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Information on EC 3.5.2.3 - dihydroorotase and Organism(s) Homo sapiens
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3.5.2.3 dihydroorotaseSpecify your search results
Word Map
- 3.5.2.3
- pyrimidine
-
transcarbamoylase
- carbamoyl-phosphate
- phosphoribosyltransferase
- atcase
- orotidine
-
carbamoyltransferase
-
glutamine-dependent
- l-dihydroorotate
-
2.1.3.2
- cpsase
-
pyre
- dihydropyrimidinase
- hydantoinase
- dihydro-ouabain
- n-phosphonacetyl-l-aspartate
-
n-carbamyl-l-aspartate
- allantoinase
- imidase
- synthesis
-
succinate-grown
-
amidohydrolases
-
6.3.5.5
- drug development
- medicine
- 5-fluoroorotate
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
dihydroorotase, dho, dhoase, dihydroorotase domain, hudhoase, type i dhoase, human dhoase domain, type ii dho, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
carbamoylaspartic dehydrase
-
-
-
-
DHOase
dihydroorotate dehydrolase
-
-
-
-
DHOase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
formation of cyclic amides
-
-
-
-
hydrolysis of cyclic amides
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
(S)-dihydroorotate amidohydrolase
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CAS REGISTRY NUMBER
COMMENTARY
9024-93-5
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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
additional information
?
-
the DHOase reaction is reversible and pH-dependent
-
-
-
additional information
?
-
-
the DHOase reaction is reversible and pH-dependent
-
-
-
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
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
Zn2+
mono-zinc metalloenzyme, the active site of the huDHOase K1556A mutant contains one metal ion. Posttranslational carbamylated Lys is not required for Znalpha binding in huDHOase
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
desferrioxamine
-
hypoxia causes a decrease in carbamoyl phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase expression incubated under desferrioxamine-induced HIF-1alpha accumulation detected in A293T, IMR32, colo320DM and HeLa cell lines
additional information
-
hypoxia causes a decrease in carbamoyl phosphate synthetase-aspartate carbamoyltransferase-dihydroorotase expression detected in A293T, IMR32, HeLa cell lines and human endometiral stromal cells
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
a huDHOase chimera bearing the Escherichia coli DHOase flexible loop is inactive, suggesting the presence of distinctive elements in the flexible loop of huDHOase that cannot be replaced by the bacterial sequence. Substitutions of Phe1563 with Ala, Leu, or Thr prevent the closure of the flexible loop and inactivated the protein, whereas substitution with Tyr enhances the interactions of the loop in the closed position and reduced fluctuations and the reaction rate
metabolism
the dihydroorotase (DHOase) domain of the multifunctional protein carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) catalyzes the third step in the de novo biosynthesis of pyrimidine nucleotides in animals
additional information
evolution
despite evolutionary divergence, the CAD DHOase active site components are highly conserved with those in bacterial DHOases, encoded as monofunctional enzymes. An important element for catalysis, conserved from Escherichia coli to humans, is a flexible loop that closes as a lid over the active site. The flexible loop exhibits a two-amino acid signature that is characteristic for each DHOase type
evolution
dihydroorotase (DHOase) is a member of the cyclic amidohydrolase family, which also includes allantoinase, hydantoinase, dihydropyrimidinase (DHPase), and imidase. Almost all of these zinc metalloenzymes possess a binuclear metal center in which two metal ions are bridged by a post-translational carbamylated Lys
additional information
analysis of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD, molecular dynamics simulations, overview. Residue Phe1563, a residue absolutely conserved at the tip of the flexible loop in CAD's DHOase domain, is a critical element for the conformational equilibrium between the two catalytic states of the protein. Key role of Phe-1563 in configuring the active site and in promoting substrate strain and catalysis. The flexible loop reaches in toward the active site with N-carbamoyl-L-aspartate bound and is proposed to aid in catalysis by orienting and increasing the electrophilicity of the substrate, excluding water molecules, and stabilizing the transition-state. Then, upon the formation of DHO, the loop moves away from the active site, facilitating product release. As an exception, bacterial type I DHOases present a rigid and shorter loop that interacts minimally with the substrate, requiring the intimate association with ATCase to complete the active site and attain full activity
additional information
-
analysis of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD, molecular dynamics simulations, overview. Residue Phe1563, a residue absolutely conserved at the tip of the flexible loop in CAD's DHOase domain, is a critical element for the conformational equilibrium between the two catalytic states of the protein. Key role of Phe-1563 in configuring the active site and in promoting substrate strain and catalysis. The flexible loop reaches in toward the active site with N-carbamoyl-L-aspartate bound and is proposed to aid in catalysis by orienting and increasing the electrophilicity of the substrate, excluding water molecules, and stabilizing the transition-state. Then, upon the formation of DHO, the loop moves away from the active site, facilitating product release. As an exception, bacterial type I DHOases present a rigid and shorter loop that interacts minimally with the substrate, requiring the intimate association with ATCase to complete the active site and attain full activity
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). PYR1_HUMAN
2225
0
242984
Swiss-Prot
other Location (Reliability: 2)
Q53SY7_HUMAN
2151
0
235178
TrEMBL
other Location (Reliability: 5)
F8VPD4_HUMAN
2162
0
236023
TrEMBL
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
replacement of the flexible loop weakens the dimerization of huDHOase
additional information
-
replacement of the flexible loop weakens the dimerization of huDHOase
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
human DHOase domain K1556A mutant, hanging drop vapor diffusion method, mixing of 20 mg/ml protein in 20 mM HEPES and 100 mM NaCl, pH 7.0, with reservoir solution containing 2 M sodium chloride, 100 mM MES, 200 mM sodium acetate, pH 6.5, at room temperature, X-ray diffraction structure determination and analysis at 2.77 A resolution
several F1563 mutant variants of huDHOase bound to dihydroorotate, X-ray diffraction structure determination and analysis at 1.46-2.12 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
F1563A
site-directed mutagenesis, the mutation prevents the closure of the flexible loop and inactivates the enzyme
F1563L
site-directed mutagenesis, the mutation prevents the closure of the flexible loop and inactivates the enzyme
F1563T
site-directed mutagenesis, the mutation prevents the closure of the flexible loop and inactivates the enzyme
F1563Y
site-directed mutagenesis, the mutation prevents enhances the interactions of the flexible loop in the closed position and reduces fluctuations and the reaction rate
K1556A
site-directed mutagenesis, the mutant shows no lysine carbamylation within the active site
additional information
additional information
construction of a huDHOase chimera bearing the Escherichia coli DHOase flexible loop, the mutant is inactive
additional information
-
construction of a huDHOase chimera bearing the Escherichia coli DHOase flexible loop, the mutant is inactive
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant mutant His-tagged enzyme by nickel affinity chromatography and dialysis
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Lee, M.; Chan, C.W.; Mitchell Guss, J.; Christopherson, R.I.; Maher, M.J.
Dihydroorotase from Escherichia coli: loop movement and cooperativity between subunits
J. Mol. Biol.
348
523-533
2005
Arabidopsis thaliana (O04904), Escherichia coli (P05020), Escherichia coli, Mesocricetus auratus (P08955), Saccharomyces cerevisiae (P20051), Homo sapiens (P27708), Helicobacter pylori (P56465), Plasmodium falciparum (Q8IKA9)
Robles Lopez, S.M.; Hortua Triana, M.A.; Zimmermann, B.H.
Cloning and preliminary characterization of the dihydroorotase from Toxoplasma gondii
Mol. Biochem. Parasitol.
148
93-98
2006
Saccharomyces cerevisiae, Mycobacterium leprae, Plasmodium berghei (A0A509AX79), Arabidopsis thaliana (O04904), Trypanosoma cruzi (O76138), Escherichia coli (P05020), Mesocricetus auratus (P08955), Homo sapiens (P27708), Ustilago maydis (P31301), Toxoplasma gondii (Q8MXA5), Toxoplasma gondii
Chen, K.F.; Lai, Y.Y.; Sun, H.S.; Tsai, S.J.
Transcriptional repression of human cad gene by hypoxia inducible factor-1alpha
Nucleic Acids Res.
33
5190-5198
2005
Homo sapiens
Cheng, J.H.; Huang, Y.H.; Lin, J.J.; Huang, C.Y.
Crystal structures of monometallic dihydropyrimidinase and the human dihydroorotase domain K1556A mutant reveal no lysine carbamylation within the active site
Biochem. Biophys. Res. Commun.
505
439-444
2018
Homo sapiens (P27708), Homo sapiens
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