Human Metabolome Database: Showing metabocard for Dihydrouracil (HMDB0000076)

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Identification Taxonomy Ontology Physical properties Spectra Biological properties Concentrations Links References enzymes (2) Show 2 proteins XML

enzymes (2) Show 2 proteins

Record Information

Version

4.0

Status

Detected and Quantified

Creation Date

2005-11-16 15:48:42 UTC

Update Date

2020-02-27 20:29:29 UTC

HMDB ID

HMDB0000076

Secondary Accession Numbers

HMDB00076

Metabolite Identification

Common Name

Dihydrouracil

Description

Dihydrouracil is an intermediate breakdown product of uracil. Dihydropyrimidine dehydrogenase (DHP) catalyzes the reduction of uracil into 5,6-dihydrouracil then dihydropyrimidinase hydrolyzes 5,6-dihydrouracil into N-carbamyl-beta-alanine. Finally, beta-ureidopropionase catalyzes the conversion of N-carbamyl-beta-alanine into beta-alanine. When present at abnormally high levels, dihydrouracil can be toxic although the mechanism of toxicity is not clear. In particular, patients with dihydropyrimidinase deficiency exhibit highly increased concentrations of 5,6-dihydrouracil and 5,6-dihydrothymine, and moderately increased concentrations of uracil and thymine can be detected in urine. Dihydropyrimidinase deficiency is a disorder that can cause neurological and gastrointestinal problems in some affected individuals (OMIM: 222748 ). The neurological abnormalities that occur most often in people with dihydropyrimidinase deficiency are intellectual disability, seizures, weak muscle tone (hypotonia), an abnormally small head size (microcephaly), and autistic behaviours that affect communication and social interaction. Gastrointestinal problems that occur in dihydropyrimidinase deficiency include backflow of acidic stomach contents into the esophagus (gastroesophageal reflux) and recurrent episodes of vomiting. The direct measurement of the activity of DHP in patients has been hampered by the fact that the enzyme is expressed almost exclusively in liver tissue.

Structure

MOL SDF PDB SMILES InChI

Synonyms

Value	Source
2,4-Dioxotetrahydropyrimidine	ChEBI
5,6-Dihydro-2,4-dihydroxypyrimidine	ChEBI
Dihydro-2,4(1H,3H)-pyrimidinedione	ChEBI
DIHYDROPYRIMIDINE-2,4(1H,3H)-dione	ChEBI
Dihydrouracile	ChEBI
Hydrouracil	ChEBI
5,6-Dihydro-2,4(1H,3H)-pyrimidinedione	HMDB
5,6-Dihydrouracil	HMDB
Dihydro-pyrimidine-2,4-dione	HMDB

Chemical Formula

C₄H₆N₂O₂

Average Molecular Weight

114.1026

Monoisotopic Molecular Weight

114.042927446

IUPAC Name

1,3-diazinane-2,4-dione

Traditional Name

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

Description

belongs to the class of organic compounds known as pyrimidones. Pyrimidones are compounds that contain a pyrimidine ring, which bears a ketone. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.

Kingdom

Organic compounds

Super Class

Organoheterocyclic compounds

Class

Diazines

Sub Class

Pyrimidines and pyrimidine derivatives

Direct Parent

Pyrimidones

Alternative Parents

Substituents

N-acyl urea
Pyrimidone
Ureide
1,3-diazinane
Dicarboximide
Urea
Carbonic acid derivative
Azacycle
Carboxylic acid derivative
Organic oxide
Organopnictogen compound
Organooxygen compound
Organonitrogen compound
Organic oxygen compound
Organic nitrogen compound
Carbonyl group
Hydrocarbon derivative
Aliphatic heteromonocyclic compound

Molecular Framework

Aliphatic heteromonocyclic compounds

External Descriptors

pyrimidone (CHEBI:15901 )
a base derivative (DI-H-URACIL )
a pyrimidine-related compound (DI-H-URACIL )

Ontology

Hypertension

Metabolism and nutrition disorders:

Dihydropyrimidine dehydrogenase deficiency

Disposition

Route of exposure:

Enteral:

Ingestion

Source:

Biological:

Animal

Plant:

Biological location:

Organ and components:

Cell and elements:

Cell:

Fibroblast

Biofluid and excreta:

Subcellular:

Process

Naturally occurring process:

Metabolite

Industrial application:

Pharmaceutical industry:

Pharmaceutical

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	-1.3	ALOGPS
logP	-1.2	ChemAxon
logS	-0.64	ALOGPS
pKa (Strongest Acidic)	11.73	ChemAxon
pKa (Strongest Basic)	-7.6	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	58.2 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	25.75 m³·mol⁻¹	ChemAxon
Polarizability	10.13 Å³	ChemAxon
Number of Rings	1	ChemAxon
Bioavailability	Yes	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	View
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (2 TMS)	splash10-00di-9700000000-4adeeb2f4f5a1111afb7	Spectrum
GC-MS	GC-MS Spectrum - GC-MS (1 TMS)	splash10-00di-5900000000-8af1b81502646fa5b417	Spectrum
GC-MS	GC-MS Spectrum - GC-MS (2 TMS)	splash10-0fdo-9750000000-d2aaeeba1cf962175f84	Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-00di-9700000000-4adeeb2f4f5a1111afb7	Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-00di-5900000000-8af1b81502646fa5b417	Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-0fdo-9750000000-d2aaeeba1cf962175f84	Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0f6w-2940000000-3430a0e2d1819021af1d	Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-00di-3900000000-79f2d90a419b7469cb61	Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-004l-9100000000-55536f0571922b6c69fe	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-03k9-9800000000-da772cea603c785c1df4	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-0a4i-9100000000-94a5f543e8c6be7b3204	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-0btc-9200000000-e9bf2ae82714a2a3a737	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF (UPLC Q-Tof Premier, Waters) , Positive	splash10-014i-5900000000-0fe83e63f6e5d1347894	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , negative	splash10-03xr-6900000000-08aca1bc7f27b0e7cb08	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QTOF , positive	splash10-014i-5900000000-53ea361c86b4f9fa284b	Spectrum
LC-MS/MS	LC-MS/MS Spectrum - , positive	splash10-00di-9300000000-a8599c09cd21e2f84329	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-014i-2900000000-ad7f91d5265e53403dd6	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0603-9200000000-4b30a83fb454e5bbffb8	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-ce54e3c860a95b0af401	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-9800000000-d705e188f6700a76ef72	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0006-9000000000-a26409d69a4259731004	Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9000000000-f00c4df547660023bee4	Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-03fu-9400000000-5b9edda3479e7d0a0d28	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	1H NMR Spectrum	Not Available	Spectrum
1D NMR	13C NMR Spectrum	Not Available	Spectrum
2D NMR	[1H,13C] 2D NMR Spectrum	Not Available	Spectrum

Biological Properties

Cellular Locations

Cytoplasm
Nucleus

Biospecimen Locations

Blood
Cerebrospinal Fluid (CSF)
Feces
Saliva
Urine

Tissue Locations

Fibroblasts
Kidney
Liver
Prostate

Pathways

Name	SMPDB/Pathwhiz	KEGG
Pyrimidine Metabolism
Beta-Alanine Metabolism
GABA-Transaminase Deficiency		Not Available
Ureidopropionase Deficiency		Not Available
Carnosinuria, carnosinemia		Not Available

Normal Concentrations

Biospecimen	Status	Value	Age	Sex	Condition	Reference	Details
Blood	Detected and Quantified	0.31 (0.02-1.63) uM	Adult (>18 years old)	Female	Normal	11936689	details
Blood	Detected and Quantified	0.31 (0.02-1.63) uM	Adult (>18 years old)	Both	Normal	11936689	details
Blood	Detected and Quantified	0.32 ( 0.10-0.74) uM	Adult (>18 years old)	Male	Normal	11936689	details
Cerebrospinal Fluid (CSF)	Detected and Quantified	2.1 +/- 1.0 uM	Adult (>18 years old)	Not Specified	Normal	15385443	details
Feces	Detected but not Quantified		Adult (>18 years old)	Both	Normal	25037050	details
Saliva	Detected and Quantified	700 +/- 199 uM	Adult (>18 years old)	Male	Normal	Sugimoto et al. (...	details
Saliva	Detected and Quantified	2168.16 +/- 127.94 uM	Adult (>18 years old)	Both	Normal	Zerihun T. Dame, ...	details
Saliva	Detected and Quantified	2000 +/- 223 uM	Adult (>18 years old)	Female	Normal	Sugimoto et al. (...	details
Saliva	Detected and Quantified	2000 +/- 223 uM	Adult (>18 years old)	Not Specified	Normal	Sugimoto et al. (...	details
Saliva	Detected and Quantified	2210 +/- 353 uM	Adult (>18 years old)	Not Specified	Normal	Sugimoto et al. (...	details
Saliva	Detected and Quantified	2240 +/- 380 uM	Adult (>18 years old)	Female	Normal	Sugimoto et al. (...	details
Saliva	Detected and Quantified	2350 +/- 654 uM	Adult (>18 years old)	Female	Normal	Sugimoto et al. (...	details
Urine	Detected and Quantified	0.79 umol/mmol creatinine	Adult (>18 years old)	Both	Normal	12798197	details
Urine	Detected and Quantified	3.8 (2.1-8.3) umol/mmol creatinine	Adult (>18 years old)	Both	Normal	24023812	details
Urine	Detected and Quantified	2.4 +/- 4.7 umol/mmol creatinine	Adult (>18 years old)	Male	Normal	9816152	details
Urine	Detected and Quantified	3.0 +/- 2.7 umol/mmol creatinine	Adult (>18 years old)	Female	Normal	9816152	details
Urine	Detected and Quantified	2.5-20 umol/mmol creatinine	Children (1 - 18 years old)	Both	Normal	BC Children's Hos...	details
Urine	Detected and Quantified	12.2 +/- 6.2 umol/mmol creatinine	Infant (0-1 year old)	Both	Normal	8581129	details
Urine	Detected but not Quantified		Adult (>18 years old)	Both	Normal	21389975	details
Urine	Detected and Quantified	<3.4 umol/mmol creatinine	Infant (0-1 year old)	Both	Normal	30817767	details

Abnormal Concentrations

Biospecimen	Status	Value	Age	Sex	Condition	Reference	Details
Cerebrospinal Fluid (CSF)	Detected and Quantified	81.5 (46.0-117.0) uM	Adult (>18 years old)	Both	Dihydropyrimidine dehydrogenase (DPD) deficiency	14705962	details
Feces	Detected but not Quantified		Adult (>18 years old)	Both	Colorectal cancer	27015276	details
Feces	Detected but not Quantified		Adult (>18 years old)	Both	Colorectal cancer	25037050	details
Urine	Detected and Quantified	2.4 +/- 1.67 umol/mmol creatinine	Adult (>18 years old)	Both	Hypertension	9816152	details
Urine	Detected and Quantified	627.0 umol/mmol creatinine	Infant (0-1 year old)	Both	Dihydropyrimidine dehydrogenase (DPD) deficiency	8581129	details
Urine	Detected and Quantified	2.4 +/- 2.00 umol/mmol creatinine	Adult (>18 years old)	Both	Cerebral infarction	9816152	details
Urine	Detected and Quantified	2.8 +/- 1.9 umol/mmol creatinine	Adult (>18 years old)	Both	Malignancy	9816152	details
Urine	Detected and Quantified	2.7 +/- 1.9 umol/mmol creatinine	Adult (>18 years old)	Both	Liver dysfunction	9816152	details
Urine	Detected and Quantified	2.5 +/- 2.00 umol/mmol creatinine	Adult (>18 years old)	Both	Nephropathy	9816152	details

Associated Disorders and Diseases

Disease References

Colorectal cancer
Sinha R, Ahn J, Sampson JN, Shi J, Yu G, Xiong X, Hayes RB, Goedert JJ: Fecal Microbiota, Fecal Metabolome, and Colorectal Cancer Interrelations. PLoS One. 2016 Mar 25;11(3):e0152126. doi: 10.1371/journal.pone.0152126. eCollection 2016. [PubMed:27015276 ] Goedert JJ, Sampson JN, Moore SC, Xiao Q, Xiong X, Hayes RB, Ahn J, Shi J, Sinha R: Fecal metabolomics: assay performance and association with colorectal cancer. Carcinogenesis. 2014 Sep;35(9):2089-96. doi: 10.1093/carcin/bgu131. Epub 2014 Jul 18. [PubMed:25037050 ]
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 ]
Cerebral infarction
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 ]
Liver disease
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

114500 (Colorectal cancer)
274270 (Dihydropyrimidine dehydrogenase deficiency)
145500 (Hypertension)

External Links

DrugBank ID

DB01849

Phenol Explorer Compound ID

Not Available

FoodDB ID

FDB030556

KNApSAcK ID

Not Available

Chemspider ID

KEGG Compound ID

BioCyc ID

BiGG ID

Wikipedia Link

METLIN ID

PubChem Compound

PDB ID

Not Available

ChEBI ID

15901

Food Biomarker Ontology

Not Available

VMH ID

56DURA

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. doi: 10.1038/nature07762. [PubMed:19212411 ]

Enzymes

Enzyme Details

1. Dihydropyrimidinase

General function:: Involved in hydrolase activity
Specific function:: Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Can catalyze the ring opening of 5,6-dihydrouracil to N-carbamyl-alanine and of 5,6-dihydrothymine to N-carbamyl-amino isobutyrate.
Gene Name:: DPYS
Uniprot ID:: Q14117
Molecular weight:: 56629.36

Reactions

Dihydrouracil + Water → Ureidopropionic acid	details

Enzyme Details

2. Dihydropyrimidine dehydrogenase [NADP(+)]

General function:: Involved in electron carrier activity
Specific function:: Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
Gene Name:: DPYD
Uniprot ID:: Q12882
Molecular weight:: 111400.32

Reactions

Dihydrouracil + NADP → Uracil + NADPH	details
Dihydrouracil + NADP → Uracil + NADPH + Hydrogen Ion	details

Showing metabocard for Dihydrouracil (HMDB0000076)

Structure for HMDB0000076 (Dihydrouracil)

Enzymes

Reactions

Reactions