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Information on EC 1.3.1.2 - dihydropyrimidine dehydrogenase (NADP+) and Organism(s) Homo sapiens and UniProt Accession Q12882
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1.3.1.2 dihydropyrimidine dehydrogenase (NADP+)IUBMB Comments
Also acts on dihydrothymine.
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Word Map
- 1.3.1.2
- 5-fluorouracil
- thymidine
- phosphorylase
- uridine
- medicine
-
phosphoribosyltransferase
- orotate
-
2.4.2.4
- thymidylate
-
fluoropyrimidine
-
fdurd
-
2.7.1.21
- beta-ureidopropionase
- urdpase
- dihydropyrimidinase
- beta-alanine
- drug development
- analysis
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
dihydrouracil dehydrogenase, dhpdhase, dhpdh, dhu dehydrogenase, dihydrouracil dehydrogenase (nadp+), 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4,5-dihydrothymine: oxidoreductase
-
-
-
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dehydrogenase, dihydrouracil (nicotinamide adenine dinucleotide phosphate)
-
-
-
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DHPDH
-
-
-
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DHPDHase
-
-
-
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DHU dehydrogenase
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-
-
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dihydrothymine dehydrogenase
-
-
-
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Dihydrouracil dehydrogenase
-
-
-
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dihydrouracil dehydrogenase (NADP)
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-
-
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dihydrouracil dehydrogenase (NADP+)
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-
-
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DPD
hydropyrimidine dehydrogenase
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-
-
-
DPD
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
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oxidation
-
-
-
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reduction
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-
-
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PATHWAY SOURCE
PATHWAYS
KEGG
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-, -
SYSTEMATIC NAME
IUBMB Comments
5,6-dihydrouracil:NADP+ 5-oxidoreductase
Also acts on dihydrothymine.
CAS REGISTRY NUMBER
COMMENTARY
9029-01-0
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NADP+
uracil + NADPH
-
first and rate-limiting enzyme in the three-step pathway for the degradation of uracil
-
-
?
dihydrofluorouracil + NADP+
5-fluorouracil + NADPH + H+
-
-
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
dihydrofluorouracil + NADP+
5-fluorouracil + NADPH + H+
-
development of a detection method using 2'-fluoro-beta-alanine derivatization with o-phthalaldehyde at room temperature and mass spectrometric analysis by the liquid chromatography-mass spectrometry-electrospray ionization system, method evaluation and optimization, overview
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme of thymidine and uridine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
-
rate limiting enzyme in pyrimidine degradation
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NADP+
uracil + NADPH
-
first and rate-limiting enzyme in the three-step pathway for the degradation of uracil
-
-
?
dihydrofluorouracil + NADP+
5-fluorouracil + NADPH + H+
-
-
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
-
rate-limiting enzyme of thymidine and uridine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
-
rate limiting enzyme in pyrimidine degradation
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(E)-5-[2-bromovinyl-]uracil
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50% inhibition at 0.01 mM, no inhibition by free base
additional information
-
no inhibition or inactivation with 5-nitro-, 5-fluoro-,5-carbamido-, 5-formyl-, 5-acetamido-, 5-hydroxymethyl- or 5-chlorouracil
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
for 5-ethynyl-, 5-diazo-, 5-cyano-, 5-bromvinyl-, 5-propynyl-, 5-bromo- and 5-trifluoromethyluracil
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
-
efficacy of the chemotherapeutic drug 5'-fluorouracil is reduced by catabolism to 2'-fluoro-beta-alanine, a three-step reaction in which dihydropyrimidine dehydrogenase catalyzes the ratelimiting step
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DPYD_HUMAN
1025
0
111401
Swiss-Prot
other Location (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A551T
natural mutation identified in a patient with complete loss of enzymic activity
E244V
natural mutation identified in a patient with complete loss of enzymic activity
G366A
-
natural mutation, marked decrease in enzyme affinity to NADPH, reduction of Vmax for 5-fluorouracil degrading activity
R235Q
-
the mutation is expected to weaken the binding of the FAD ring system and to change the electronic environment and hence, the redox potential of the cofactor
T768K
-
natural mutation identified in healthy Japanese volunteer, rapid loss of enzyme activity
additional information
additional information
natural mutant IVS11+1G to T leads to a cryptic splice site within exon 11 that results in loss of amino acid residues 400-446 in enzyme primary sequence
additional information
-
PCR and sequence analysis of point mutations occurring in patients, modified cofactor binding and electron transport with exchanges: S201R, P86L, S492L, D949V, H978R, reduced activity in mutants
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
identification of mutations E244V and A551T and splice site mutation IVS11+1G to T in patients with complete loss of enzymic activity
analysis
-
study on DPD enzyme expression using RT-PCR, immunohistochemistry, enzymatic activity and ELISA. Highest correlation is observed between protein expression measured by ELISA and enzyme activity, correlation of gene expression and ELISA is also significant
medicine
medicine
-
target for inhibitor design to enhance the cytotoxical effect of 5-fluorouracil in tumor cells by inhibiting the DPD activity with 5-fluorouracil as substrate
medicine
-
rate limiting enzyme for detoxification of exogenous fluoropyrimidines, antitumor drug design
medicine
-
development of a HPLC method, sufficient, accurate, fast and sensitive to be applied to the analysis of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil in plasma and cytoplasmic samples, allowing accurate pharmacokinetic analyses and measurements of dihydropyrimidine dehydrogenase in patients who are candidates for fluoropyrimidine-based chemotherapy without the need of a labeled substrate for enzyme studies
medicine
-
identification of mutants G366A and T768K in healthy Japanese volunteers. G366A results in marked decrease in enzyme affinity to NADPH, reduction of Vmax for 5-fluorouracil degrading activity, T768K leads to rapid loss of enzyme activity
medicine
-
uracil breath test breath 13CO2 pharmacokinetics parallel plasma [2-13C]uracil and [2-13C]dihydrouracil pharmacokinetics and are an accurate measure of interindividual variation in enzyme activity. Data support the use of uracil breath test to identify enzyme deficiency before 5-fluorouracil-based therapy
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Haaz, M.C.; Fischel, J.L.; Formento, P.; Renee, N.; Etienne, M.C.; Milano, G.
Impact of different fluorouracil biochemical modulators on cellular dihydropyrimidine dehydrogenase
Cancer Chemother. Pharmacol.
38
52-58
1996
Homo sapiens
Milano, G.; Fischel, J.L.; Etienne, M.C.; Renee, N.; Formento, P.; Thyss, A.; Gaspard, M.H.; Thill, L.; Cupissol, D.
Inhibition of dihydropyrimidine dehydrogenase by alpha-interferon: Experimental data on human tumor cell lines
Cancer Chemother. Pharmacol.
34
147-152
1994
Homo sapiens
Tuchman, M.; Roemeling, R.V.; Hrushesky, W.A.M.; Sothern, R.B.; O'Dea, R.F.
Dihydropyrimidine dehydrogenase activity in human blood mononuclear cells
Enzyme
42
15-24
1989
Homo sapiens
Porter, D.J.T.; Chestnut, W.G.; Merrill, B.M.; Spector, T.
Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil
J. Biol. Chem.
267
5236-5242
1992
Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus
Balzarini, J.; Sienaert, R.; Liekens, S.; Van Kuilenburg, A.; Carangio, A.; Esnouf, R.; De Clercq, E.; McGuigan, C.
Lack of susceptibility of bicyclic nucleoside analogs, highly potent inhibitors of varicella-zoster virus, to the catabolic action of thymidine phosphorylase and dihydropyrimidine dehydrogenase
Mol. Pharmacol.
61
1140-1145
2002
Homo sapiens, Mus musculus
Lu, Z.H.; Zhang, R.; Diasio, R.B.
Comparison of dihydropyrimidine dehydrogenase from human, rat, pig and cow liver. Biochemical and immunological properties
Biochem. Pharmacol.
46
945-952
1993
Bos taurus, Homo sapiens, Rattus norvegicus, Sus scrofa
Van Kuilenburg, A.B.P.; Dobritzsch, D.; Meinsma, R.; Haasjes, J.; Waterham, H.R.; Nowaczyk, M.J.M.; Maropoulos, G.D.; Hein, G.; Kalhoff, H.; Kirk, J.M.; Baaske, H.; Aukett, A.; Duley, J.A.; Ward, K.P.; Lindqvist, Y.; Van Gennip, A.H.
Novel disease-causing mutations in the dihydropyrimidine dehydrogenase gene interpreted by analysis of the three-dimensional protein structure
Biochem. J.
364
157-163
2002
Homo sapiens
Schnackerz, K.D.; Dobritzsch, D.; Lindqvist, Y.; Cook, P.F.
Dihydropyrimidine dehydrogenase: a flavoprotein with four iron-sulfur clusters
Biochim. Biophys. Acta
1701
61-74
2004
Bos taurus, Cupriavidus necator, Homo sapiens, Rattus norvegicus, Sus scrofa
Di Paolo, A.; Danesi, R.; Ciofi, L.; Vannozzi, F.; Bocci, G.; Lastella, M.; Amatori, F.; Martelloni, B.M.; Ibrahim, T.; Amadori, D.; Falcone, A.; Del Tacca, M.
Improved analysis of 5-Fluorouracil and 5,6-dihydro-5-Fluorouracil by HPLC with diode array detection for determination of cellular dihydropyrimidine dehydrogenase activity and pharmacokinetic profiling
Ther. Drug Monit.
27
362-368
2005
Homo sapiens
Van Kuilenburg, A.B.; Meinsma, R.; Beke, E.; Bobba, B.; Boffi, P.; Enns, G.M.; Witt, D.R.; Dobritzsch, D.
Identification of three novel mutations in the dihydropyrimidine dehydrogenase gene associated with altered pre-mRNA splicing or protein function
Biol. Chem.
386
319-324
2005
Homo sapiens (Q12882), Sus scrofa
Ogura, K.; Ohnuma, T.; Minamide, Y.; Mizuno, A.; Nishiyama, T.; Nagashima, S.; Kanamaru, M.; Hiratsuka, A.; Watabe, T.; Uematsu, T.
Dihydropyrimidine dehydrogenase activity in 150 healthy Japanese volunteers and identification of novel mutations
Clin. Cancer Res.
11
5104-5111
2005
Homo sapiens
Mattison, L.; Fourie, J.; Hirao, Y.; Koga, T.; Desmond, R.A.; King, J.R.; Shimizu, T.; Diasio, R.B.
The uracil breath test in the assessment of dihydropyrimidine dehydrogenase activity: pharmacokinetic relationship between expired 13CO2 and plasma [2-13C]dihydrouracil
Clin. Cancer Res.
12
549-555
2006
Homo sapiens
van Kuilenburg, A.B.; Meijer, J.; Dobritzsch, D.; Lohkamp, B.; Ruitenbeek, W.; Roelofsen, J.; Abeling, N.G.; Duran, M.; Buzing, C.
Identification of two novel mutations C79X and R235Q in the dihydropyrimidine dehydrogenase gene in a patient presenting with hematuria
Nucleosides Nucleotides Nucleic Acids
27
809-815
2008
Homo sapiens
Tsuchida, M.; Yamato, Y.; Hashimoto, T.; Shinohara, H.; Umezu, H.; Yoshiya, K.; Koike, T.; Hayashi, J.
Expression of 5-fluorouracil-related enzymes in lung cancer: ELISA characterizes enzyme activity and messenger RNA expression
Oncol. Rep.
21
1037-1043
2009
Homo sapiens
Serve, K.M.; Darnell, J.L.; Takemoto, J.K.; Davies, N.M.; Black, M.E.
Validation of an isocratic HPLC method to detect 2-fluoro-beta-alanine for the analysis of dihydropyrimidine dehydrogenase activity
J. Chromatogr. B
878
1889-1892
2010
Homo sapiens
Danielyan, K.E.
Dependence of cell survival on correlative activities of xanthine oxidase and dihydopyrimidine dehydrogenase in human brain-derived cell culture
Cent. Nerv. Syst. Agents Med. Chem.
13
108-113
2013
Homo sapiens
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