A2 ChemAxon Rotatable Bond Count 0 ChemAxon Refractivity 25.75 ChemAxon Polarizability 10.13 ChemAxon Formal Charge 0 ChemAxon Physiological Charge 0 ChemAxon
Spectra
	1H NMR Spectrum MS/MS Spectrum Quattro_QQQ 10 MS/MS Spectrum Quattro_QQQ 25 MS/MS Spectrum Quattro_QQQ 40 MS/MS Spectrum GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) MS/MS Spectrum LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) MS/MS Spectrum GC-MS MS/MS Spectrum GC-MS [1H,13C] 2D NMR Spectrum
Biological Properties
Cellular Locations	Cytoplasm Nucleus
Biofluid Locations	Blood Cerebrospinal Fluid (CSF) Urine
Tissue Location	Fibroblasts Kidney Liver Prostate
Pathways	Name SMPDB Link KEGG Link Pyrimidine Metabolism SMP00046 map00240 Beta-Alanine Metabolism SMP00007 map00410
Normal Concentrations
	Biofluid Status Value Age Sex Condition Comments Blood Detected and Quantified 0.31 (0.02-1.63) uM Adult (>18 years old) Female Normal Not Available Blood Detected and Quantified 0.31 (0.02-1.63) uM Adult (>18 years old) Both Normal Not Available Blood Detected and Quantified 0.32 ( 0.10-0.74) uM Adult (>18 years old) Male Normal Not Available Cerebrospinal Fluid (CSF) Detected and Quantified 2.1 +/- 1.0 uM Adult (>18 years old) Not Specified Normal Not Available Urine Detected and Quantified 0.79 umol/mmol creatinine Adult (>18 years old) Both Normal Not Available Urine Detected and Quantified 3.8 (2.1-8.3) umol/mmol creatinine Adult (>18 years old) Both Normal by NMR Urine Detected and Quantified 2.4 +/- 4.7 umol/mmol creatinine Adult (>18 years old) Male Normal Not Available Urine Detected and Quantified 3.0 +/- 2.7 umol/mmol creatinine Adult (>18 years old) Female Normal Not Available Urine Detected and Quantified 12.2 +/- 6.2 umol/mmol creatinine Infant (0-1 year old) Both Normal Not Available Urine Detected and not Quantified Not Applicable Adult (>18 years old) Both Normal Not Available
Abnormal Concentrations
	Biofluid Status Value Age Sex Condition Comments Cerebrospinal Fluid (CSF) Detected and Quantified 81.5 (46.0-117.0) uM Adult (>18 years old) Both Dihydropyrimidine dehydrogenase (DPD) deficiency Not Available Urine Detected and Quantified 2.4 +/- 1.67 umol/mmol creatinine Adult (>18 years old) Both Hypertension Not Available Urine Detected and Quantified 627.0 umol/mmol creatinine Infant (0-1 year old) Both Dihydropyrimidine dehydrogenase (DPD) deficiency Not Available Urine Detected and Quantified 2.4 +/- 2.00 umol/mmol creatinine Adult (>18 years old) Both Cerebral infarction Not Available Urine Detected and Quantified 2.8 +/- 1.9 umol/mmol creatinine Adult (>18 years old) Both Malignancy Not Available Urine Detected and Quantified 2.7 +/- 1.9 umol/mmol creatinine Adult (>18 years old) Both Liver dysfunction Not Available Urine Detected and Quantified 2.5 +/- 2.00 umol/mmol creatinine Adult (>18 years old) Both Nephrophathy Not Available
Associated Disorders and Diseases
Disease References	Dihydropyrimidine dehydrogenase deficiency Sumi S, Kidouchi K, Ohba S, Wada Y: Automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1995 Oct 20;672(2):233-9. Pubmed: 8581129 Van Kuilenburg AB, Stroomer AE, Van Lenthe H, Abeling NG, Van Gennip AH: New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid? Biochem J. 2004 Apr 1;379(Pt 1):119-24. Pubmed: 14705962 Hypertension Hayashi K, Kidouchi K, Sumi S, Mizokami M, Orito E, Kumada K, Ueda R, Wada Y: Possible prediction of adverse reactions to pyrimidine chemotherapy from urinary pyrimidine levels and a case of asymptomatic adult dihydropyrimidinuria. Clin Cancer Res. 1996 Dec;2(12):1937-41. Pubmed: 9816152
Associated OMIM IDs	274270 (Dihydropyrimidine dehydrogenase deficiency) 145500 (Hypertension)
External Links
DrugBank ID	Not Available
Phenol Explorer Compound ID	Not Available
Phenol Explorer Metabolite ID	Not Available
FoodDB ID	FDB021890
KNApSAcK ID	Not Available
Chemspider ID	629
KEGG Compound ID	C00429
BioCyc ID	DI-H-URACIL
BiGG ID	34956
Wikipedia Link	Not Available
NuGOwiki Link	HMDB00076
Metagene Link	HMDB00076
METLIN ID	285
PubChem Compound	649
PDB ID	DUC
ChEBI ID	15901
References
Synthesis Reference	Bhat, K. S.; Rao, A. S. Synthesis of uracil, 6-methyluracil and some dihydrouracils. Organic Preparations and Procedures International (1983), 15(5), 303-13.
Material Safety Data Sheet (MSDS)	Download (PDF)
General References	Van Kuilenburg AB, Stroomer AE, Van Lenthe H, Abeling NG, Van Gennip AH: New insights in dihydropyrimidine dehydrogenase deficiency: a pivotal role for beta-aminoisobutyric acid? Biochem J. 2004 Apr 1;379(Pt 1):119-24. Pubmed: 14705962 Grem JL: Intratumoral molecular or genetic markers as predictors of clinical outcome with chemotherapy in colorectal cancer. Semin Oncol. 2005 Feb;32(1):120-7. Pubmed: 15726514 Assmann B, Hoffmann GF, Wagner L, Brautigam C, Seyberth HW, Duran M, Van Kuilenburg AB, Wevers R, Van Gennip AH: Dihydropyrimidinase deficiency and congenital microvillous atrophy: coincidence or genetic relation? J Inherit Metab Dis. 1997 Sep;20(5):681-8. Pubmed: 9323563 Megyeri A, Bacso Z, Shields A, Eliason JF: Development of a stereological method to measure levels of fluoropyrimidine metabolizing enzymes in tumor sections using laser scanning cytometry. Cytometry A. 2005 Apr;64(2):62-71. Pubmed: 15729713 Nakamura A, Kikuchi K, Ohishi T, Masuike T: [Assay method for uracil, dihydrouracil, 5-fluorouracil and 5-fluoro-5, 6-dihydrouracil by high-performance liquid chromatography] Gan To Kagaku Ryoho. 2004 Mar;31(3):381-6. Pubmed: 15045945 van Lenthe H, van Kuilenburg AB, Ito T, Bootsma AH, van Cruchten A, Wada Y, van Gennip AH: Defects in pyrimidine degradation identified by HPLC-electrospray tandem mass spectrometry of urine specimens or urine-soaked filter paper strips. Clin Chem. 2000 Dec;46(12):1916-22. Pubmed: 11106323 Sumi S, Kidouchi K, Ohba S, Wada Y: Automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography. J Chromatogr B Biomed Appl. 1995 Oct 20;672(2):233-9. Pubmed: 8581129 Hofmann 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. Pubmed: 12798197 Shen GP, Galick H, Inoue M, Wallace SS: Decline of nuclear and mitochondrial oxidative base excision repair activity in late passage human diploid fibroblasts. DNA Repair (Amst). 2003 Jun 11;2(6):673-93. Pubmed: 12767347 Tan BR, McLeod HL: Pharmacogenetic influences on treatment response and toxicity in colorectal cancer. Semin Oncol. 2005 Feb;32(1):113-9. Pubmed: 15726513 Garcia AA, Blessing JA, Lenz HJ, Darcy KM, Mannel RS, Miller DS, Husseinzadeh N: Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study. Gynecol Oncol. 2005 Mar;96(3):810-7. Pubmed: 15721430 Schneider S, Uchida K, Brabender J, Baldus SE, Yochim J, Danenberg KD, Salonga D, Chen P, Tsao-Wei D, Groshen S, Hoelscher AH, Schneider PM, Danenberg PV: Downregulation of TS, DPD, ERCC1, GST-Pi, EGFR, and HER2 gene expression after neoadjuvant three-modality treatment in patients with esophageal cancer. J Am Coll Surg. 2005 Mar;200(3):336-44. Pubmed: 15737843 Jiang H, Jiang J, Hu P, Hu Y: Measurement of endogenous uracil and dihydrouracil in plasma and urine of normal subjects by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Mar 25;769(1):169-76. Pubmed: 11936689 Sreekumar 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. Pubmed: 19212411

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Enzymes
Name: Dihydropyrimidinase Reactions: 5,6-dihydrouracil + H2O = 3-ureidopropanoate [RN:R02269] Gene Name: DPYS Uniprot ID: Q14117 Protein Sequence: FASTA Gene Sequence: FASTA
Name: Dihydropyrimidine dehydrogenase [NADP+] Reactions: 5,6-dihydrouracil + NADP+ = uracil + NADPH + H+ [RN:R00978] Gene Name: DPYD Uniprot ID: Q12882 Protein Sequence: FASTA Gene Sequence: FASTA

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