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Dopamine beta-monooxygenase

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Title: Dopamine beta-monooxygenase  
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Subject: Pyrroloquinoline quinone, Dopamine beta-hydroxylase, Copper deficiency, Morpheein
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Dopamine beta-monooxygenase

dopamine beta-monooxygenase
EC number
CAS number 9013-38-1
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Dopamine beta-hydroxylase (dopamine beta-monooxygenase)
Symbols  ; DBM
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Dopamine beta-monooxygenase, also known as dopamine beta-hydroxylase, is an enzyme that in humans is encoded by the DBH gene. Dopamine beta-monooxygenase catalyzes the chemical reaction:

The 3 substrates of this enzyme are 3,4-dihydroxyphenethylamine, ascorbate, and O2, whereas its 3 products are noradrenaline, dehydroascorbate, and H2O.

This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with reduced ascorbate as one donor, and incorporation of one atom of oxygen into the other donor. This enzyme participates in tyrosine metabolism. It has 3 cofactors: copper, PQQ, and Fumarate.

DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires ascorbate as a cofactor.[1]

It is the only enzyme involved in the synthesis of small-molecule neurotransmitters that is membrane-bound, making norepinephrine the only transmitter synthesized inside vesicles. It is expressed in noradrenergic nerve terminals of the central and peripheral nervous systems, as well as in chromaffin cells of the adrenal medulla.

Mechanism of catalysis

Based on the observations of what happens when there's no substrate, or oxygen, the following steps seem to constitute the hydroxylation reaction.[2][3]

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.[4]

Human biosynthesis pathway for trace amines and catecholamines[7]

In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

Substrate specificity

Dopamine beta-hydroxylase catalyzes the hydroxylation of not only dopamine but also other phenylethylamine derivatives when available. The minimum requirement seems to be a benzene ring with a two-carbon side chain that terminates in an amino group.[2]

Clinical significance

DBH primarily contributes to catecholamine and trace amine biosynthesis.[7] DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism[8] and smoking,[9] attention deficit hyperactivity disorder,[10] schizophrenia,[11] and Alzheimer's disease.[12] Inadequate DBH is called dopamine beta hydroxylase deficiency.


Because it is difficult to obtain a stable crystal of dopamine beta-hydroxylase, its crystal structure is yet to be discovered. However, a model based on the primary sequence and comparison to PHM is available.[13]

Experimental DBH structural model based upon in silico prediction and physiochemical validation[14]

Regulation and inhibition

Types of dopamine beta-hydroxylase inhibition by: hydralazine(HYD); 2-hydrazinopyridine(HP); 2-quinoline-carboxylic acid (QCA); l-isoquinolinecarboxylic acid (IQCA); 2,2'-biimidazole(BI); and imidazole-4-acetic acid(IAA) with respect to ascorbate (cofactor) and tyramine (substitute for dopamine, DBH's substrate).

This protein may use the morpheein model of allosteric regulation.[15]


DBH is inhibited by disulfiram,[16] tropolone,[17] and, most selectively, by nepicastat.[18]

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.[19]


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


  1. ^ Rush RA, Geffen LB (1980). "Dopamine beta-hydroxylase in health and disease". Crit Rev Clin Lab Sci 12 (3): 241–77. PMID 6998654. doi:10.3109/10408368009108731. 
  2. ^ a b Kaufman S , Bridgers WF, Baron J (1968). "The Mechanism of Action of Dopamine beta-Hydroxylase.". Advances in Chemistry. 77: 172–176. doi:10.1021/ba-1968-0077.ch073. 
  3. ^ Friedman S, Kaufman S (1966). "An electron paramagnetic resonance study of 3,4-dihydroxyphenylethylamine beta-hydroxylase". J. Biol. Chem. 241 (10): 2256–9. PMID 4287853. 
  4. ^ Prigge ST, Mains RE, Eipper BA, Amzel LM (August 2000). "New insights into copper monooxygenases and peptide amidation: structure, mechanism and function". Cell. Mol. Life Sci. 57 (8-9): 1236–59. PMID 11028916. doi:10.1007/pl00000763. 
  5. ^ Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. PMID 19948186. doi:10.1016/j.pharmthera.2009.11.005. 
  6. ^ Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. PMID 15860375. doi:10.1016/ 
  7. ^ a b [5][6]
  8. ^ Mutschler J, Abbruzzese E, Witt SH, Dirican G, Nieratschker V, Frank J, Grosshans M, Rietschel M, Kiefer F (2012). "Functional polymorphism of the dopamine β-hydroxylase gene is associated with increased risk of disulfiram-induced adverse effects in alcohol-dependent patients.". Journal of Clinical Psychopharmacology 32 (4): 578–80. PMID 22760354. doi:10.1097/jcp.0b013e31825ddbe6. 
  9. ^ Ella E, Sato N, Nishizawa D, Kageyama S, Yamada H, Kurabe N, Ishino K, Tao H, Tanioka F, Nozawa A, Renyin C, Shinmura K, Ikeda K, Sugimura H (2012). "Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese.". Journal of Human Genetics 57 (6): 385–90. PMID 22513716. doi:10.1038/jhg.2012.40. 
  10. ^ Bhaduri N, Sinha S, Chattopadhyay A, Gangopadhyay PK, Singh M, Mukhopadhyay KK (2005). "Analysis of polymorphisms in the dopamine beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children". Indian Pediatr 42 (2): 123–9. PMID 15767706. 
  11. ^ Cubells JF, Sun X, Li W, Bonsall RW, McGrath JA, Avramopoulos D, Lasseter VK, Wolyniec PS, Tang YL, Mercer K, Pulver AE, Elston RC (2011). "Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia.". Human Genetics 130 (5): 635–43. PMID 21509519. doi:10.1007/s00439-011-0989-6. 
  12. ^ 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 Biomedical Genetics 11 (161). PMID 21070631. doi:10.1186/1471-2350-11-162. 
  13. ^ Kapoor A, Shandilya M, Kundu S (2011). "Structural Insight of Dopamine β-Hydroxylase, a Drug Target for Complex Traits, and Functional Significance of Exonic Single Nucleotide Polymorphisms". PLOS ONE 6 (10). PMID 22028891. doi:10.1371/journal.pone.0026509. 
  14. ^ Kapoor A, Shandilya M, Kundu S (2011). "Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms". PLoS ONE 6 (10): e26509. PMC 3197665. PMID 22028891. doi:10.1371/journal.pone.0026509. 
  15. ^ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. PMC 3298769. PMID 22182754. doi:10.1016/ 
  16. ^ Goldstein M, Anagnoste B, Lauber E, Mckeregham MR (1964). "Inhibition of dopamine-beta-hydroxylase by Disulfiram.". Life Sci 3 (7): 763–7. PMID 14203977. doi:10.1016/0024-3205(64)90031-1. 
  17. ^ Goldstein M, Lauber E, Mckereghan MR (1964). "Inhibition of dopamine-beta-hydroxylase by tropolone and other chelating agents.". Biochem Pharmacol 13 (7): 1103–6. PMID 14201135. doi:10.1016/0006-2952(64)90109-1. 
  18. ^ Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, Walker K, Martinez G, Eglen RM, Whiting RL, Hegde SS (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. PMC 1564872. PMID 9283721. doi:10.1038/sj.bjp.0701315. 
  19. ^ Townes S, Titone C, Rosenberg RC (1990). "Inhibition of dopamine beta-hydroxylase by bidentate chelating agents". Biochim. Biophys. Acta 1037 (2): 240–7. PMID 2306475. doi:10.1016/0167-4838(90)90174-E. 

Further reading

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

External links

  • GeneReviews/NIH/NCBI/UW entry on Dopamine Beta-Hydroxylase Deficiency
  • Dopamine beta-Hydroxylase at the US National Library of Medicine Medical Subject Headings (MeSH)
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