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Information on EC 1.3.98.1 - dihydroorotate dehydrogenase (fumarate)
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EC Tree
1.3.98.1 dihydroorotate dehydrogenase (fumarate)IUBMB Comments
Binds FMN. The reaction, which takes place in the cytosol, is the only redox reaction in the de novo biosynthesis of pyrimidine nucleotides. Molecular oxygen can replace fumarate in vitro. Other class 1 dihydroorotate dehydrogenases use either NAD+ (EC 1.3.1.14) or NADP+ (EC 1.3.1.15) as electron acceptor. The membrane bound class 2 dihydroorotate dehydrogenase (EC 1.3.5.2) uses quinone as electron acceptor.
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Word Map
- 1.3.98.1
- pyrimidine
- leflunomide
- brequinar
- uridine
- plasmodium
- falciparum
- ubiquinone
- teriflunomide
-
dhods
-
1.3.3.1
- ump
-
dihydro-orotate
- triazolopyrimidine
- atovaquone
-
1.3.99.11
- dysostosis
- analysis
- medicine
-
acrofacial
The enzyme appears in viruses and cellular organisms
Synonyms
dhodh, dhodehase, dhoda, lmdhodh, dihydroorotate oxidase, tcdhod, (dho) dehydrogenase, class 1a dhod, class 1a dhodh, dhod3, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
(DHO) dehydrogenase
-
-
-
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4,5-L-dihydroorotate:oxygen oxidoreductase
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-
-
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ACT/DHOD
DHOD
DHOD2
DHODA
DHOdehase
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-
-
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DHODH
dihydroorotate dehydrogenase class 1A
Dihydroorotate oxidase
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-
-
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EC 1.3.3.1
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-
formerly
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oxidase, dihydroorotate
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-
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additional information
ACT/DHOD
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gene fusion encoding aspartate carbamoyltransferase and dihyroorotate dehydrogenase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
(S)-dihydroorotate + fumarate = orotate + succinate
light sensitivity seems to result in a conformational change and a partial loss of enzymatic activity
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(S)-dihydroorotate + fumarate = orotate + succinate
A flavoprotein (FAD, FMN). Ferricyanide can act as accetor
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-
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(S)-dihydroorotate + fumarate = orotate + succinate
mechanism, pyrimidine biosynthetic pathways
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(S)-dihydroorotate + fumarate = orotate + succinate
cysteine and serine are active site base residues. One-site ping-pong mechanism with fumarate as electron acceptor
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(S)-dihydroorotate + fumarate = orotate + succinate
cysteine and serine are active site base residues. One-site ping-pong mechanism with fumarate as electron acceptor
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(S)-dihydroorotate + fumarate = orotate + succinate
sulfhydryl groups suggested to be located near the active site, suggested that enzyme produces superoxide free radicals upon reaction with oxygen
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(S)-dihydroorotate + fumarate = orotate + succinate
the active site contains a water filled cavity buried beneath a highly conserved and flexible loop. Orotate is bound by four conserved asparagine side chains. Implications for differences in substrate binding and in the catalytic mechanism between the different enzyme families are given
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(S)-dihydroorotate + fumarate = orotate + succinate
ping-pong bi-bi mechanism
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(S)-dihydroorotate + fumarate = orotate + succinate
light
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-
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(S)-dihydroorotate + fumarate = orotate + succinate
two-site ping-pong mechanism, catalytic base is serine
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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redox reaction
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-
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reduction
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-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
(S)-dihydroorotate:fumarate oxidoreductase
Binds FMN. The reaction, which takes place in the cytosol, is the only redox reaction in the de novo biosynthesis of pyrimidine nucleotides. Molecular oxygen can replace fumarate in vitro. Other class 1 dihydroorotate dehydrogenases use either NAD+ (EC 1.3.1.14) or NADP+ (EC 1.3.1.15) as electron acceptor. The membrane bound class 2 dihydroorotate dehydrogenase (EC 1.3.5.2) uses quinone as electron acceptor.
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CAS REGISTRY NUMBER
COMMENTARY
9029-03-2
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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
dihydroorotate + 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone
orotate + reduced 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone
-
-
-
?
dihydroorotate + 2,6-dichloroindophenol
orotate + reduced 2,6-dichloroindophenol
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-
-
?
dihydroorotate + 2,6-dichlorophenolindophenol
orotate + ?
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-
-
-
?
dihydroorotate + 2,6-dichlorophenolindophenol
orotate + reduced 2,6-dichlorophenolindophenol
dihydroorotate + fumarate
orotate + succinate
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prefers fumarate over ubiquinone-1
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-
?
L-dihydroorotate + 2,6-dichlorophenolindophenol
orotate + reduced 2,6-dichlorophenolindophenol
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-
-
-
?
L-dihydroorotate + mesaconate
orotate + 2-methylbutanedioate
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-
-
-
?
S-dihydroorotate + 2,6-dichlorophenolindophenol
orotate + reduced 2,6-dichlorophenolindophenol
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-
-
-
?
S-dihydroorotate + menadione
orotate + menadiol
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20% activity with menadione compared to fumarate
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-
?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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fumarate and ferricyanide tested as electron acceptors
-
?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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fumarate and ferricyanide tested as electron acceptors
-
?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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2,6-dichlorophenolindophenol, potassium hexacyanoferrate(III) and molecular oxygen used as electron acceptors
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?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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fourth step in synthesis of pyrimidine nucleotides
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?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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fourth step in UMP-biosynthesis
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?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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preferred electron acceptors in the decreasing order: ferricyanide, 2,6-dichlorophenolindophenol, ubiquinone-0, fumarate and O2
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?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
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fourth step in synthesis of pyrimidine nucleotides
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?
(S)-dihydroorotate + ferricyanide
orotate + ferrocyanide
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-
-
?
(S)-dihydroorotate + ferricyanide
orotate + ferrocyanide
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ferricyanide usually used as electon acceptor in the assay
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?
(S)-dihydroorotate + fumarate
orotate + succinate
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enzyme is responsible for biosynthesis of succinate and orotate
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-
?
(S)-dihydroorotate + O2
orotate + H2O2
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ferricyanide, 2,6-dichlorophenolindophenol, cytochrome c and quinones as alternate electron acceptor, with ferricyanide 12 times faster rate of catalysis than with air alone
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?
(S)-dihydroorotate + O2
orotate + H2O2
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different dihydroorotate isotopes tested for mechanistic and stereochemical analysis
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?
(S)-dihydroorotate + O2
orotate + H2O2
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ferricyanide, cytochrome c and 2,6-dichlorophenolindolphenol as alternate electron acceptor
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?
(S)-dihydroorotate + O2
orotate + H2O2
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redox dyes, 2,6-dichlorophenolindophenol, ferricyanide are most active electron acceptors, oxygen and cytochrome c are much slower
-
?
(S)-dihydroorotate + O2
orotate + H2O2
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pathway of pyrimidine biosynthesis, constitutive biosynthetic enzyme
-
?
(S)-dihydroorotate + O2
orotate + H2O2
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pathway of pyrimidine biosynthesis, constitutive biosynthetic enzyme
-
?
(S)-dihydroorotate + O2
orotate + H2O2
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ferricyanide as alternate electron acceptor, enzyme produced regardless of the carbon source
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?
(S)-dihydroorotate + O2
orotate + H2O2
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ferricyanide, 2,6-dichlorophenolindophenol, cytochrome c and quinones as alternate electron acceptor, with ferricyanide 12 times faster rate of catalysis than with air alone
-
?
(S)-dihydroorotate + O2
orotate + H2O2
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ferricyanide, 2,6-dichlorophenolindophenol, cytochrome c and quinones as alternate electron acceptor, with ferricyanide 12 times faster rate of catalysis than with air alone
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?
dihydroorotate + 2,6-dichlorophenolindophenol
orotate + reduced 2,6-dichlorophenolindophenol
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?
dihydroorotate + 2,6-dichlorophenolindophenol
orotate + reduced 2,6-dichlorophenolindophenol
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-
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor: 2,6-dichlorophenolindophenol
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-
?
dihydroorotate + acceptor
orotate + reduced acceptor
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not acceptors: NAD+, NADP+, coenzymes Q6, Q10, K2
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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discussion of substrate binding and catalytic mechanism
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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no substrate: dihydrouracil
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-
?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptors: potassium hexacyanoferrate(III), to a lower extent molecular oxygen
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-
?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor: 2,6-dichlorophenolindophenol
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-
?
dihydroorotate + acceptor
orotate + reduced acceptor
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kinetic isotope effects
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-
?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor: ferricyanide, coenzyme Q0, fumarate, molecular oxygen
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?
dihydroorotate + fumarate
orotate + reduced fumarate
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-
-
?
dihydrooxonate + acceptor
oxonate + reduced acceptor
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fumarate and ferricyanide tested as electron acceptors
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?
dihydrooxonate + acceptor
oxonate + reduced acceptor
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fumarate and ferricyanide tested as electron acceptors
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?
L-dihydroorotate + fumarate
orotate + succinate
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fumarate is the most effective electron acceptor
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-
?
L-dihydroorotate + fumarate
orotate + succinate
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DHODH catalyzes a coupled redox reaction in which dihydroorotate is oxidized to orotate and fumarate is reduced to succinate
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-
?
additional information
?
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three-dimensional active site structure, profile of interactions for molecular recognition, interaction of DHODH with orotate via residues Asn212, Asn284, Ser215, Phe149, Lys100, Gly148, Asn217, Asn145, and Thr285, overview
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-
?
additional information
?
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no acceptor: fumarate, NAD+, coenzymes ubiquinone-6, ubiquinone-10
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?
additional information
?
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maleate, glutaconate, cis-aconitate, trans-aconitate, and cinnamate do not function as electron acceptor
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?
additional information
?
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does not perform electron transfer to menaquinone, Q0, Q1, Q2, QD, O2, or to NAD+
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?
additional information
?
-
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enzyme has methylviologen-fumarate reductase activity
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-
?
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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
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
-
fourth step in synthesis of pyrimidine nucleotides
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?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
-
fourth step in UMP-biosynthesis
-
?
(S)-dihydroorotate + acceptor
orotate + reduced acceptor
-
fourth step in synthesis of pyrimidine nucleotides
-
?
(S)-dihydroorotate + fumarate
orotate + succinate
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enzyme is responsible for biosynthesis of succinate and orotate
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-
?
(S)-dihydroorotate + O2
orotate + H2O2
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pathway of pyrimidine biosynthesis, constitutive biosynthetic enzyme
-
?
(S)-dihydroorotate + O2
orotate + H2O2
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pathway of pyrimidine biosynthesis, constitutive biosynthetic enzyme
-
?
L-dihydroorotate + fumarate
orotate + succinate
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DHODH catalyzes a coupled redox reaction in which dihydroorotate is oxidized to orotate and fumarate is reduced to succinate
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
FMN
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flavoprotein, each mol of native dimer contains 1 mol of tightly bound FMN
FMN
-
flavoprotein, enzyme contains 1 FMN as prosthetic group
additional information
-
no FAD as prosthetic group
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additional information
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no cofactor: NAD+, coenzymes ubiquinone-6, ubiquinone-10
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additional information
-
oxidized 2,6-dichlorophenol-indophenol, ferricyanide, or 1-ubiquinone can act as artificial electron acceptors
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
(NH4)2SO4
-
enhances enzymatic activity up to a concentration of 0.0014 mM
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-(1-naphthyl)-3-[2-(trifluoromethyl)phenyl]urea
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50% inhibition at 0.0004 mM, wild type, 0.00034 mM, mutant R265A, above 0.2, mutant H185A
1-(2-methoxyphenyl)-3-(1-naphthyl)urea
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50% inhibition at 0.00023 mM, wild type, 0.00024 mM, mutant R265A, 0.140, mutant H185A
1-(4-Chloro-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-(4-methyl-benzylamide) 5-phenylamide
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minimum inhibitory concentration 0.032 mg/ml
1-(4-Chloro-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-benzylamide 5-(isobutyl-amide)
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minimum inhibitory concentration above 0.064 mg/ml
1-(4-Chloro-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-benzylamide 5-[(4-carbamoyl-phenyl)-amide]
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minimum inhibitory concentration 0.008 mg/ml
1-(4-Chloro-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 5-phenylamide 3-[(pyridin-3-ylmethyl)-amide]
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minimum inhibitory concentration 0.00025 mg/ml
1-(4-Chloro-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 5-[(4-piperidin-1-yl-phenyl)-amide] 3-[(pyridin-3-ylmethyl)-amide]
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minimum inhibitory concentration 0.002 mg/ml
1-(4-chlorophenyl)-3-quinolin-8-ylurea
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50% inhibition at 0.00078 mM, wild type, 0.002 mM, mutant R265A, above 0.4, mutant H185A
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-(isobutyl-amide) 5-[[4-(pyrrolidine-1-carbonyl)-phenyl]-amide]
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minimum inhibitory concentration 0.064 mg/ml
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-benzhydryl-amide 5-benzylamide
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minimum inhibitory concentration above 0.032 mg/ml
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 3-benzylamide 5-[[4-(pyrrolidine-1-carbonyl)-phenyl]-amide]
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minimum inhibitory concentration 0.003 mg/ml
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 5-benzylamide 3-[[4-(pyrrolidine-1-carbonyl)-phenyl]-amide]
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minimum inhibitory concentration above 0.032 mg/ml
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 5-phenylamide 3-[(pyridin-3-ylmethyl)-amide]
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minimum inhibitory concentration 0.0005 mg/ml
1-(4-Methoxy-phenyl)-1H-pyrazole-3,5-dicarboxylic acid 5-[[4-(pyrrolidine-1-carbonyl)-phenyl]-amide] 3-[(tetrahydro-furan-2-yl)-amide]
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minimum inhibitory concentration above 0.032 mg/ml
2-methyl-3-nitro-N-[3-(trifluoromethyl)phenyl]benzamide
-
50% inhibition at 0.00008 mM, wild type, 0.00037 mM, mutant R265A, 0.120, mutant H185A
2-methyl-N-1-naphthyl-3-nitrobenzamide
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50% inhibition at 0.00008 mM, wild type, 0.00048 mM, mutant R265A, 0.180, mutant H185A
5-[(dimethylamino)methyl]-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid
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Barbiturate
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dead-end inhibitor, competitive with respect to (S)-dihydroorotate
leflunomide
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cell line A20R resistant to leflunomide shows enhanced expression of enzyme to bypass the inhibitory effect, following long-time exposure, enzyme gene amplification can be assumed
Mercuric chloride
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40% inhibition after 15 min at 0.000045 mM
methanol extract of brown algae Fucus evanescens
-
59% inhibition, noncompetitive
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methanol extract of brown algae Pelvetia babingtonii
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58% inhibition, noncompetitive
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N-(2,4-dichlorophenyl)-2-naphthamide
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50% inhibition at 0.00005 mM, wild type, 0.00008 mM, mutant R265A, above 0.05, mutant H185A
N-(2-fluorophenyl)naphthalene-2-carboxamide
-
50% inhibition at 0.00047 mM, wild type, 0.00030 mM, mutant R265A, 0.21, mutant H185A
N-(3,4-dichlorophenyl)-2-methyl-3-nitrobenzamide
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50% inhibition at 0.00008 mM, wild type, 0.0028 mM, mutant R265A, 0.06, mutant H185A
N-(3,4-difluorophenyl)-2-methyl-3-nitrobenzamide
-
50% inhibition at 0.00026 mM, wild type, 0.00082 mM, mutant R265A, 0.25, mutant H185A
N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide
-
50% inhibition at 0.00002 mM, wild type, 0.0004 mM, mutant R265A, 0.13, mutant H185A
N-(3-bromophenyl)-2-methyl-3-nitrobenzamide
-
50% inhibition at 0.00006 mM, wild type, 0.0012 mM, mutant R265A, 0.140, mutant H185A
N-(3-chloro-4-fluorophenyl)-2-methyl-3-nitrobenzamide
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50% inhibition at 0.0001 mM, wild type, 0.0005 mM, mutant R265A, 0.13, mutant H185A
N-(4-bromo-2-methylphenyl)-2-naphthamide
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50% inhibition at 0.00005 mM, wild type, 0.00005 mM, mutant R265A, 0.57, mutant H185A
N3-benzyl-1-(4-chlorophenyl)-N5-phenyl-1H-pyrazole-3,5-dicarboxamide
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minimum inhibitory concentration 0.000125 mg/ml
p-hydroxymercuribenzoate
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98% inhibition after 5 min at 0.00227 mM
Tiron
-
inhibits cytochrome c reduction and sulfite autoxidation
Orotate
-
competitive to dihydroorotate in ferricyanide reduction assay
Orotate
competitively inhibits all three DHOD enzymes to a comparable level
additional information
-
markable sensitivity to sulfhydryl inhibitors
-
additional information
-
visible light is inactivating
-
additional information
brequinar and DPC-AE661100 have no effect, even at a concentration of 1 mM
-
additional information
-
brequinar and DPC-AE661100 have no effect, even at a concentration of 1 mM
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-mercaptoethanol
-
0.175 mM restores inhibited enzyme after 3 min incubation to 90% of full activity