Dopamine beta-hydroxylase

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC 1.14.17.1) that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.

Dopamine is converted to norepinephrine by the enzyme dopamine β-hydroxylase. Ascorbic acid serves as a cofactor.
DBH
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesDBH, DBM, Dopamine beta-monooxygenase, dopamine beta-hydroxylase, Dopamine β-hydroxylase, ORTHYP1
External IDsOMIM: 609312 MGI: 94864 HomoloGene: 615 GeneCards: DBH
EC number1.14.17.1
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9q34.2Start133,636,363 bp[1]
End133,659,329 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1621

13166

Ensembl

ENSG00000123454

n/a

UniProt

P09172

Q64237

RefSeq (mRNA)

NM_000787

NM_138942

RefSeq (protein)

NP_000778

NP_620392

Location (UCSC)Chr 9: 133.64 – 133.66 Mbn/a
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

The three substrates of the enzyme are dopamine, vitamin C (ascorbate), and O2. The products are norepinephrine, dehydroascorbate, and H2O.

DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires ascorbate as a cofactor.[4]

It is the only enzyme involved in the synthesis of small-molecule neurotransmitters that is membrane-bound, making norepinephrine the only known transmitter synthesized inside vesicles. It is expressed in noradrenergic neurons of the central nervous system (i.e. locus coeruleus) and peripheral nervous systems (i.e. sympathetic ganglia), as well as in chromaffin cells of the adrenal medulla.

Mechanism of catalysis
dopamine beta-monooxygenase
Identifiers
EC number1.14.17.1
CAS number9013-38-1
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

Based on the observations of what happens when there is no substrate, or oxygen, the following steps seem to constitute the hydroxylation reaction.[5][6]

In the absence of oxygen, dopamine or other substrates, the enzyme and ascorbate mixture produces reduced enzyme and dehydroascorbate. Exposing the reduced enzyme to oxygen and dopamine results in oxidation of the enzyme and formation of noradrenaline and water, and this step doesn't require ascorbate.

Although details of DBH mechanism are yet to be confirmed, DBH is homologous to another enzyme, peptidylglycine α-hydroxylating monooxygenase (PHM). Because DBH and PHM share similar structures, it is possible to model DBH mechanism based on what is known about PHM mechanism.[7]

Substrate specificity
Biosynthetic pathways for catecholamines and trace amines in the human brain[8][9][10]
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

Dopamine beta-hydroxylase catalyzes the hydroxylation of not only dopamine but also other phenylethylamine derivatives when available. The minimum requirement seems to be the phenylethylamine skeleton: a benzene ring with a two-carbon side chain that terminates in an amino group.[5]

Assays for DBH activity in human serum and Cerebrospinal fluid

DBH activity in human serum could be estimated by a spectrophotometric method [11] or with the aid of Ultra high performance liquid chromatography with Photo Diode Array detector (UHPLC-PDA).[12] A sensitive assay for the detection of DBH activity in cerebrospinal fluid using High-performance liquid chromatography with Electrochemical detector(HPLC-ECD) was also described earlier.[13]

Expression quantitative trait loci (eQTLs) at DBH loci

Genetic variants such as single-nucleotide polymorphisms(SNPs)[14][15] at DBH loci were found to be associated with DBH activity and are well known expression quantitative trait loci. Allele variants at two regulatory SNPs namely rs1611115 [16] and rs1989787 [17] were shown to affect transcription of this gene. Mutations identified in Dopamine beta hydroxylase deficiency [18] and non-synonymous SNPs such as rs6271 in this gene were found to cause defective secretion of the protein from the endoplasmic reticulum.[19]

Clinical significance

DBH primarily contributes to catecholamine and trace amine biosynthesis. It also participates in the metabolism of xenobiotics related to these substances; for example, the human DBH enzyme catalyzes the beta-hydroxylation of amphetamine and para-hydroxyamphetamine, producing norephedrine and para-hydroxynorephedrine respectively.[20][21][22]

DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism[23] and smoking,[24] attention deficit hyperactivity disorder,[25] schizophrenia,[26] and Alzheimer's disease.[27] Inadequate DBH is called dopamine beta hydroxylase deficiency.

The proximal promoter(genetics) SNPs rs1989787 and rs1611115 were found to be associated with cognition in Schizophrenia subjects.[28] Further these SNPs and a distal promoter variant 19bp Ins/Del(rs141116007) were important in Tardive dyskinesia and Positive and Negative Syndrome Scale(PANSS) scores in schizophrenia subjects.[28]

Structure

It was difficult to obtain a stable crystal of dopamine beta-hydroxylase. Hence an homology model based on the primary sequence and comparison to PHM is available.[29]

Experimental DBH structural model based upon in silico prediction and physiochemical validation[29]

However, a crystal structure was also put forward in 2016.[30]

Regulation and inhibition

This protein may use the morpheein model of allosteric regulation.[31]

Inhibitors
Types of dopamine beta-hydroxylase inhibition
HYD[lower-alpha 1] HP[lower-alpha 2] QCA[lower-alpha 3] IQCA[lower-alpha 4] BI[lower-alpha 5] IAA[lower-alpha 6]
Competitive Ascorbate Ascorbate Ascorbate Ascorbate Ascorbate Ascorbate
Uncompetitive Tyramine Tyramine
Mixed Tyramine Tyramine Tyramine Tyramine
Ascorbate is cofactor; tyramine is substitute for dopamine, DBH's namesake substrate
  1. hydralazine
  2. 2-hydrazinopyridine
  3. 2-quinoline-carboxylic acid
  4. l-isoquinolinecarboxylic acid
  5. 2,2'-biimidazole
  6. imidazole-4-acetic acid

DBH is inhibited by disulfiram,[32] tropolone,[33] and, most selectively, by nepicastat.[34]

DBH is reversibly inhibited by l-2H-Phthalazine hydrazone (hydralazine; HYD), 2-1H-pyridinone hydrazone (2-hydrazinopyridine; HP), 2-quinoline-carboxylic acid (QCA), l-isoquinolinecarboxylic acid (IQCA), 2,2'-bi-lH-imidazole (2,2'-biimidazole; BI), and IH-imidazole-4-acetic acid (imidazole-4-acetic acid; IAA). HYD, QCA, and IAA are allosteric competitive.[35]

Nomenclature

The systematic name of this enzyme class is 3,4-dihydroxyphenethylamine, ascorbate:oxygen oxidoreductase (beta-hydroxylating).

Other names in common use include:

  • dopamine beta-monooxygenase
  • dopamine beta-hydroxylase
  • membrane-associated dopamine beta-monooxygenase (MDBH)
  • soluble dopamine beta-monooxygenase (SDBH)
  • dopamine-B-hydroxylase
  • 3,4-dihydroxyphenethylamine beta-oxidase
  • 4-(2-aminoethyl) pyrocatechol beta-oxidase
  • dopa beta-hydroxylase
  • dopamine beta-oxidase
  • dopamine hydroxylase
  • phenylamine beta-hydroxylase
  • (3,4-dihydroxyphenethylamine) beta-mono-oxygenase
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References
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  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  21. Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). J. Biol. Chem. 249 (2): 454–458. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
  22. Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circ. Res. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID 4713201. Subjects with exceptionally low levels of serum dopamine-β-hydroxylase activity showed normal cardiovascular function and normal β-hydroxylation of an administered synthetic substrate, hydroxyamphetamine.
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  27. Combarros O, Warden DR, Hammond N, Cortina-Borja M, Belbin O, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, Barber R, Coto E, Alvarez V, Deloukas P, Gwilliam R, Heun R, Kölsch H, Mateo I, Oulhaj A, Arias-Vásquez A, Schuur M, Aulchenko YS, Ikram MA, Breteler MM, van Duijn CM, Morgan K, Smith AD, Lehmann DJ (2010). "The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project". BMC Medical Genetics. 11 (161): 162. doi:10.1186/1471-2350-11-162. PMC 2994840. PMID 21070631.
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  33. Goldstein M, Lauber E, Mckereghan MR (July 1964). "The inhibitionof dopamine-β-hydroxylase by tropolone and other chelating agents". Biochemical Pharmacology. 13 (7): 1103–6. doi:10.1016/0006-2952(64)90109-1. PMID 14201135.
  34. Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, Walker K, Martinez G, Eglen RM, Whiting RL, Hegde SS (August 1997). "Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel, potent and selective inhibitor of dopamine-beta-hydroxylase". British Journal of Pharmacology. 121 (8): 1803–9. doi:10.1038/sj.bjp.0701315. PMC 1564872. PMID 9283721.
  35. Townes S, Titone C, Rosenberg RC (February 1990). "Inhibition of dopamine beta-hydroxylase by bidentate chelating agents". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1037 (2): 240–7. doi:10.1016/0167-4838(90)90174-E. PMID 2306475.

Further reading
  • Friedman S, Kaufman S (December 1965). "3,4-dihydroxyphenylethylamine beta-hydroxylase. Physical properties, copper content, and role of copper in the catalytic activity". The Journal of Biological Chemistry. 240 (12): 4763–73. PMID 5846992.
  • Levin EY, Levenberg B, Kaufman S (1960). "The enzymatic conversion of 3,4-dihydroxyphenylethylamine to norepinephrine". J. Biol. Chem. 235: 2080–2086. PMID 14416204.

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