Information on EC 1.3.1.1 - dihydropyrimidine dehydrogenase (NAD+)

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

EC NUMBER
COMMENTARY hide
1.3.1.1
-
RECOMMENDED NAME
GeneOntology No.
dihydropyrimidine dehydrogenase (NAD+)
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
5,6-dihydrothymine + NAD+ = thymine + NADH + H+
show the reaction diagram
-
-
-
-
5,6-dihydrouracil + NAD+ = uracil + NADH + H+
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
beta-Alanine metabolism
-
-
Metabolic pathways
-
-
Pantothenate and CoA biosynthesis
-
-
Pyrimidine metabolism
-
-
SYSTEMATIC NAME
IUBMB Comments
5,6-dihydropyrimidine:NAD+ oxidoreductase
An iron-sulfur flavoenzyme. The enzyme was originally discovered in the uracil-fermenting bacterium, Clostridium uracilicum, which utilizes uracil and thymine as nitrogen and carbon sources for growth [1]. Since then the enzyme was found in additional organisms including Alcaligenes eutrophus [2], Pseudomonas strains [3,4] and Escherichia coli [5,6].
CAS REGISTRY NUMBER
COMMENTARY hide
9026-89-5
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain Bristol N2
-
-
Manually annotated by BRENDA team
strain Bristol N2
-
-
Manually annotated by BRENDA team
Clostridium uracilicum
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
strain 2a
-
-
Manually annotated by BRENDA team
strain 2a
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
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 rate limiting step
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NAD+
uracil + NADH
show the reaction diagram
-
-
-
-
r
5,6-dihydrouracil + NAD+
uracil + NADH + H+
show the reaction diagram
-
-
-
?
5-fluorouracil + NAD+
5-fluoro-5,6-dihydrouracil + NADH
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NAD+
5-fluoro-5,6-dihydrouracil + NADH + H+
show the reaction diagram
5-fluorouracil + NAD+
? + NADH
show the reaction diagram
5-fluorouracil + NAD+
alpha-fluoro-beta-alanine + NADH + H+
show the reaction diagram
-
-
-
-
?
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
capecitabine + NAD+
?
show the reaction diagram
-
-
-
-
?
dihydrothymine + NAD+
thymine + NADH + H+
show the reaction diagram
-
-
-
?
thymine + NAD(P)H
dihydrothymine + NAD(P)+
show the reaction diagram
-
-
-
r
thymine + NADH + H+
dihydrothymine + NAD+
show the reaction diagram
-
-
-
r
uracil + NAD(P)H
5,6-dihydrouracil + NAD(P)+
show the reaction diagram
uracil + NAD+
5,6-dihydrouracil + NADH + H+
show the reaction diagram
-
-
-
-
?
uracil + NADH + H+
5,6-dihydrouracil + NAD+
show the reaction diagram
-
-
-
r
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
5,6-dihydrouracil + NAD+
uracil + NADH
show the reaction diagram
-
-
-
-
r
5-fluorouracil + NAD+
5-fluoro-5,6-dihydrouracil + NADH + H+
show the reaction diagram
-
-
dihydrofluorouracil is further metabolized to 2'-fluoro-beta-alanine
-
?
5-fluorouracil + NAD+
? + NADH
show the reaction diagram
-
rate-limiting step in the elimination of the chemotherapeutic drug fluoropyrimidine
-
-
r
5-fluorouracil + NADPH
5-fluoro-5,6-dihydrouracil + NADP+
show the reaction diagram
uracil + NAD(P)H
5,6-dihydrouracil + NAD(P)+
show the reaction diagram
Clostridium uracilicum
-
reductive pathway of uracil degradation
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
iron-sulfur centre
;
NADP+
-
less activity than with NAD+
NADPH
-
less activity than with NADH
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5-chloro-2,4-dihydroxypyridine
-
potent inhibitor
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
Hydroxyurea
-
cell lines CAL 27, CAL 33, CAL 51, ORL 1, PANC 3
interferon-alpha-2a
-
cell lines CAL 27, CAL 33, CAL 51, CAL 7, PANC 3
-
Uracil
-
reversible inhibition
additional information
-
combined oral treatment with uracil and tegafur has no influence on DPD activity
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
allopurinol
-
cell lines CAL 27, CAL 51, ORL 1, PANC 3
cisplatin
-
cell line ORL 1
leucovorin
-
-
phorbol-12-myristate
-
activates gene expression
specificity protein 1
-
transcription activator
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.16
5,6-dihydrouracil
pH 11.0, 30C; pH 11.0, 30C
0.13
Dihydrothymine
pH 11.0, 30C; pH 11.0, 30C
0.087
thymine
pH 6.0, 30C; pH 6.0, 30C
0.038
Uracil
pH 6.0, 30C; pH 6.0, 30C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.65
5,6-dihydrouracil
Escherichia coli
P25889, P76440
pH 11.0, 30C; pH 11.0, 30C
0.28
Dihydrothymine
Escherichia coli
P25889, P76440
pH 11.0, 30C; pH 11.0, 30C
0.39
thymine
Escherichia coli
P25889, P76440
pH 6.0, 30C; pH 6.0, 30C
0.64
Uracil
Escherichia coli
P25889, P76440
pH 6.0, 30C; pH 6.0, 30C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
6.5
5,6-dihydrouracil
Escherichia coli
P25889, P76440
pH 11.0, 30C; pH 11.0, 30C
1913
2.8
Dihydrothymine
Escherichia coli
P25889, P76440
pH 11.0, 30C; pH 11.0, 30C
3198
4.5
thymine
Escherichia coli
P25889, P76440
pH 6.0, 30C; pH 6.0, 30C
438
17
Uracil
Escherichia coli
P25889, P76440
pH 6.0, 30C; pH 6.0, 30C
334
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
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
0.535
-
NADH, uracil reduction
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6
reduction of uracil, assay at; reduction of uracil, assay at
7 - 7.8
Clostridium uracilicum
-
uracil reduction
11
oxidation of dihydrouracil, assay at; oxidation of dihydrouracil, assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 8.2
Clostridium uracilicum
-
pH 6.5: 33.6% of activity maximum, pH 8.2: 59% of activity maximum
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
colorectal cancer cells
Manually annotated by BRENDA team
-
mucosa
Manually annotated by BRENDA team
-
peripheral blood
Manually annotated by BRENDA team
-
intestine
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
40400
-
SDS-PAGE
44329
2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA; 2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA
45069
2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA; 2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA
110000
-
2 * 110000, SDS-PAGE
220000
-
SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
homodimer
-
2 * 110000, SDS-PAGE
tetramer
2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA; 2 * 44329, subunit PreT, plus 2 * 45069, subunit PreA
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hanging drop vapour diffusion method using PEG 20k or NaCl as a precipitant
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
-
high performance liquid chromatography method for quantification of dihydrouracil to uracil ratio in plasma and application in screening for dihydropyrimidine dehydrogenase deficiency in patients treated with 5-fluorouracil. Plasma dihydrouracil to uracil ratio values are highly correlated with the plasma 5-fluorouracil-half-life values and are significantly associated with the toxic side effects, whereas, data set provided from genetic analysis of the coding sequences of the DPD gene are found to be insufficient to explain all the cases of the 5-fluorouracil-related toxicity pattern. Assay is suitable for routine clinical use for dihydropyrimidine dehydrogenase deficiency assessment in patients prior to 5-fluorouracil administration
medicine
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