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EC Tree
IUBMB Comments This Class 2 dihydroorotate dehydrogenase enzyme contains FMN . The enzyme is found in eukaryotes in the mitochondrial membrane, in cyanobacteria, and in some Gram-negative and Gram-positive bacteria associated with the cytoplasmic membrane [2,5,6]. The reaction is the only redox reaction in the de-novo biosynthesis of pyrimidine nucleotides [2,4]. The best quinone electron acceptors for the enzyme from bovine liver are ubiquinone-6 and ubiquinone-7, although simple quinones, such as benzoquinone, can also act as acceptor at lower rates . Methyl-, ethyl-, tert-butyl and benzyl (S)-dihydroorotates are also substrates, but methyl esters of (S)-1-methyl and (S)-3-methyl and (S)-1,3-dimethyldihydroorotates are not . Class 1 dihydroorotate dehydrogenases use either fumarate (EC 1.3.98.1), NAD+ (EC 1.3.1.14) or NADP+ (EC 1.3.1.15) as electron acceptor.
The taxonomic range for the selected organisms is: Rattus norvegicus The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
dihydroorotate dehydrogenase, pfdhodh, hdhodh, dho-dh, hsdhodh, dihydroorotate dehydrogenase (quinone),
more
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(S)-dihydroorotate + a quinone = orotate + a quinol
in liver, myocardium and skeletal muscle tissues the activity intensities vary from animal to animal, but are similar in ileum, colon and kidney cortex. Cardiac enzyme expresses a pronounced oxidase activity
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(S)-dihydroorotate:quinone oxidoreductase
This Class 2 dihydroorotate dehydrogenase enzyme contains FMN [4]. The enzyme is found in eukaryotes in the mitochondrial membrane, in cyanobacteria, and in some Gram-negative and Gram-positive bacteria associated with the cytoplasmic membrane [2,5,6]. The reaction is the only redox reaction in the de-novo biosynthesis of pyrimidine nucleotides [2,4]. The best quinone electron acceptors for the enzyme from bovine liver are ubiquinone-6 and ubiquinone-7, although simple quinones, such as benzoquinone, can also act as acceptor at lower rates [2]. Methyl-, ethyl-, tert-butyl and benzyl (S)-dihydroorotates are also substrates, but methyl esters of (S)-1-methyl and (S)-3-methyl and (S)-1,3-dimethyldihydroorotates are not [2]. Class 1 dihydroorotate dehydrogenases use either fumarate (EC 1.3.98.1), NAD+ (EC 1.3.1.14) or NADP+ (EC 1.3.1.15) as electron acceptor.
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(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
dihydroorotate + acceptor
orotate + reduced acceptor
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?
(S)-dihydroorotate + decylubiquinone
orotate + decylubiquinol
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-
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r
(S)-dihydroorotate + ubiquinone
orotate + reduced ubiquinone
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
dihydroorotate + acceptor
orotate + reduced acceptor
L-dihydroorotate + 2,6-dihydrophenolindophenol
orotate + reduced 2,6-dihydrophenolindophenol
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r
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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-
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
fourth enzyme in pyrimidine synthesis
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ir
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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fourth enzyme in pyrimidine synthesis
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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six-step biosynthesis of pyrimidine uridine monophosphate
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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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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acceptors: e.g. phenazine methosulfate
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dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor (low activity): 1,4-naphthoquinone, 5,8-hydroxy-naphthoquinone, juglon, plumbagin, polyporic acid
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor: ubiquinone
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?
dihydroorotate + acceptor
orotate + reduced acceptor
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acceptor: oxygen, slowly
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dihydroorotate + acceptor
orotate + reduced acceptor
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fourth step in pyrimidine biosynthesis
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?
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(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
fourth enzyme in pyrimidine synthesis
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ir
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
dihydroorotate + acceptor
orotate + reduced acceptor
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fourth step in pyrimidine biosynthesis
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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fourth enzyme in pyrimidine synthesis
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?
(S)-dihydroorotate + ubiquinone
orotate + ubiquinol
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six-step biosynthesis of pyrimidine uridine monophosphate
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?
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FMN
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0.8-1.1 mol/mol
FMN
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does not contain FMN
additional information
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flavoenzyme, 0.6-1.2 mol flavin per mol protein
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additional information
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enzyme does not contain FAD, FMN, covalently bound flavin or ubiquinone
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brequinar sodium
complete activity termination in all tissues at 0.01 mM
toltrazuril
50% inhibition at 0.1 mM
dichloroallyl-lawsone
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competitive to quinone
MNA 279
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malononitrilamide, 50% inhibition at 22-715 nM
MNA 715
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malononitrilamide, 50% inhibition at 41-109 nM
redoxal
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50% inhibition at 45-88 nM
Thenoyltrifluoroacetone
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-
A77 1726
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-
A77 1726
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malononitrilamide, 50% inhibition at 18-773 nM
atovaquone
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competitive to quinone
atovaquone
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50% inhibition at 0.000698 mM, wild-type enzyme, 0.000904 mM, DELTA1-29 mutant
brequinar
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brequinar
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50% inhibition at 0.000367 mM, wild-type enzyme, 0.000127 mM, DELTA1-29 mutant
brequinar sodium
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brequinar sodium
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50% inhibition at 6-127 nM
additional information
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kinetics of inhibition
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additional information
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not: bathophenathroline, sulfonate, ethylendiaminetetraacetate, cyanide, azide
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0.0058
2,6-dihydrophenolindophenol
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-
0.0095
decyclubiquinone
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recombinant enzyme
0.0065 - 0.0095
decylubiquinone
0.015
dihydroorotate
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recombinant enzyme
0.011 - 0.0146
S-dihydroorotate
0.0065
decylubiquinone
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expressed in SF21 insect cells
0.0095
decylubiquinone
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expressed in Escherichia coli
0.011
S-dihydroorotate
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0.0135
S-dihydroorotate
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expressed in SF21 insect cells
0.0146
S-dihydroorotate
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expressed in Escherichia coli
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0.00001
dichloro-allyllawsone
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-
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130
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expressed in SF21 insect cells
83
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expressed in Escherichia coli
additional information
highest activities in ileum and colon
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7.1
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dihydroorotate + 2,6-dichlorophenolindophenol
8 - 8.1
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8 - 8.1
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recombinant enzymes with His-tags
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Uniprot
brenda
Wistar rats, both sexes, 6 month
Uniprot
brenda
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brenda
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brenda
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brenda
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brenda
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brenda
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brenda
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regiospecific distribution of DHODH, immunohistochemic analysis, overview
brenda
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high enzyme level
brenda
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high level both of expression and activity
brenda
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brenda
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high level both of expression and activity
brenda
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brenda
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high level both of expression and activity
brenda
additional information
distribution in various tissues
brenda
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brenda
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presence of enzymatically active DHODH in many regions of the central nervous system, albeit at different intensities. High levels of both DHODH activity and immunoreactivity are observed in the neocortex, hippocampus, spinal cord and choroid plexus. Lower levels are seen in the cerebellum, and only marginal expression in brain stem
brenda
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very low enzyme level
brenda
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very low level both of expression and activity
brenda
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low enzyme level
brenda
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low level both of expression and activity
brenda
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high enzyme level
brenda
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high level both of expression and activity
brenda
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brenda
inner membrane
brenda
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brenda
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inner membrane
brenda
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metabolism
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DHODH is the fourth enzyme in the biosynthesis of pyrimidines
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PYRD_RAT
395
1
42663
Swiss-Prot
Secretory Pathway (Reliability: 4 )
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45000
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x * 45100, SDS-PAGE, recombinant from SF21 insect cells, x * 45000, SDS-PAGE, recombinant from Escherichia coli
45100
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x * 45100, SDS-PAGE, recombinant from SF21 insect cells, x * 45000, SDS-PAGE, recombinant from Escherichia coli
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monomer
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folds into small N-terminal domain and an (alphabeta)8 barrel comprising the C-terminal domain, crystallization data
?
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?
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x * 45100, SDS-PAGE, recombinant from SF21 insect cells, x * 45000, SDS-PAGE, recombinant from Escherichia coli
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mutant DELTA1-29 in complex with brequinar and with atovaquone
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DELTA1-29
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deletion of N-terminal 29 amino acids
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-80°C, slight activity loss after freezing and storage
great inactivation by repeated thawing and freezing
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Ni2+/nitrilotriacetate column
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expressed in Escherichia coli XL-1 Blue, histidine tagged
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expression of complete catalytically active enzyme in SF21 insect cells of Spodoptera frugiperda with baculovirus vector system
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medicine
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medicine
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great interest in inhibitors as potential therapeutic agents for the treatment of diseases involving aberrant cell proliferation
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Ullrich, A.; Knecht, W.; Fries, M.; Loffler, M.
Recombinant expression of N-terminal truncated mutants of the membrane bound mouse, rat and human flavoenzyme dihydroorotate dehydrogenase. A versatile tool to rate inhibitor effects?
Eur. J. Biochem.
268
1861-1868
2001
Homo sapiens, Mus musculus, Rattus norvegicus
brenda
Loeffler, M.; Becker, C.; Wegerle, E.; Schuster, G.
Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria
Histochem. Cell Biol.
105
119-128
1996
Bos taurus, Cavia porcellus, Homo sapiens, Mus musculus, Rattus norvegicus (Q63707), Sus scrofa
brenda
Bader, B.; Knecht, W.; Fries, M.; Loffler, M.
Expression, purification, and characterization of histidine-tagged rat and human flavoenzyme dihydroorotate dehydrogenase
Protein Expr. Purif.
13
414-422
1998
Homo sapiens, Rattus norvegicus
brenda
Forman, H.J.; Kennedy, J.
Mammalian dihydroorotate dehydrogenase: physical and catalytic properties of the primary enzyme
Arch. Biochem. Biophys.
191
23-31
1978
Rattus norvegicus
brenda
Knecht, w.; Altekruse, D.; Rotgeri, A.; Gonski, S.; Loffler, M.
Rat dihydroorotate dehydrogenase: isolation of the recombinant enzyme from mitochondria of insect cells
Protein Expr. Purif.
10
89-99
1997
Rattus norvegicus (Q63707)
brenda
Knecht, W.; Henseling, J.; Loffler, M.
Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid
Chem. Biol. Interact.
124
61-76
2000
Homo sapiens, Rattus norvegicus
brenda
Hansen, M.; Le Nours, J.; Johansson, E.; Antal, T.; Ullrich, A.; Loffler, M.; Larsen, S.
Inhibitor binding in a class 2 dihydroorotate dehydrogenase causes variations in the membrane-associated N-terminal domain
Protein Sci.
13
1031-1042
2004
Rattus norvegicus
brenda
Schaefer, C.h.M.; Schaefer, M.K.; Loefflerr, M.
Region-specific distribution of dihydroorotate dehydrogenase in the rat central nervous system points to pyrimidine de novo synthesis in neurons
Nucleosides Nucleotides Nucleic Acids
29
476-481
2010
Rattus norvegicus
brenda
Hey-Mogensen, M.; Goncalves, R.L.; Orr, A.L.; Brand, M.D.
Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria
Free Radic. Biol. Med.
72
149-155
2014
Rattus norvegicus
brenda