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Information on EC 4.2.1.96 - 4a-hydroxytetrahydrobiopterin dehydratase and Organism(s) Homo sapiens
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4.2.1.96 4a-hydroxytetrahydrobiopterin dehydrataseIUBMB Comments
In concert with EC 1.5.1.34, 6,7-dihydropteridine reductase, the enzyme recycles 4a-hydroxytetrahydrobiopterin back to tetrahydrobiopterin, a cosubstrate for several enzymes, including aromatic amino acid hydroxylases. The enzyme is bifunctional, and also acts as a dimerization cofactor of hepatocyte nuclear factor-1alpha (HNF-1).
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Word Map
- 4.2.1.96
- pterins
- hyperphenylalaninemias
- dihydropteridine
- bh4
- hydroxylases
-
cyclohydrolase
-
7-biopterin
- 6-pyruvoyl-tetrahydropterin
- vitiligo
-
hnf1alpha
- sepiapterin
- tetrahydropterins
-
depigmentation
- gtpch
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
pcd/dcoh, pterin-4a-carbinolamine dehydratase, dcoh/pcd, dcoh2, dcohalpha, xdcoh, 4a-carbinolamine dehydratase, pterin-4alpha-carbinolamine dehydratase, pterin-4 alpha-carbinolamine dehydratase, cdcoh, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
4 alpha-Hydroxy-tetrahydropterin dehydratase
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-
-
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4-alpha-hydroxy-tetrahydropterin dehydratase
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-
-
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4a-Carbinolamine dehydratase
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-
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4a-Hydroxytetrahydrobiopterin dehydratase
4a-Hydroxytetrahydropterin dehydratase
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-
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cDcoH
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-
-
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DCoH
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-
-
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DCoH/PCD
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-
-
-
DCoHalpha
Dehydratase, 4a-carbinolamine
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-
-
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Dimerization cofactor of hepatocyte nuclear factor 1-alpha
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-
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Dimerization cofactor of HNF1
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-
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Dimerization factor of HNF1/pterin-4alpha-carbinolamine dehydratase
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-
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GenBank AE000671-derived protein GI 2982796
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-
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P4aCD
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-
-
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PCD
PCD/DCoH
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-
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PCD/PhhB
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-
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PCDH
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-
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Phenylalanine hydroxylase-stimulating protein
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-
-
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Phenylalanine hydroxylase-stimulating protein/pterin-4alpha-carbinolamine dehydratase
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-
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PHS
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-
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PHS/PCD
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-
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Pterin carbinolamine dehydratase
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-
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Pterin-4 alpha-carbinolamine dehydratase
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-
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Pterin-4-alpha-carbinolamine dehydratase
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-
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Pterin-4a-carbinolamine dehydratase
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-
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Pterin-4a-carbinolamine dehydratase (Aquifex aeolicus gene phhB)
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Pterin-4a-carbinolamine dehydratase/dimerization cofactor of HNF1
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-
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Pterin-4alpha-carbinolamine dehydratase
Pterin-4alpha-carbinolamine dehydratase (PCD)/dimerization cofactor for the transcription factor HBF-1alpha
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XDCoH
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4a-Hydroxytetrahydrobiopterin dehydratase
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-
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PCD
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Pterin-4alpha-carbinolamine dehydratase
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
4a-hydroxytetrahydrobiopterin = 6,7-dihydrobiopterin + H2O
the mechanism of dehydration involves base catalysis at the N(5)-H group of the substrate by His61
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
elimination of H2O
elimination of H2O
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-
-
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SYSTEMATIC NAME
IUBMB Comments
4a-hydroxytetrahydrobiopterin hydro-lyase (6,7-dihydrobiopterin-forming)
In concert with EC 1.5.1.34, 6,7-dihydropteridine reductase, the enzyme recycles 4a-hydroxytetrahydrobiopterin back to tetrahydrobiopterin, a cosubstrate for several enzymes, including aromatic amino acid hydroxylases. The enzyme is bifunctional, and also acts as a dimerization cofactor of hepatocyte nuclear factor-1alpha (HNF-1).
CAS REGISTRY NUMBER
COMMENTARY
204788-56-7
pterin-4a-carbinolamine dehydratase (Aquifex aeolicus gene phhB), genBank AE000671-derived protein GI 2982796
87683-70-3
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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
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-7,8-dihydro-6H-pterin + H2O
-
-
-
?
4a-Hydroxy-6(S)-methyltetrahydropterin
Quinoid 6(S)-methyldihydropterin
-
-
-
-
?
6,6-dimethyl-4a-hydroxy-tetrahydropterin
6,6-dimethyl-7,8-dihydropterin + H2O
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-
-
-
?
additional information
?
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a defect in 4a-hydroxytetrahydrobiopterin dehydratase provoces the conversion of the 6-substituted pterins to their 7-substituted isomers
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-
?
additional information
?
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the mutant enzyme form C82R and the 18-amino acid-truncated mutant Glu87-termination occur naturally associated with hyperphenyalaninemia
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-
?
additional information
?
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-
the codevelopment of 4a-hydroxytetrahydropterin dehydratase with dihydropteridine reductase strongly supports a physiologically significant role for the dehydratase in tetrahydrobiopterin regeneration
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-
?
additional information
?
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the cytosolic enzyme is involved in the regeneration of tetrahydrobiopterin, the cofactor of aromatic amino acid monooxygenases
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-
?
additional information
?
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the enzyme is essentially identical to a cofactor that regulates dimerization of a nuclear homeodomain-containing protein involved in transcription
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-
?
additional information
?
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dehydratase/DCoHalpha, has the kinetic properties necessary for regenerating tetrahydrobiopterin cofactor for phenylalanine hydroxylase. Properties of dehydratase/DCoHalpha are consistent with the hypothesis that the activity of this isozyme could account for the relatively mild symptoms reported for patients with a defect in dehydratase/DCoH
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-
?
additional information
?
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DCoHalpha is coactivator of HNF1alpha-depndent transcription
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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
additional information
?
-
-
a defect in 4a-hydroxytetrahydrobiopterin dehydratase provoces the conversion of the 6-substituted pterins to their 7-substituted isomers
-
-
?
additional information
?
-
-
the mutant enzyme form C82R and the 18-amino acid-truncated mutant Glu87-termination occur naturally associated with hyperphenyalaninemia
-
-
?
additional information
?
-
-
the codevelopment of 4a-hydroxytetrahydropterin dehydratase with dihydropteridine reductase strongly supports a physiologically significant role for the dehydratase in tetrahydrobiopterin regeneration
-
-
?
additional information
?
-
-
the cytosolic enzyme is involved in the regeneration of tetrahydrobiopterin, the cofactor of aromatic amino acid monooxygenases
-
-
?
additional information
?
-
-
the enzyme is essentially identical to a cofactor that regulates dimerization of a nuclear homeodomain-containing protein involved in transcription
-
-
?
additional information
?
-
-
dehydratase/DCoHalpha, has the kinetic properties necessary for regenerating tetrahydrobiopterin cofactor for phenylalanine hydroxylase. Properties of dehydratase/DCoHalpha are consistent with the hypothesis that the activity of this isozyme could account for the relatively mild symptoms reported for patients with a defect in dehydratase/DCoH
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-
?
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.004
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
wild-type
0.0044
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
Q45R/K98Q
0.0052
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
N61D
0.0053
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
N61D/Q45R/K98Q
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
23
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
N61D
23
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
N61D/Q45R/K98Q
23
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
Q45R/K98Q
24
(6R)-6-(L-erythro-1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin
wild-type
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
wild type and mutant enzymes E57A, H61A, H62A, H79A, Y69F, and D60A and double-mutant H61A,H62A expressed in Escherichia coli
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
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PCD deficiency causes in newborns a mild form of hyperphenylalaninaemia with persistent high urinary levels of primapterin. Affected patients appear completely normal, but have elevated phenylalanine levels at birth, which normalize after few months of life and remain normal or just above the normal range of phenylalanine with an unrestricted diet
physiological function
-
PCD is required for the regeneration of tetrahydrobiopterin after phenylalanine hydroxylation. PCD can dimerize with HNF-1a and work as a transcription factor
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). PHS_HUMAN
104
0
12000
Swiss-Prot
other Location (Reliability: 2)
PHS2_HUMAN
130
0
14365
Swiss-Prot
Mitochondrion (Reliability: 1)
Q6LEE1_HUMAN
27
0
3250
TrEMBL
other Location (Reliability: 2)
H0YA52_HUMAN
119
0
13409
TrEMBL
Mitochondrion (Reliability: 2)
Q6FGB3_HUMAN
104
0
12010
TrEMBL
other Location (Reliability: 2)
Q6LEE2_HUMAN
43
0
5111
TrEMBL
other Location (Reliability: 2)
Q6LEE0_HUMAN
32
0
3473
TrEMBL
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
tetramer
tetramer
-
4 * 12675, mutant enzyme C81S, electrospray-ionisation mass spectrometry
tetramer
mutant enzyme N61D/Q45R/K98Q shows no evidence of a dimeric spiecies
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C82R
E57A
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the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
E97K
-
a biopsy of duodenal mucosa from a patient with homozygous E97K mutation has 17% of normal activity
H61A
-
the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
H61A/H62A
-
the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
H62A
-
the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
H79A
-
the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
H79S
-
the His79Ala mutant and the His79Ser mutant exhibit about 40% the activity of the wild-type enzyme. In the mutant enzymes His61Ala and His62Ala the activity is reduced to 10%. In the mutant enzymes Asp60Ala and Arg87Ala the activity is reduced to 30%. The Glu57Ala mutant and the His61Ala,His62Ala double mutant show no activity
N61D
The decreased ability of the N61D mutant to affect HNF1alpha-dependent DNA binding is likely a direct result of altered quaternary structure.
N61D/Q45R/K98Q
site-directed mutagenesis, triple DCoHa mutant (Q45R/K98Q/N61D) is unable to affect HNF1alpha-dependent DNA binding in vitro.
Q45R/K98Q
mutant Q45R/K98Q is not able to affect HNF1alpha-dependent DNA binding in vitro
additional information
C82R
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mutant enzyme C82R reveals 60% decrease in Vmax and a slight decrease in Km-value for 4a-hydroxytetrahydrobiopterin. The susceptibility to proteolysis of mutant C82R, however is markedly increased compared with the wild type enzyme
additional information
-
nine different mutations detected in patients with PCD deficiency. All these mutations are associated with a benign form of tetrahydrobiopterin deficiency, characterized by persistent urinary excretion of 7-substituted biopterin (primapterin or primapterinuria) and transient hyperphenylalaninemia. Most of the mutations recognized in patients with PCD deficiency are either a single amino acid change or a stop codon
additional information
3 residues, Asn61, Gln45, and Lys98 in DCoHalpha play a role in oligomeric flexibility, which enables DCoHalpha to more readily interact with HNF1alpha and increase DNA binding
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
mutant proteins require the inclusion of 10% glycerol in the storage buffer to maintain solubility
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
the 18 amino acid-truncated mutant E87T cannot be overexpressed in Escherichia coli
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hauer, C.R.; Rebrin, I.; Thoeny, B.; Neuheiser, F.; Curtius, H.C.; Hunziker, P.; Blau, N.; Ghisla, S.; Heizmann, C.W.
Phenylalanine hydoxylase-stimulating protein/pterin-4alpha-carbinolamine dehydratase from rat and human liver
J. Biol. Chem.
268
4828-4831
1993
Homo sapiens, Rattus norvegicus
Rebrin, I.; Bailey, S.W.; Ayling, J.E.
Activity of the bifunctional protein 4alpha-hydroxy-tetrahydropterin dehydratase/DCOH during human fetal development: correlation with dihydropteridine reductase activity and tetrahydrobiopterin levels
Biochem. Biophys. Res. Commun.
217
958-965
1995
Homo sapiens
Curtius, H.C.; Ghisla, S.; Hasegawa, H.; Blau, N.; Rebrin, I.
Progress in the study of biosynthesis and role of 7-substituted pterins: function of pterin-4a-carbinolamine dehydratase
Adv. Exp. Med. Biol.
338
107-110
1993
Homo sapiens
Thoeny, B.; Neuheiser, F.; Blau, N.; Heizmann, C.W.
Characterization of the human PCBD gene encoding the bifunctional protein pterin-4alpha-carbinolamine dehydratase/dimerization cofactor for the transcription factor HNF-1alpha
Biochem. Biophys. Res. Commun.
210
966-973
1995
Homo sapiens
Kster, S.; Stier, G.; Kubasch, N.; Curtius, H.C.; Ghisla, S.
Pterin-4alpha-carbinolamine dehydratase from Pseudomonas aeruginosa: characterization, catalytic mechanism and comparison to the human enzyme
Biol. Chem.
379
1427-1432
1998
Homo sapiens, Pseudomonas aeruginosa
Rebrin, I.; Petruschka, L.; Curtius, H.Ch.; Adler, C.; Herrmann, F.H.
Human liver pterin 4alpha-carbinolamine dehydratase. Purification and characterization
Pteridines
3
55-57
1992
Homo sapiens
-
Koester, S.; Thoeny, B.; Macheroux, P.; Curtius, H.C.; Heizmann, C.W.; Pfleiderer, W.; Ghisla, S.
Human pterin-4alpha-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor-1alpha
Eur. J. Biochem.
231
414-423
1995
Homo sapiens
Kster, S.; Stier, G.; Ficner, R.; Hoezer, M.; Curtius, H.C.; Suck, D.; Ghisla, S.
Location of the active site and proposed catalytic mechanism of pterin-4alpha-carbinolamine dehydratase
Eur. J. Biochem.
241
858-864
1996
Homo sapiens, Rattus norvegicus
Johen, G.; Kowlessur, D.; Citron, B.A.; Kaufman, S.
Characterization of the wild-type form of 4a-carbinolamine dehydratase and two naturally occuring mutants associated with hyperphenylalaninemia
Proc. Natl. Acad. Sci. USA
92
12384-12388
1995
Homo sapiens
Citron, B.A.; Davis, M.D.; Milstien, S.; Gutierrez, J.; Mendel, D.B.; Crabtree, G.R.; Kaufman, S.
Identity of 4a-carbinolamine dehydratase, a component of the phenylalanine hydroxylation system, and DCoH, a transregulator of homeodomain proteins
Proc. Natl. Acad. Sci. USA
89
11891-11894
1992
Homo sapiens
Thoeny, B.; Blau, N.
Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase
Hum. Mutat.
27
870-878
2006
Homo sapiens
Hevel, J.M.; Stewart, J.A.; Gross, K.L.; Ayling, J.E.
Can the DCoHalpha isozyme compensate in patients with 4a-hydroxy-tetrahydrobiopterin dehydratase/DCoH deficiency?
Mol. Genet. Metab.
88
38-46
2006
Homo sapiens
Hevel, J.M.; Pande, P.; Viera-Oveson, S.; Sudweeks, T.J.; Jaffree, L.S.; Hansen, C.M.; Ayling, J.E.
Determinants of oligomerization of the bifunctional protein DCoHalpha and the effect on its enzymatic and transcriptional coactivator activities
Arch. Biochem. Biophys.
477
356-362
2008
Homo sapiens (Q9H0N5)
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