Information on EC 1.3.1.2 - dihydropyrimidine dehydrogenase (NADP+)

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
1.3.1.2
-
RECOMMENDED NAME
GeneOntology No.
dihydropyrimidine dehydrogenase (NADP+)
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
nonclassical ping-pong mechanism
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
abstraction of pro-S hydrogen of NADPH and thus B-side stereospecific class dehydrogenase
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
abstraction of pro-S hydrogen of NADPH and thus B-side stereospecific class dehydrogenase
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
comparison of substrate and cofactor binding to wild-type and mutant enzyme
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
random rapid-equilibrium mechanism
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
mechanism, rate-determining half-reaction for reduction of flavin by NADPH has minor rate limitation, while the following protonation of flavin at N-1 is slow
-
5,6-dihydrouracil + NADP+ = uracil + NADPH + H+
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
beta-Alanine metabolism
-
Drug metabolism - other enzymes
-
Metabolic pathways
-
Pantothenate and CoA biosynthesis
-
Pyrimidine metabolism
-
thymine degradation
-
uracil degradation I (reductive)
-
SYSTEMATIC NAME
IUBMB Comments
5,6-dihydrouracil:NADP+ 5-oxidoreductase
Also acts on dihydrothymine.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4,5-dihydrothymine: oxidoreductase
-
-
-
-
dehydrogenase, dihydrouracil (nicotinamide adenine dinucleotide phosphate)
-
-
-
-
DHPDH
-
-
-
-
DHPDHase
-
-
-
-
DHU dehydrogenase
-
-
-
-
dihydropyrimidine dehydrogenase
-
-
dihydropyrimidine dehydrogenase
-
-
dihydropyrimidine dehydrogenase
Q28943
-
dihydrothymine dehydrogenase
-
-
-
-
Dihydrouracil dehydrogenase
-
-
-
-
dihydrouracil dehydrogenase (NADP)
-
-
-
-
dihydrouracil dehydrogenase (NADP+)
-
-
-
-
DPD
-
-
-
-
DPD
Q28943
-
hydropyrimidine dehydrogenase
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9029-01-0
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
healthy Japanese volunteers
-
-
Manually annotated by BRENDA team
patients who underwent curative resection for lung cancer
-
-
Manually annotated by BRENDA team
extensive overview of literature data concerning inhibitors and substrates
-
-
Manually annotated by BRENDA team
biotype B, strain ATCC 17536
-
-
Manually annotated by BRENDA team
recombinant enzyme
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
metabolism
Q28943
in mammals, the pyrimidines uracil and thymine are metabolised by a three-step reductive degradation pathway. Dihydropyrimidine dehydrogenase catalyses its first and rate-limiting step, reducing uracil and thymine to the corresponding 5,6-dihydropyrimidines in an NADPH-dependent reaction
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
additional information
Q28943
the N-terminal half of DPD is a member of a family of FAD-containing NADPH oxidoreductases, which transfer electrons to an acceptor protein or domain through [4Fe-4S] clusters of low to very low potential
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
ir
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
reversibility of the reaction only in vitro
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
C671A mutant only forms complex with dihydrouracil nearly without oxidizing it
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
first and rate-limiting enzyme in the three-step pathway for the degradation of uracil
-
-
?
5-aminouracil + NADPH
?
show the reaction diagram
-
-
-
-
?
5-aminouracil + NADPH
?
show the reaction diagram
-
-
-
-
?
5-bromouracil + NADPH
5-bromo-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-bromouracil + NADPH
5-bromo-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
r
5-diazouracil + NADPH
?
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-iodouracil + NADPH
5-iodo-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
5-iodouracil + NADPH
5-iodo-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
r
5-iodouracil + NADPH
5-iodo-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
alkylating and therefore in vivo inactivating product
-
5-nitrouracil + NADPH
?
show the reaction diagram
-
-
-
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
-
-
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
Q28943
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
-
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
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
Q28943
pyrimidine binding to this enzyme is accompanied by active site loop closure that positions a catalytically crucial cysteine 671 residue. The deprotonation of the loop residue H673 is required for active site closure, while S670 is important for substrate recognition. R235 is crucial for FAD binding
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH
show the reaction diagram
-
-
-
r
dihydrothymine + NADP+
thymine + NADPH + H+
show the reaction diagram
Q28943
-
-
-
?
dihydrouracil + NADP+
uracil + NADPH + H+
show the reaction diagram
Q28943
-
-
-
?
thymine + NAD(P)H + H+
5,6-dihydrothymine + NAD(P)+
show the reaction diagram
-
-
-
-
?
thymine + NADP+
5,6-dihydrothymine + NADPH + H+
show the reaction diagram
-
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?, r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme of thymidine and uridine degradation
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme of thymidine and uridine degradation
-
r
uracil + NAD(P)H + H+
5,6-dihydrouracil + NAD(P)+
show the reaction diagram
-
-
-
-
?
uracil + NADP+
5,6-dihydrouracil + NADPH + H+
show the reaction diagram
-
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
-
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
reversibility of the reaction only in vitro
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
hydrouridylic acid + NADPH
?
show the reaction diagram
-
low activity
-
-
?
additional information
?
-
-
-
-
-
-
additional information
?
-
-
not: orotate, cytosine
-
-
-
additional information
?
-
Q28943
the first FeS cluster, with unusual coordination, cannot be reduced and displays no activity when Q156 is mutated to glutamate. The active site loop comprising residues 670-683 are observed in open and closed conformational states, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
-
?
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
ir
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
-
-
r
5,6-dihydrouracil + NADP+
uracil + NADPH
show the reaction diagram
-
first and rate-limiting enzyme in the three-step pathway for the degradation of uracil
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
-
-
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
dihydrofluorouracil + NADP+
5'-fluorouracil + NADPH + H+
show the reaction diagram
Q28943
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
-
?
dihydrothymine + NADP+
thymine + NADPH + H+
show the reaction diagram
Q28943
-
-
-
?
dihydrouracil + NADP+
uracil + NADPH + H+
show the reaction diagram
Q28943
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
-
-
r
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme in catabolic detoxification of exogenous fluoropyrimidines
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme of thymidine and uridine degradation
-
?
thymine + NADPH
dihydrothymine + NADP+
show the reaction diagram
-
rate-limiting enzyme of thymidine and uridine degradation
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
-
-
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
-
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting step in catabolic breakdown of uracil to beta-alanine
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
r
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
uracil + NADPH
5,6-dihydrouracil + NADP+
show the reaction diagram
-
rate limiting enzyme in pyrimidine degradation
-
?
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
FAD
-
1 FAD per subunit
FAD
Q28943
absolutely required, R235 is crucial for FAD binding
flavin
-
enzyme contains 4 mol of FAD per mol of enzyme
flavin
-
contains 2 mol FMN and 2 mol FAD per mol of enzyme, tightly associated
flavin
-
4.1 mol FMN per mole of enzyme
flavin
-
contains 2 mol FMN and 2 mol FAD per mol of enzyme, tightly associated
FMN
-
1 FMN per subunit
NAD+
-
less activity than with NADP+, high concentration necessary
NADH
-
less activity than with NADPH, high concentration necessary
NADPH
-
strictly dependent on
NADPH
Q28943
dependent on
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Fe2+
Q28943
iron-sulfur cluster binding, overview
Iron
-
1 mol of enzyme contains 3 mol of iron; iron atoms are probably present in iron-sulfur centers
Iron
-
contains 32 iron atoms per 206000 MW protein; iron atoms are probably present in iron-sulfur centers
Iron
-
24.5 mol iron per mol of enzyme; iron atoms are probably present in iron-sulfur centers
Iron
-
16 iron atoms per enzyme, wild-type and mutant C671A, [4Fe-4S] clusters
Iron
-
2 [4Fe-4S] clusters per subunit with 9.0 mol iron per mol of subunit
Iron
-
2 * 2 [4Fe-4S] clusters close in space with 16 atoms of non-heme iron, structure
Iron
-
each subunit contains 16 nonheme-irons in 4 [4Fe-4S] clusters
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(E)-5-[2-bromovinyl-]uracil
-
50% inhibition at 0.01 mM, no inhibition by free base
1-deazauracil
-
i.e. 2,6-pyridinediol
2,6-dihydrouracil
-
-
-
2,6-dihydrouracil
-
-
-
2,6-dihydrouracil
-
competitive
-
2,6-Dihydroxypyridine
-
competitive vs. uracil
3-aminopyridine ADP
-
-
3-deazauracil
-
i.e. 2,4-pyridinediol
5,6-Dihydropyrimidine
-
-
5,6-Dihydrouracil
-
-
5,6-Dihydrouracil
-
-
5,6-dioxyuracil
-
i.e. alloxan
5-(phenylselenenyl)uracil
-
-
5-(phenylthio)uracil
-
-
5-benzyloxybenzyluracil
-
-
5-benzyluracil
-
-
5-Ethynyluracil
-
inactivation rate is dependent on dithiothreitol content
5-Ethynyluracil
-
suicide inactivator covalently modifying a cysteinyl residue
5-Ethynyluracil
-
mechanism-based inhibition
5-Iodo-uracil
-
mechanism-based inhibition
5-Iodo-uracil
-
mechanism-based inactivator
5-Iodouracil
-
dithiothreitol and thymine protect against inactivation
5-Iodouracil
-
inhibition mechanism
5-nitrobarbituric acid
-
-
alpha-2a-interferon
-
cell lines CAL 27, CAL 33, CAL 51, CAL 7, PANC 3
-
ATP-ribose
-
dead-end inhibition
ATP-ribose
-
dead-end inhibition
ATP-ribose
-
competitive
Chloramphenicol
-
2.0fold reduced activity in chloramphenicol-treated cells
cisplatin
-
cell lines CAL 27, CAL 33, CAL 51, PANC 3
dipyridamole
-
cell lines CAL 27, CAL 33, CAL 51, ORL 1, PANC 3, mechanism
NADP+
-
competitive versus NADPH
NADP+
-
competitive versus NADPH
NADP+
-
competitive versus NADPH
Hydroxyurea
-
cell lines CAL 27, CAL 33, CAL 51, ORL 1, PANC 3
additional information
-
no inhibition or inactivation with 5-nitro-, 5-fluoro-,5-carbamido-, 5-formyl-, 5-acetamido-, 5-hydroxymethyl- or 5-chlorouracil
-
additional information
-
not: thio-NADPH, cyclo-NADPH, deamino-NADPH
-
additional information
-
-
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
allopurinol
-
cell lines CAL 27, CAL 51, ORL 1, PANC 3
cisplatin
-
cell line ORL 1
Sulfide
-
23.4 mol per mol of enzyme
-
Sulfide
-
8.0 mol acid-labile sulfide per mol of subunit
-
Sulfide
-
-
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.24
-
5,6-Dihydrouracil
-
in presence of NADP+
2
-
5,6-Dihydrouracil
-
-
0.0011
-
5-Fluorouracil
-
-
0.0018
-
5-Fluorouracil
-
-
0.0033
-
5-Fluorouracil
-
-
0.0089
-
5-Fluorouracil
-
-
0.043
-
Dihydrothymine
-
-
0.6
-
Dihydrothymine
-
in presence of dihydrouracil
0.0004
-
NADP+
-
in presence of 5,6-dihydrouracil
0.0029
-
NADP+
-
in presence of dihydrouracil
0.0038
-
NADP+
-
in presence of dihydrothymine
0.00012
-
NADPH
-
-
0.0057
-
NADPH
Q28943
pH 7.5, 30C, recombinant wild-type enzyme
0.006
-
NADPH
-
-
0.0061
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant C126A
0.0062
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant H673Q
0.0066
-
NADPH
-
in presence of 2,6-dihydrouracil
0.0068
-
NADPH
-
in presence of uracil
0.007
-
NADPH
-
-
0.0075
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant H673N
0.0082
-
NADPH
-
in presence of 5-fluorouracil
0.0085
-
NADPH
-
in presence of 5-fluorouracil
0.0089
-
NADPH
-
in presence of uracil
0.0096
-
NADPH
-
in presence of uracil
0.01
-
NADPH
-
-
0.01
-
NADPH
-
in presence of 5-fluorouracil
0.011
-
NADPH
-
in presence of uracil
0.0119
-
NADPH
-
in presence of uracil
0.015
-
NADPH
-
in presence of thymine
0.0158
-
NADPH
-
in presence of thymine
0.0167
-
NADPH
-
in presence of thymine
0.017
-
NADPH
-
-
0.0188
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant S670A
0.0206
-
NADPH
-
in presence of uracil
0.0209
-
NADPH
-
in presence of 5-fluorouracil
0.0289
-
NADPH
-
in presence of thymine
0.001
-
thymine
-
-
0.0026
-
thymine
-
-
0.0046
-
thymine
-
-
0.0048
-
thymine
-
-
0.0068
-
thymine
-
-
0.00012
-
Uracil
-
-
0.0008
-
Uracil
-
cofactor NADPH
0.001
-
Uracil
-
-
0.0011
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant C126A
0.0012
-
Uracil
Q28943
pH 7.5, 30C, recombinant wild-type enzyme
0.0018
-
Uracil
-
-
0.0024
-
Uracil
-
-
0.0039
-
Uracil
-
-
0.004
-
Uracil
-
-
0.0042
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673Q
0.0049
-
Uracil
-
-
0.0049
-
Uracil
-
-
0.0059
-
Uracil
-
-
0.007
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673N
0.023
-
Uracil
-
in presence of 2,6-dihydrouracil
0.0366
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant S670A
0.193
-
dihydrouracil
-
-
additional information
-
additional information
Q28943
pH dependence and kinetics of recombinant wild-type and mutant enzymes, overview
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.4
-
5,6-Dihydrouracil
-
-
0.068
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673N
0.117
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673Q
0.177
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant S670A
0.242
-
Uracil
Q28943
pH 7.5, 30C, recombinant wild-type enzyme
0.256
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant C126A
1.6
-
Uracil
-
-
kcat/KM VALUE [1/mMs-1]
kcat/KM VALUE [1/mMs-1] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
9000
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant H673N; pH 7.5, 30C, recombinant mutant S670A
27498
19000
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant H673Q
27498
42000
-
NADPH
Q28943
pH 7.5, 30C, recombinant mutant C126A; pH 7.5, 30C, recombinant wild-type enzyme
27498
5000
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant S670A
17744
10000
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673N
17744
28000
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant H673Q
17744
208000
-
Uracil
Q28943
pH 7.5, 30C, recombinant wild-type enzyme
17744
238000
-
Uracil
Q28943
pH 7.5, 30C, recombinant mutant C126A
17744
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0005
-
1-deazauracil
-
-
0.0021
-
3-deazauracil
-
-
0.0066
-
5,6-dioxyuracil
-
-
0.0048
-
5-(phenylselenenyl)uracil
-
-
0.0054
-
5-(phenylthio)uracil
-
-
0.0002
-
5-benzyloxybenzyluracil
-
-
0.0034
-
5-benzyluracil
-
-
0.0038
-
5-nitrobarbituric acid
-
-
0.001
-
NADP+
-
-
0.011
-
NADP+
-
-
0.007
-
NADPH
-
-
0.15
-
dihydrouracil
-
-
additional information
-
additional information
-
for 5-ethynyl-, 5-diazo-, 5-cyano-, 5-bromvinyl-, 5-propynyl-, 5-bromo- and 5-trifluoromethyluracil
-
additional information
-
additional information
-
inhibitory reactions between uracil, NADP+ and dihydrouracil
-
additional information
-
additional information
-
inhibitory reactions between uracil, NADP+ and dihydrouracil; Ki for ATP-ribose, 3-aminopyridine ADP, and 2,6-dihydrouracil
-
additional information
-
additional information
-
-
-
additional information
-
additional information
-
inhibitory reactions between uracil, NADP+ and dihydrouracil
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.00018
-
-
at 30C
0.0043
-
-
mutant C671A
0.118
-
-
cell line CAL 27
0.122
-
-
cell line CAL 7
0.184
-
-
cell line CAL 33
0.265
-
-
cell line PANC 3
0.318
-
-
cell line CAL 51
0.35
-
-
-
0.38
-
-
purified enzyme
0.417
0.5
-
purified enzyme
0.43
-
-
-
2.2
-
-
substrate hydrothymine
4.7
-
-
substrate nitouracil
14
-
-
recombinant from Escherichia coli
20.9
-
-
substrate 5-iodouracil
21
-
-
purified enzyme
21.5
-
-
substrate 5-diazouracil
27.9
-
-
substrate thymine
34.9
-
-
substrate uracil
46.9
-
-
substrate 5-bromouracil
47.4
-
-
substrate 5-fluorouracil
182.1
-
-
purified enzyme
additional information
-
-
-
additional information
-
-
-
additional information
-
-
HPLC method for determination of low activities of dihydropyrimidine dehydrogenase
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
7.6
-
uracil reduction
7.4
-
-
-
7.5
-
Q28943
assay at
additional information
-
-
investigation of pH-dependency of the reaction and inhibition by 2,6-dihydrouracil and ATP-ribose, kinetics
additional information
-
Q28943
pH dependence and kinetics of recombinant wild-type and mutant enzymes, overview
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.8
8.5
-
-
6.7
7.9
-
about 80% of activity maximum at pH 6.7 and 7.9, uracil reduction
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
-
-
assay at
30
-
Q28943
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
204000
-
-
HPLC gel filtration
206000
-
-
gel filtration
207000
210000
-
gel fitration or gradient native PAGE
210000
-
-
gel filtration
214000
-
-
recombinant from E. coli, native PAGE
216000
-
-
gel filtration
218000
-
-
gel filtration
220000
-
-
gel filtration, sedimentation equilibrium
220000
-
-
-
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 * 110000, SDS-PAGE
dimer
-
2 * 111000, SDS-PAGE
dimer
-
2 * 108000, SDS-PAGE
dimer
-
2 * 105000, SDS-PAGE
dimer
-
2 * 102000, SDS-PAGE
dimer
-
2 * 107000, SDS-PAGE
tetramer
-
4 * 52000, SDS-PAGE
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cocrystallization with 5-iodouracil 1 mM and NADPH 5 mM, ternary complex in 100 mM HEPES, pH 7.5, 22% polyethylene glycol 6000, uracil-4-acetic acid 1 mM, structure determination at different pH-values
-
crystals diffract to 1.9 A
-
mutants E244V and A551T
-
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
45
-
-
t1/2: 2 min without 2-mercaptoethanol, 2.5 min with 5 mM 2-mercaptoethanol
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
dithiothreitol stabilizes against inactivation via 5-alkylyluracils
-
dithiothreitol stabilizes against inactivation via 5-alkylyluracils
-
2-mercaptoethanol stabilizes during dialysis and heating
-
24 h dialysis against 35 mM potassium phosphate buffer, pH 7.4, with addition of 5 mM 2-mercaptoethanol or dithiothreitol, stable
-
dithiothreitol stabilizes against inactivation via 5-alkylyluracils
-
irreversible denaturation of enzyme in dilute solutions below 1 mg/ml
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-80C, 35 mM potassium phosphate, pH 7.4, 1 mM dithioerythritol, more than 2 months without loss of activity, without dithioerythritol 50% loss of activity
-
-15C, 20% loss of activity after 1 month
-
-20C, 2 mg/ml protein, 10% loss of activity after 2 weeks
-
-20C, protein concentration 0.5-1 mg/ml, 1 mM dithiothreitol, stable for several months
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
partial
-
recombinant protein
-
recombinant wild-type and mutant enzymes from Escherichia coli by affinity chromatography and gel filtration
Q28943
wild-type and mutant enzyme
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cloning of cDNA
-
expression in Escherichia coli
-
expression of wild-type and mutant enzymes in Escherichia coli strain Tuner(DE3)
Q28943
overproduction of wild-type and mutant enzyme in Escherichia coli
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
A551T
Q12882
natural mutation identified in a patient with complete loss of enzymic activity
E244V
Q12882
natural mutation identified in a patient with complete loss of enzymic 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
A551T
-
natural mutation identified in a human with complete loss of enzymic activity. Crystallization data of Sus scrofa recombinant mutant, mutation might prevent binding of the prosthetic group FMN and affect folding of the enzyme protein
C126A
Q28943
site-directed mutagenesis, a potential [4Fe-4S]-cluster binding residue, the mutant shows slightly increased activity compared to the wild-type enzyme
C671A
-
1% activity compared to that of the wild-type enzyme
E244V
-
natural mutation identified in a human with complete loss of enzymic activity. Crystallization data of Sus scrofa recombinant mutant, mutation interferes with the electron flow between NADPH and the pyrimidine binding site of the enzyme
H673N
Q28943
site-directed mutagenesis, active site loop residue, the mutant shows reduced activity compared to the wild-type enzyme
H673Q
Q28943
site-directed mutagenesis, active site loop residue, the mutant shows reduced activity compared to the wild-type enzyme
Q156E
Q28943
site-directed mutagenesis, [4Fe-4S]-cluster binding residue, inactive mutant
R235A
Q28943
site-directed mutagenesis, FAD binding residue, inactive mutant
R235K
Q28943
site-directed mutagenesis, FAD binding residue, inactive mutant
S670A
Q28943
site-directed mutagenesis, active site loop residue, the mutant shows reduced activity compared to the wild-type enzyme
G366A
-
natural mutation, marked decrease in enzyme affinity to NADPH, reduction of Vmax for 5-fluorouracil degrading activity
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
additional information
Q12882
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
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
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
-
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
Q12882
identification of mutations E244V and A551T and splice site mutation IVS11+1G to T in patients with complete loss of enzymic activity
medicine
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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
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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
drug development
Q28943
the enzyme is an adjunct target in cancer therapy since it rapidly breaks down the anti-cancer drug 5-fluorouracil and related compounds
medicine
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rate limiting enzyme in catabolic degradation of pyrimidine derivatives, selective inhibition is strategy for design of antitumor, antimicrobial and potentially antiparasitic agents
medicine
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rate limiting enzyme for detoxification of exogenous fluoropyrimidines, antitumor drug design
medicine
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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
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identification of mutations E244V and A551T and splice site mutation IVS11+1G to T in patients with complete loss of enzymic activity