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Information on EC 1.14.17.1 - dopamine beta-monooxygenase and Organism(s) Homo sapiens and UniProt Accession P09172

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IUBMB Comments
A copper protein. Stimulated by fumarate.
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Select one or more organisms in this record:
This record set is specific for:
Homo sapiens
UNIPROT: P09172
Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
3,4-dihydroxy-phenylethylamine, ascorbate: oxygen oxidoreductase (3-hydroxylating), 3,4-dihydroxyphenethylamine beta-oxidase, 3,4-dihydroxyphenylethylamine beta-hydoxylase, 4-(2-aminoethyl)pyrocatechol beta-oxidase, DbetaH, DbetaM, DBH, DBM, Dopa beta-hydroxylase, dopamine beta hydroxylase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
3,4-dihydroxyphenethylamine beta-oxidase
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-
-
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3,4-dihydroxyphenylethylamine beta-hydoxylase
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-
-
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4-(2-aminoethyl)pyrocatechol beta-oxidase
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-
-
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DbetaH
247
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DbetaM
247
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Dopa beta-hydroxylase
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-
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dopamine beta-hydrolase
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dopamine beta-hydroxylase
dopamine beta-monooxygenase
247
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dopamine beta-oxidase
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dopamine hydroxylase
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dopamine(3,4-dihydroxyphenethylamine)beta-mono-oxygenase
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dopamine-beta hydroxylase
247
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dopamine-beta-hydroxylase
oxygenase, dopamine beta-mono-
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-
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pDbetaH
247
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phenylamine beta-hydroxylase
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plasma DbetaH activity
247
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plasma dopamine beta-hydroxylase
247
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plDbetaH
247
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
dopamine + ascorbate + O2 = noradrenaline + dehydroascorbate + H2O
show the reaction diagram
during the reaction, an O atom from molecular O2 is inserted at the beta-carbon in dopamine with retention of configuration, and the second O atom goes to water. The reaction also requires two electrons provided by two ascorbate molecules that are oxidized to semihydroascorbate
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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redox reaction
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reduction
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PATHWAY SOURCE
PATHWAYS
SYSTEMATIC NAME
IUBMB Comments
3,4-dihydroxyphenethylamine,ascorbate:oxygen oxidoreductase (beta-hydroxylating)
A copper protein. Stimulated by fumarate.
CAS REGISTRY NUMBER
COMMENTARY hide
9013-38-1
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dopamine + ascorbate + O2
noradrenaline + dehydroascorbate + H2O
show the reaction diagram
3,4-dihydroxyphenethylamine + ascorbate + O2
noradrenaline + dehydroascorbate + H2O
show the reaction diagram
tyramine + ascorbate + O2
octopamine + dehydroascorbate + H2O
show the reaction diagram
additional information
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
dopamine + ascorbate + O2
noradrenaline + dehydroascorbate + H2O
show the reaction diagram
3,4-dihydroxyphenethylamine + ascorbate + O2
noradrenaline + dehydroascorbate + H2O
show the reaction diagram
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-
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-
?
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ascorbate
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
copper
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contains copper
additional information
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the structure of the common DOMON (dopamine beta-monooxygenase N-terminal) domain reveals a possible metal-binding site and a ligand-binding pocket, coordinating residues are Asp99, Leu100, Ala115, and Asp130
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
etamicastat
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nepicastat
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CaNa2EDTA
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weak
Disulfiram
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Sodium diethyldithiocarbamate
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additional information
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dithiocarbamate pesticides: increase of inhibitory potency from methyl- and dimethyldithiocarbamates to diethyldithiocarbamates up to the most potent ethylenbisdithiocarbamates
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.8
ascorbate
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2
tyramine
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.2
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assay at
5
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pI: 5.8
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
37
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assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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the DBH activity:DBH protein ratio is the same in human serum and cerebrospinal fluid and does not change in patients with Parkinson disease, whose cerebrospinal fluid has very low DBH activity and protein levels compared with cerebrospinal fluid from healthy individuals
Manually annotated by BRENDA team
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SH-SY5Y-AH1861
Manually annotated by BRENDA team
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neuroblastoma cell line
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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DBH is a member of a small unique class of copper-containing hydroxylases that are found in eukaryotes, and all play a critical role in the biosynthesis of neurotransmitters and hormones. The other members of the family are the bifunctional enzyme peptidylglycine alpha-hydroxylating (and alpha-amidating) monooxygenase (PHM), monooxygenase X (DBH-like monooxygenase protein 1, MOXD1), and tyramine beta-monooxygease (TBH), which is the insect homologue of DBH
malfunction
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genotype-phenotype correlations. Mutant L317P shows secretory deficiency and is localized in the endoplasmic reticulum
physiological function
malfunction
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no major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction in a Brazilian sample of 689 cocaine addicts and 832 healthy controls, even after correction for sex age, education and population stratification
physiological function
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determinant role of Phox2a and Phox2b on the expression and function of DBH in vitro
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
Sequence
DOPO_HUMAN
617
1
69065
Swiss-Prot
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
72000
300000
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dimeric form, SDS-PAGE
610000
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tetrameric form, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer or tetramer
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the enzyme occurs borh as dimer and tetramer, which can be separated by size exclusion chromatography. The dimer and tetramer do not interconvert in the pH interval pH 4-9. Under denaturing conditions, the tetramer converts to a dimer, and upon addition of a reducing agent, the dimer converts to a monomer. The dimeric structure is asymmetric. In the A chain, the two catalytic CuH and CuM domains are in a closed conformation, and in the B chain, they adopt the same open conformation as seen in peptidylglycine alpha-hydroxylating (and alpha-amidating) monooxygenase (PHM), the catalytic CuH domain in chain A is moved away from the DOMON domain and closer to the catalytic CuM domain. The DOMON domain has an immunoglobulin (Ig)–like beta-sandwich structure, the catalytic core (the CuH and CuM domains) has the same topology as the structure of PHM, and the dimerization domains consisting of two antiparallel alpha helices form a four-helix bundle. Following the dimerization domain, there is a beta-strand (residues 561 to 566) taking part in the catalytic CuM domain and a beta-strand (residues 608 to 614) that is part of the DOMON domain, creating a very integrated structure, coordinating residues are Asp99, Leu100, Ala115, and Asp130. The DOMON domain and the dimerization domain are linked via C154-C596. Chain A is linked via two intermolecular disulfide bonds with chain B in the dimerization domain. Enzyme structure analysis, detailed overview
?
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x * 72000, secreted and modified (N-glycosylation) form, Western blot analysis
tetramer
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4 * 72000 SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
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DBH is an ascorbate-dependent glycoprotein, glycosylation is observed at all four predicted sites: Asn64, Asn184, Asn344, and Asn566
glycoprotein
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A318S
D460N
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site-directed mutagenesis, the mutant shows reduced expression levels compared to the wild-type enzyme, the mutant shows reduced expression levels compared to the wild-type enzyme
G482R
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the mutation has subsequent effect on the activity of the enzyme as it is present close to the active site
L317P
R549C
W544S
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site-directed mutagenesis, the enzyme shows a marginal decrease in homospecific activity, the mutant shows reduced expression levels compared to the wild-type enzyme
A348E
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retained inside cell in a premature endoplasmic reticulum form, also naturally occuring mutation
C1021T
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naturally occuring gene polymorphism, determination of the frequency in combat veterans with or without chronic posttraumatic stress disorder, overview
D100E
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retained inside cell in a premature endoplasmic reticulum form, also naturally occuring mutation
D331N
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retained inside cell in a premature endoplasmic reticulum form, also naturally occuring mutation
additional information
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
freezing and subsequent thawing results in rapid decrease of activity
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C, 0.5 M NaCl in 0.02 M sodium phosphate, pH 7.0, several weeks
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PURIFICATION/commentary
ORGANISM
UNIPROT
LITERATURE
CLONED/commentary
ORGANISM
UNIPROT
LITERATURE
gene dbh, recombinant expression of wild-type and mutant enzymes in HEK293 cells, generation of transient and stable lines expressing the mutant variant enzymes, genotype-phenotype correlations
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recombinant expression in HEK 293S cells
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gene DBH containing 12 exons that span approximately 23 kb of human chromosome 9, DNA and amino acid sequence determination and analysis, genotyping of ns/del, rs1611115, rs2519152, and rs6271
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gene DBH, DNA and amino acid sequence determination and analysis, a GATA-3 response sequence of the distal DBH promoter, the ubiquitously expressed AP4 protein physically interacts with the upstream DBH promoter subdomain at -863 to -858 bp and regulates DBH promoter function, interaction analysis, the AP4 protein-DBH/AP4 DNA complex is not affected by addition of nonspecific Sp1 sequences, overview
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gene DBH, DNA and amino acid sequence determination and analysis, genotyping, overview
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myc-tagged version expressed in CHO cell
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
alpha-SYN enters the nucleus and binds directly to the DBH promoter region. alpha-Syn atteniśates the forskolin-induced DBH upregulation in SK-N-BE(2) cells
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forskolin, dexamethasone, ionomycin, and 17-beta-estradiol all induce a significant increase in DBH promoter activity, the most significant 15.8fold upregulation of DBH transcription is observed in forskolin-treated cells The forskolin-induced DBH upregulation in SK-N-BE(2) cells is attenuated by alpha-Syn. CRE-mediated transcriptional regulation of tyrosine hydroxylase and enzyme DBH plays a crucial role in stress response
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transfection of 0.1 to 5 microg of cDNAs of Phox2a or Phox2b significantly increases mRNA and protein levels of DBH (up to 47%) in a concentration-dependent manner. Simultanoeus transfection with both Phox2a and Phox2b does not further increase mRNA and protein levels of DBH
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transfection of shRNAs specific to Phox2a or Phox2b genes significantly reduces mRNA and protein levels of DBH after shutdown of endogenous Phox2, which is accompanied by a decreased [(3)H]norepinephrine uptake. Reduced DBH expression caused by the shRNA specific to Phox2a can be reversed by transfection with Phox2b cDNA and vice versa. Cotransfection with both shRNAs specific to Phox2a and Phox2b genes does not further reduce mRNA and protein levels of DBH
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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inhibitors of enzyme DBH nepicastat and etamicastat are currently in clinical development for treatment of cocaine dependence
medicine
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inhibitors of enzyme DBH nepicastat and etamicastat are currently in clinical development for treatment of cocaine dependence
diagnostics
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genotype-controlled measurement of plasma DBH activity might be used as a potential biological marker of the response to trauma
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Frigon, R.P.; Stone, R.A.
Human plasma dopamine beta-hydroxylase. Purification and properties
J. Biol. Chem.
253
6780-6786
1978
Homo sapiens
Manually annotated by BRENDA team
Caroldi, S.; De Paris, P.; Zotti, S.; Zanella, I.; Brugnone, F.
Effects of disulfiram on serum dopamine-beta-hydroxylase and blood carbon disulphide concentrations in alcoholics
J. Appl. Toxicol.
14
77-80
1994
Homo sapiens
Manually annotated by BRENDA team
De Paris, P.; Caroldi, S.
In vitro effect of dithiocarbamate pesticides and of CaNa2EDTA on human serum dopamine-beta-hydroxylase
Biomed. Environ. Sci.
8
114-121
1995
Homo sapiens
Manually annotated by BRENDA team
Hassan, S.; Duong, B.; Kim, K.S.; Miles, M.F.
Pharmacogenomic analysis of mechanisms mediating ethanol regulation of dopamine beta-hydroxylase
J. Biol. Chem.
278
38860-38869
2003
Homo sapiens
Manually annotated by BRENDA team
Paclt, I.; Koudelova, J.
Changes of dopamine-beta-hydroxylase activity during ontogenesis in healthy subjects and in an experimental model (rats)
Physiol. Res.
53
661-667
2004
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Abe, M.; Wu, Z.; Yamamoto, M.; Jin, J.J.; Tabara, Y.; Mogi, M.; Kohara, K.; Miki, T.; Nakura, J.
Association of dopamine beta-hydroxylase polymorphism with hypertension through interaction with fasting plasma glucose in Japanese
Hypertens. Res.
28
215-221
2005
Homo sapiens
Manually annotated by BRENDA team
Klinman, J.P.
The copper-enzyme family of dopamine b-monooxygenase and peptidylglycine a-hydroxylating monooxygenase: Resolving the chemical pathway for substrate hydroxylation
J. Biol. Chem.
281
3013-3016
2006
Homo sapiens
Manually annotated by BRENDA team
Mustapic, M.; Pivac, N.; Kozaric-Kovacic, D.; Dezeljin, M.; Cubells, J.F.; Mueck-Seler, D.
Dopamine beta-hydroxylase (DBH) activity and -1021C/T polymorphism of DBH gene in combat-related post-traumatic stress disorder
Am. J. Med. Genet. B Neuropsychiatr. Genet.
144B
1087-1089
2007
Homo sapiens
Manually annotated by BRENDA team
Bhaduri, N.; Mukhopadhyay, K.
Correlation of plasma dopamine beta-hydroxylase activity with polymorphisms in DBH gene: a study on Eastern Indian population
Cell. Mol. Neurobiol.
28
343-350
2008
Homo sapiens
Manually annotated by BRENDA team
Tang, Y.L.; Epstein, M.P.; Anderson, G.M.; Zabetian, C.P.; Cubells, J.F.
Genotypic and haplotypic associations of the DBH gene with plasma dopamine beta-hydroxylase activity in African Americans
Eur. J. Hum. Genet.
15
878-883
2007
Homo sapiens
Manually annotated by BRENDA team
Hong, S.J.; Choi, H.J.; Hong, S.; Huh, Y.; Chae, H.; Kim, K.S.
Transcription factor GATA-3 regulates the transcriptional activity of dopamine beta-hydroxylase by interacting with Sp1 and AP4
Neurochem. Res.
33
1821-1831
2008
Coturnix japonica, Homo sapiens
Manually annotated by BRENDA team
Guindalini, C.; Laranjeira, R.; Collier, D.; Messas, G.; Vallada, H.; Breen, G.
Dopamine-beta hydroxylase polymorphism and cocaine addiction
Behav. Brain Funct.
4
1-4
2008
Homo sapiens
Manually annotated by BRENDA team
Nagatsu, T.
Simple photometric assay of dopamine-beta-hydroxylase activity in human blood: Useful in clinical chemistry
Clin. Chem.
55
193-194
2009
Homo sapiens
Manually annotated by BRENDA team
Fan, Y.; Huang, J.; Kieran, N.; Zhu, M.Y.
Effects of transcription factors Phox2 on expression of norepinephrine transporter and dopamine beta-hydroxylase in SK-N-BE(2)C cells
J. Neurochem.
110
1502-1513
2009
Homo sapiens
Manually annotated by BRENDA team
Kim, C.H.; Leung, A.; Huh, Y.H.; Yang, E.; Kim, D.J.; Leblanc, P.; Ryu, H.; Kim, K.; Kim, D.W.; Garland, E.M.; Raj, S.R.; Biaggioni, I.; Robertson, D.; Kim, K.S.
Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase
J. Biol. Chem.
286
9196-9204
2011
Homo sapiens
Manually annotated by BRENDA team
Kapoor, A.; Shandilya, M.; Kundu, S.
Structural insight of dopamine beta-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms
PLoS ONE
6
e26509
2011
Homo sapiens (P09172)
Manually annotated by BRENDA team
Kim, S.; Park, J.; Moon, J.; Choi, H.
Alpha-synuclein interferes with cAMP/PKA-dependent upregulation of dopamine beta-hydroxylase and is associated with abnormal adaptive responses to immobilization stress
Exp. Neurol.
252
63-74
2014
Homo sapiens (P09172), Mus musculus (Q64237)
Manually annotated by BRENDA team
Punchaichira, T.J.; Dey, S.K.; Mukhopadhyay, A.; Kundu, S.; Thelma, B.K.
Characterization of SNPs in the dopamine-beta-hydroxylase gene providing new insights into its structure-function relationship
Neurogenetics
18
155-168
2017
Homo sapiens (P09172)
Manually annotated by BRENDA team
Vendelboe, T.V.; Harris, P.; Zhao, Y.; Walter, T.S.; Harlos, K.; El Omari, K.; Christensen, H.E.
The crystal structure of human dopamine beta-hydroxylase at 2.9 A resolution
Sci. Adv.
2
e1500980
2016
Homo sapiens (P09172)
Manually annotated by BRENDA team
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