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Information on EC 4.2.1.75 - uroporphyrinogen-III synthase and Organism(s) Homo sapiens
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4.2.1.75 uroporphyrinogen-III synthaseIUBMB Comments
In the presence of EC 2.5.1.61, hydroxymethylbilane synthase, the enzyme forms uroporphyrinogen III from porphobilinogen.
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Word Map
- 4.2.1.75
- porphyria
-
erythropoietic
- heme
-
photosensitivity
-
5-aminolevulinic
- tetrapyrrole
- coproporphyrins
-
delta-aminolevulinic
-
ferrochelatase
-
pbgase
-
mutilate
-
erythrodontia
-
transfusion-dependent
- protoporphyria
-
hypertrichosis
-
urologists
- coproporphyrinogen
-
aymaras
-
amerindian
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
uros, uroporphyrinogen iii synthase, porphobilinogenase, uro-synthase, uroiiis, uroporphyrinogen iii cosynthase, u3s, uro synthase, uroporphyrinogen-iii synthase, uro'gen iii synthase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Hydroxymethylbilane hydrolyase [cyclizing]
-
-
-
-
Isomerase, uroporphyrinogen
-
-
-
-
Porphobilinogenase
-
-
-
-
Synthase, uroporphyrinogen III co-
-
-
-
-
U3S
URO-synthase
UROIIIS
Uroporphyrinogen III co-synthase
-
-
-
-
Uroporphyrinogen III cosynthase
Uroporphyrinogen III synthase
Uroporphyrinogen isomerase
-
-
-
-
Uroporphyrinogen-III cosynthase
-
-
-
-
Uroporphyrinogen-III cosynthetase
-
-
-
-
UROS
URO-synthase
-
-
-
-
UROIIIS
-
-
-
-
Uroporphyrinogen III cosynthase
-
-
-
-
Uroporphyrinogen III synthase
-
-
-
-
UROS
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hydroxymethylbilane = uroporphyrinogen III + H2O
in the presence of hydroxymethylbilane synthase EC 4.3.1.8, enzyme forms uroporphyrinogen III from porphobilinogen, reaction mechanism, does not require acid/base catalysis, active site structure
-
hydroxymethylbilane = uroporphyrinogen III + H2O
in the presence of hydroxymethylbilane synthase EC 4.3.1.8, enzyme forms uroporphyrinogen III from porphobilinogen, reaction mechanism, does not require acid/base catalysis, active site structure
hydroxymethylbilane = uroporphyrinogen III + H2O
reaction mechanism, modelling, overview
hydroxymethylbilane = uroporphyrinogen III + H2O
reaction mechanism, modeling involving Tyr168, overview
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cyclization
elimination
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -
SYSTEMATIC NAME
IUBMB Comments
hydroxymethylbilane hydro-lyase (cyclizing; uroporphyrinogen-III-forming)
In the presence of EC 2.5.1.61, hydroxymethylbilane synthase, the enzyme forms uroporphyrinogen III from porphobilinogen.
CAS REGISTRY NUMBER
COMMENTARY
37340-55-9
-
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
?
-
-
hydroxymethylbilane synthase and uroporphyrinogen III synthase catalyze two consecutive reactions, the third and fourth step, in the heme biosynthetic pathway, generating the first linear and the first cyclic tetrapyrroles, respectively. Hydroxymethylbilane synthase, 2.5.1.61, and uroporphyrinogen III synthase may function independently and sequentially with hydroxymethylbilane as a free intermediate, heme biosynthetic pathway, overview. Hypoxia downregulates UROS mRNA expression in hepatic cells, reduction of UROS mRNA is associated with the accumulation of hypoxia-inducible factor 1alpha under normoxia. Deferoxamine, cobalt chloride, or hypoxia downregulate UROS mRNA expression in hepatic cells, reduction of UROS mRNA is associated with the accumulation of hypoxia-inducible factor 1alpha under normoxia
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
-
intramolecular rearrangement of the d-pyrrole group and ring closure
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
the D-ring of the hydroxymethylbilane substrate binds to the enzyme in a conformation that shields its terminal portion from reacting with ring A and prevents the formation of the biologically useless uroporphyrinogen I, reaction mechanism, overview
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
the enzyme catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane to uroporphyrinogen III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
the enzyme catalyzes the inversion of one of the four heterocyclic rings present in the substrate. Reaction mechanism analysis by high-level quantum mechanical calculations on model systems of the enzyme
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
-
enzymatic conversion of preuroporphyrinogen. The substrate must bind the enzyme in a conformation that prevents C19 from reacting with C20
-
-
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
linear tetrapyrrole, fourth step in the biosynthesis of porphyrin, essential reaction, decreased enzyme activity leads to the autosomal recessive disorder congenital erythropetic porphyria
macrocyclic uroporphyrinogen III is a precurosr for synthesis of diverse compounds, e.g. heme, siroheme, chlorophyll, F430, and vitamin B12
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
-
macrocyclic, role of the enzyme in tetrapyrrole based copound biosynthesis, overview
-
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
-
fourth enzyme in heme biosynthesis. Congenital erythropoietic porphyria is a very rare disease that is inherited as an autosomal recessive trait and results from a profound deficiency of uroporphyrinogen III cosynthase, the fourth enzyme in heme biosynthesis. The degree of severity of clinical symptoms mainly depends on the amount of residual uroporphyrinogen III cosynthase activity
-
-
?
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
additional information
?
-
-
hydroxymethylbilane synthase and uroporphyrinogen III synthase catalyze two consecutive reactions, the third and fourth step, in the heme biosynthetic pathway, generating the first linear and the first cyclic tetrapyrroles, respectively. Hydroxymethylbilane synthase, 2.5.1.61, and uroporphyrinogen III synthase may function independently and sequentially with hydroxymethylbilane as a free intermediate, heme biosynthetic pathway, overview. Hypoxia downregulates UROS mRNA expression in hepatic cells, reduction of UROS mRNA is associated with the accumulation of hypoxia-inducible factor 1alpha under normoxia. Deferoxamine, cobalt chloride, or hypoxia downregulate UROS mRNA expression in hepatic cells, reduction of UROS mRNA is associated with the accumulation of hypoxia-inducible factor 1alpha under normoxia
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
-
intramolecular rearrangement of the d-pyrrole group and ring closure
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
the D-ring of the hydroxymethylbilane substrate binds to the enzyme in a conformation that shields its terminal portion from reacting with ring A and prevents the formation of the biologically useless uroporphyrinogen I, reaction mechanism, overview
-
-
?
hydroxymethylbilane
uroporphyrinogen III + H2O
the enzyme catalyzes the cyclization and D-ring isomerization of hydroxymethylbilane to uroporphyrinogen III, the cyclic tetrapyrrole and physiologic precursor of heme, chlorophyl, and corrin
-
-
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
linear tetrapyrrole, fourth step in the biosynthesis of porphyrin, essential reaction, decreased enzyme activity leads to the autosomal recessive disorder congenital erythropetic porphyria
macrocyclic uroporphyrinogen III is a precurosr for synthesis of diverse compounds, e.g. heme, siroheme, chlorophyll, F430, and vitamin B12
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
-
macrocyclic, role of the enzyme in tetrapyrrole based copound biosynthesis, overview
-
?
hydroxymethylbilane
uroporphyrinogen-III + H2O
-
fourth enzyme in heme biosynthesis. Congenital erythropoietic porphyria is a very rare disease that is inherited as an autosomal recessive trait and results from a profound deficiency of uroporphyrinogen III cosynthase, the fourth enzyme in heme biosynthesis. The degree of severity of clinical symptoms mainly depends on the amount of residual uroporphyrinogen III cosynthase activity
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00015
Hydroxymethylbilane
-
pH not specified in the publication, temperature not specified in the publication
0.05
Hydroxymethylbilane
mutant enzyme C73R/A69E, pH and temperature not specified in the publication
0.06
Hydroxymethylbilane
wild type enzyme, pH and temperature not specified in the publication
0.07
Hydroxymethylbilane
mutant enzyme C73R/L43D, pH and temperature not specified in the publication
10
Hydroxymethylbilane
Km above 10 mM, mutant enzyme C73R, pH and temperature not specified in the publication
additional information
additional information
enzyme kinetics in relation to enzyme stability of wild-type and mutant enzymes, wild-type UROIIIS Is a kinetically stable protein, overview
-
additional information
additional information
-
enzyme kinetics in relation to enzyme stability of wild-type and mutant enzymes, wild-type UROIIIS Is a kinetically stable protein, overview
-
additional information
additional information
-
kinetic and thermodynamic analysis, thermodynamic versus kinetic stability, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
10
Hydroxymethylbilane
Km above 10 mM, mutant enzyme C73R, pH and temperature not specified in the publication
170
Hydroxymethylbilane
mutant enzyme C73R/A69E, pH and temperature not specified in the publication
890
Hydroxymethylbilane
wild type enzyme, pH and temperature not specified in the publication
1200
Hydroxymethylbilane
mutant enzyme C73R/L43D, pH and temperature not specified in the publication
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1
Hydroxymethylbilane
kcat/Km less than 1 1/sec*mM, mutant enzyme C73R, pH and temperature not specified in the publication
3700
Hydroxymethylbilane
mutant enzyme C73R/A69E, pH and temperature not specified in the publication
15000
Hydroxymethylbilane
wild type enzyme, pH and temperature not specified in the publication
16000
Hydroxymethylbilane
mutant enzyme C73R/L43D, pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
33.37
-
pH not specified in the publication, temperature not specified in the publication
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
8.2
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37 - 52
the isothermal unfolding rate is determined in the range of 37°C-52°C
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
evolution of the segment swapped topology facilitates the evolution of enzyme function for this protein by influencing its dynamic properties
malfunction
physiological function
malfunction
-
congenital erythropoietic porphyria is a rare autosomal disease ultimately related to deleterious mutations in uroporphyrinogen III synthase. In absence or dysfunction of the enzyme, hydroxymethylbilane spontaneously degrades to the by-product uroporphyrinogen I, which cannot lead to the heme group and accumulates in the body, producing some of the symptoms observed in congenital erythropoietic porphyria patients, phenotype, structural and molecular basis, overview
malfunction
congenital erythropoietic porphyria is the rarest autosomal recessive porphyria resulting from a deficiency of uroporphyrinogen III cosynthase
malfunction
congenital erythropoietic porphyria results from a deficiency in uroporphyrinogen III synthase enzyme activity
malfunction
deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria. The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission
physiological function
-
UROIIIS catalyzes the cyclization of the linear tetrapyrrole hydroxymethylbilane to produce uroporphyrin III. A Cys in position 73 is not essential for the catalytic activity of the enzyme but its mutation to Arg speeds up the process of irreversible unfolding and aggregation
physiological function
-
UROIIIS is the fourth enzyme of the biosynthetic route of the heme group and catalyzes the cyclization of the linear tetrapyrrol hydroxymethylbilane, inverting the configuration in one of the aromatic rings. It accelerates the production of uroporphyrinogen III (an energetically unfavorable chemical reaction) at the same time as it suppresses the spontaneous reaction pathway to yield uroporphyrinogen I
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). HEM4_HUMAN
265
0
28628
Swiss-Prot
other Location (Reliability: 3)
A0A087X021_HUMAN
122
0
13498
TrEMBL
other Location (Reliability: 2)
A0A3B3IS76_HUMAN
151
0
16598
TrEMBL
other Location (Reliability: 1)
Q5T3L8_HUMAN
139
0
15369
TrEMBL
other Location (Reliability: 3)
A0A3B3ISL9_HUMAN
160
0
17699
TrEMBL
other Location (Reliability: 3)
A0A087WUV7_HUMAN
110
0
12009
TrEMBL
other Location (Reliability: 1)
A0A0S2Z5C5_HUMAN
238
0
25707
TrEMBL
other Location (Reliability: 3)
A0A3B3ISX6_HUMAN
137
0
15081
TrEMBL
Secretory Pathway (Reliability: 3)
A0A0S2Z4T8_HUMAN
265
0
28628
TrEMBL
other Location (Reliability: 3)
A0A3B3IUC8_HUMAN
111
0
12301
TrEMBL
other Location (Reliability: 1)
Q5T3L9_HUMAN
185
0
20288
TrEMBL
other Location (Reliability: 1)
Q5T3L7_HUMAN
133
0
14695
TrEMBL
other Location (Reliability: 3)
A0A3B3ISM6_HUMAN
292
0
31662
TrEMBL
other Location (Reliability: 3)
A0A3B3ITJ2_HUMAN
265
0
28742
TrEMBL
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
28000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
observed interdomain flexibility might be important for catalysis, the active site is located between the domains
additional information
-
observed interdomain flexibility might be important for catalysis, the active site is located between the domains
additional information
a helical region in the molecule is essential to retain the kinetic stability of the folded conformation
additional information
-
a helical region in the molecule is essential to retain the kinetic stability of the folded conformation
additional information
mapping of the URO-synthase active site by NMR perturbation studies, modelling by by in silico docking, active site structure, overview
additional information
-
mapping of the URO-synthase active site by NMR perturbation studies, modelling by by in silico docking, active site structure, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
UROIIIS is processed via the proteosome pathway, which can be reverted by reversibly inhibiting the proteosome with the aldehyde MG132
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
5 mg/ml purified recombinant wild-type and selenomethionine-enzyme, sitting drop vapour diffusion method, 4°C, equal volumes of protein solution, containing 10 mM Tris-HCl, pH 7.5, 1 mM dithiothreitol, and reservoir solution, containing 20% 2-methyl-2,4-pentanediol, 100 mM MES, pH 6.0, X-ray diffraction structure determination and analysis at 1.85-2.1 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A104V
A66V
A69T
C73A
C73D
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
C73L
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
C73N
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
C73R
C73R/A69E
the mutant shows reduced activity compared to the wild type enzyme
C73R/L43D
the mutant shows slightly increased activity compared to the wild type enzyme
C73S
C73Y
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
E127A
site-directed mutagenesis, unaltered activity level compared to the wild-type enzyme
E81D
G188R
G188W
G225S
G236V
H173Y
I129T
I219S
K220A
site-directed mutagenesis, slightly increased activity compared to the wild-type enzyme
L237P
L4F
P248Q
P53L
Q187P
R65A
site-directed mutagenesis, slightly reduced activity compared to the wild-type enzyme
S197A
site-directed mutagenesis, unaltered activity level compared to the wild-type enzyme
S212P
S47P
S63A
site-directed mutagenesis, unaltered activity level compared to the wild-type enzyme
T103A
site-directed mutagenesis, reduced activity compared to the wild-type enzyme
T227A
site-directed mutagenesis, slightly increased activity compared to the wild-type enzyme
T228A
site-directed mutagenesis, conserved residue near to the active site cleft, reduced activity compared to the wild-type enzyme
T228M
T62A
V3F
V82F
V99A
Y168A
site-directed mutagenesis, reduced activity compared to the wild-type enzyme
Y19C
additional information
A104V
a naturally occuring mutation, 60.6% activity compared to the wild-type enzyme
A104V
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
A66V
a naturally occuring mutation, 95.6% activity compared to the wild-type enzyme
A66V
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
A69T
a naturally occuring mutation, 24.4% activity compared to the wild-type enzyme
A69T
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
C73A
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
C73R
a frequent, naturally occuring mutation of a residue of the stabilizing helical region, 14.5% activity compared to the wild-type enzyme
C73R
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria, the mutant protein retains partial catalytic activity but shows reduced the enzyme stability
C73R
-
a naturally occuring mutation in the enzyme responsible for more than one-third of all of the reported cases of the rare autosomal disease congenital erythropoietic porphyria. The mutant protein retains partial catalytic activity but shows reduced the enzyme stability
C73R
the substitution drastically reduces the enzyme activity (1500fold) and stability compared to the wild type enzyme
C73S
-
computational modeling, structure comparison with the wild-type enzyme and the other C73 mutants
E81D
a naturally occuring mutation, unaltered activity compared to the wild-type enzyme
E81D
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
G188R
a naturally occuring mutation, 41.4% activity compared to the wild-type enzyme
G188R
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
G188W
a naturally occuring mutation, 31.6% activity compared to the wild-type enzyme
G188W
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
G225S
a naturally occuring mutation, 32.4% activity compared to the wild-type enzyme
G225S
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
G236V
a naturally occuring mutation, 34.0% activity compared to the wild-type enzyme
G236V
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
H173Y
a naturally occuring mutation, 72.6% activity compared to the wild-type enzyme
H173Y
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
I129T
a naturally occuring mutation, 20.0% activity compared to the wild-type enzyme
I129T
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
I219S
a naturally occuring mutation, 85.0% activity compared to the wild-type enzyme
I219S
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
L237P
a naturally occuring mutation, 57.9% activity compared to the wild-type enzyme
L237P
the mutation is associated with congenital erythropoietic porphyria
L237P
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
L4F
a naturally occuring mutation, 20.2% activity compared to the wild-type enzyme
L4F
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
P248Q
a naturally occuring mutation, 29.2% activity compared to the wild-type enzyme
P248Q
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
P53L
a naturally occuring mutation, inactive mutant, no purification of the recombinant mutant
P53L
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
Q187P
a naturally occuring mutation, 15.0% activity compared to the wild-type enzyme
Q187P
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
S212P
a naturally occuring mutation, 20.0% activity compared to the wild-type enzyme
S212P
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
S47P
a naturally occuring mutation, unaltered activity compared to the wild-type enzyme
S47P
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
T228M
a naturally occuring mutation, 97.5% activity compared to the wild-type enzyme
T228M
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
T62A
site-directed mutagenesis, conserved residue near to the active site cleft, unaltered activity level compared to the wild-type enzyme
T62A
a naturally occuring mutation, 1.2% activity compared to the wild-type enzyme
T62A
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
V3F
a naturally occuring mutation, 19.3% activity compared to the wild-type enzyme
V3F
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
V82F
a naturally occuring mutation, 93.8% activity compared to the wild-type enzyme
V82F
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
V99A
a naturally occuring mutation, 88.2% activity compared to the wild-type enzyme
V99A
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
Y19C
a naturally occuring mutation, 13.1% activity compared to the wild-type enzyme
Y19C
-
a naturally occuring mutation in the enzyme involved in congenital erythropoietic porphyria
additional information
-
16 known mutations causing congenital erythropoietic porphyria in humans via alterations of the tertiary enzyme structure
additional information
the naturally occuring clinical mutations lead to loss in activity due to structural alterations in the enzymes, overview
additional information
-
the naturally occuring clinical mutations lead to loss in activity due to structural alterations in the enzymes, overview
additional information
-
identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria. Identification of four different mutations: C73R, a hotspot mutation, the promoter mutation 86A, and two missense mutations, designated G236V and L237P, the latter one encounters in the homozygous state in one of the patients
additional information
changes in the unfolding rate, relative to wild type, overview. Cloning, expression, and analysis of 25 missense mutants from congenital erythropoietic porphyria, CEP, patients, genotyping, overview
additional information
-
changes in the unfolding rate, relative to wild type, overview. Cloning, expression, and analysis of 25 missense mutants from congenital erythropoietic porphyria, CEP, patients, genotyping, overview
additional information
-
genotype/phenotype analysis of the studied cases of congenital erythropoietic porphyria, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
about 20% loss of activity after 48 h, about 50% loss of activity after 72 h, buffer containing 1 mM DTT
45
60
additional information
additional information
purified enzyme shows remarkable thermostability, particularly when kept in phosphate buffer containing DTT and EDTA, indicating that the activity may depend on its oxidation state
additional information
-
purified enzyme shows remarkable thermostability, particularly when kept in phosphate buffer containing DTT and EDTA, indicating that the activity may depend on its oxidation state
additional information
UROIIIS is a thermolabile enzyme undergoing irreversible denaturation, unfolding kinetics of wild-type UROIIIS and mutants, circular dichroism, overview. A helical region in the molecule is essential to retain the kinetic stability of the folded conformation
additional information
-
UROIIIS is a thermolabile enzyme undergoing irreversible denaturation, unfolding kinetics of wild-type UROIIIS and mutants, circular dichroism, overview. A helical region in the molecule is essential to retain the kinetic stability of the folded conformation
additional information
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the enzyme is metathermostabile, irreversible denaturation process. At physiological temperature and in vitro, UROIIIS has a half-life time of 61.1 h, a long time for the enzyme to exert its function in the cell, dynamic behavior of the protein, three-state model, overview. Thermodynamic versus kinetic stability, overview
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
10% glycerol stabilizes the purified recombinant enzyme in 20 mM sodium phosphate, pH 7.45, 100 mM NaCl, 2 mM DTT, and 0.1 mM EDTA at -80°C
a helical region in the molecule is essential to retain the kinetic stability of the folded conformation
activity does not change after several cycles of freeze-and thawing in potassium phosphate buffer, pH 7.4, containing DTT and glycerol
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His-tagged enzyme from Escherichia coli strain strain BL21(DE3) by ultrafiltration, nickel affinity and anion exchange chromatography, followed by gel filtration to homogeneity
recombinant wild-type UROIIIS and 25 point mutants in Escherichia coli to over 97% purity
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination and analysis, expression of wild-type and mutant enzymes
expression in Escherichia coli
expression of N-terminally His-tagged enzyme in Escherichia coli strain strain BL21(DE3)
expression of the N-terminal His-tagged wild-type and mutant enzymes in Escherichia coli BL21(DE3)
semi-quantitative real-time PCR analysis of ubiquitous and erythroid-specific UROS mRNAs, expression analysis
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stably expression of GFP-tagged UROIIIS-WT or UROIIIS-C73R proteins in MLP29cell lines, reduced expression levels of C73R-UROIIIS in the mammalian cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
branchpoint sequence mutation markedly reduces the wild type transcript and enzyme activity
-
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type enzyme from Escherichia coli, to homogeneity
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tsai, S.F.; Bishop, D.F.; Desnick, R.J.
Purification and properties of uroporphyrinogen III synthase from human erythrocytes
J. Biol. Chem.
262
1268-1273
1987
Homo sapiens
Wright, D.J.; Lim, C.K.
Simultaneous determination of hydroxymethylbilane synthase and uroporphyrinogen III synthase in erythrocytes by high-performance liquid chromatography
Biochem. J.
213
85-88
1983
Homo sapiens
Frydman, R.B.; Feinstein, G.
Studies on porphobilinogen deaminase and uroporphyrinogen III cosynthase from human erythrocytes
Biochim. Biophys. Acta
350
358-373
1974
Homo sapiens
Schubert, H.L.; Raux, E.; Matthews, M.A.; Phillips, J.D.; Wilson, K.S.; Hill, C.P.; Warren, M.J.
Structural diversity in metal ion chelation and the structure of uroporphyrinogen III synthase
Biochem. Soc. Trans.
30
595-600
2002
Homo sapiens
Mathews, M.A.; Schubert, H.L.; Whitby, F.G.; Alexander, K.J.; Schadick, K.; Bergonia, H.A.; Phillips, J.D.; Hill, C.P.
Crystal structure of human uroporphyrinogen III synthase
EMBO J.
20
5832-5839
2001
Homo sapiens (P10746), Homo sapiens
Omata, Y.; Sakamoto, H.; Higashimoto, Y.; Hayashi, S.; Noguchi, M.
Purification and characterization of human uroporphyrinogen III synthase expressed in Escherichia coli
J. Biochem.
136
211-220
2004
Homo sapiens (P10746), Homo sapiens
Wiederholt, T.; Poblete-Gutierrez, P.; Gardlo, K.; Goerz, G.; Bolsen, K.; Merk, H.F.; Frank, J.
Identification of mutations in the uroporphyrinogen III cosynthase gene in German patients with congenital erythropoietic porphyria
Physiol. Res.
55
S85-S92
2006
Homo sapiens
-
Cunha, L.; Kuti, M.; Bishop, D.F.; Mezei, M.; Zeng, L.; Zhou, M.M.; Desnick, R.J.
Human uroporphyrinogen III synthase: NMR-based mapping of the active site
Proteins
71
855-873
2007
Homo sapiens (P10746), Homo sapiens
Fortian, A.; Castano, D.; Ortega, G.; Lain, A.; Pons, M.; Millet, O.
Uroporphyrinogen III synthase mutations related to congenital erythropoietic porphyria identify a key helix for protein stability
Biochemistry
48
454-461
2009
Homo sapiens (P10746), Homo sapiens
Vargas, P.D.; Furuyama, K.; Sassa, S.; Shibahara, S.
Hypoxia decreases the expression of the two enzymes responsible for producing linear and cyclic tetrapyrroles in the heme biosynthetic pathway
FEBS J.
275
5947-5959
2008
Homo sapiens
Silva, P.J.; Ramos, M.J.
Comparative density functional study of models for the reaction mechanism of uroporphyrinogen III synthase
J. Phys. Chem. B
112
3144-3148
2008
Homo sapiens (P10746)
Bishop, D.F.; Schneider-Yin, X.; Clavero, S.; Yoo, H.W.; Minder, E.I.; Desnick, R.J.
Congenital erythropoietic porphyria: a novel uroporphyrinogen III synthase branchpoint mutation reveals underlying wild-type alternatively spliced transcripts
Blood
115
1062-1069
2010
Homo sapiens
Kang, T.; Oh, S.; Kim, M.; Lee, J.; Kim, S.
Compound heterozygosity for a premature termination codon and missense mutation in the exon 10 of the uroporphyrinogen III cosynthase gene causes a severe phenotype of congenital erythropoietic porphyria
J. Eur. Acad. Dermatol. Venereol.
23
470-471
2009
Homo sapiens
Fortian, A.; Castano, D.; Gonzalez, E.; Lain, A.; Falcon-Perez, J.M.; Millet, O.
Structural, thermodynamic, and mechanistical studies in uroporphyrinogen III synthase: Molecular basis of congenital erythropoietic porphyria
Adv. Protein Chem. Struct. Biol.
83
43-74
2011
Homo sapiens, Pseudomonas syringae (Q88B90)
Fortian, A.; Gonzalez, E.; Castano, D.; Falcon-Perez, J.M.; Millet, O.
Intracellular rescue of the uroporphyrinogen III synthase activity in enzymes carrying the hotspot mutation C73R
J. Biol. Chem.
286
13127-13133
2011
Homo sapiens
Ben Bdira, F.; Gonzalez, E.; Pluta, P.; Lain, A.; Sanz-Parra, A.; Falcon-Perez, J.M.; Millet, O.
Tuning intracellular homeostasis of human uroporphyrinogen III synthase by enzyme engineering at a single hotspot of congenital erythropoietic porphyria
Hum. Mol. Genet.
23
5805-5813
2014
Homo sapiens (P10746), Homo sapiens
Moghbeli, M.; Maleknejad, M.; Arabi, A.; Abbaszadegan, M.R.
Mutational analysis of uroporphyrinogen III cosynthase gene in Iranian families with congenital erythropoietic porphyria
Mol. Biol. Rep.
39
6731-6735
2012
Homo sapiens (P10746), Homo sapiens
Aguilera, P.; Badenas, C.; Whatley, S.D.; To-Figueras, J.
Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation
Br. J. Dermatol.
175
1346-1350
2016
Homo sapiens (P10746), Homo sapiens
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