Dopamine beta-monooxygenase

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dopamine beta-monooxygenase
Identifiers
EC number 1.14.17.1
CAS number 9013-38-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Dopamine beta-hydroxylase (dopamine beta-monooxygenase)
Identifiers
Symbols DBH ; DBM
External IDs OMIM609312 MGI94864 HomoloGene615 ChEMBL: 3102 GeneCards: DBH Gene
EC number 1.14.17.1
RNA expression pattern
PBB GE DBH 206450 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1621 13166
Ensembl ENSG00000123454 ENSMUSG00000000889
UniProt P09172 Q64237
RefSeq (mRNA) NM_000787 NM_138942
RefSeq (protein) NP_000778 NP_620392
Location (UCSC) Chr 9:
136.5 – 136.52 Mb
Chr 2:
27.17 – 27.18 Mb
PubMed search [1] [2]

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:

Dopamine is converted to norepinephrine by the enzyme dopamine β-hydroxylase. Ascorbic acid serves as a cofactor.

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 ato 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[edit]

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]

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.[4]

Substrate specificity[edit]

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]

Structure[edit]

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.[5]

A structural model of DBH based on experimental data, in silica prediction, and physiochemical validation. 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. doi:10.1371/journal.pone.0026509http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026509

Clinical significance[edit]

DBH is in the catecholamine biosynthetic pathway. DBH has been shown to be associated with decision making and addictive behaviors such as alcohol[6] and smoking,[7] attention deficit hyperactivity disorder,[8] and also with neurological diseases such as Schizophrenia[9] and Alzheimer's.[10] Inadequate DBH is called dopamine beta hydroxylase deficiency.

Inhibitors[edit]

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).

DBH is inhibited by disulfiram,[11] tropolone,[12] and, most selectively, by nepicastat.[13]

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.[14]

Regulation[edit]

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

Nomenclature[edit]

The systematic name of this enzyme class is 3,4-dihydroxyphenethylamine, ascorbate:oxygen oxidoreductase (beta-hydroxylating). Other names in common use include

  • dopamine beta-hydroxylase,
  • MDBH (membrane-associated dopamine beta-monooxygenase),
  • SDBH (soluble dopamine beta-monooxygenase),
  • dopamine-B-hydroxylase,
  • oxygenase,dopamine beta-mono-,
  • 3,4-dihydroxyphenethylamine beta-oxidase,
  • 4-(2-aminoethyl)pyrocatechol beta-oxidase,
  • dopa beta-hydroxylase,
  • dopamine beta-oxidase,
  • dopamine hydroxylase,
  • phenylamine beta-hydroxylase, and
  • (3,4-dihydroxyphenethylamine)beta-mono-oxygenase.

References[edit]

  1. ^ Rush RA, Geffen LB (1980). "Dopamine beta-hydroxylase in health and disease". Crit Rev Clin Lab Sci 12 (3): 241–77. doi:10.3109/10408368009108731. PMID 6998654. 
  2. ^ a b S Kaufman, WF Bridgers, J Baron (1968). 73. "The Mechanism of Action of Dopamine beta-Hydroxylase.". Advances in Chemistry. 77: 172–176. doi:10.1021/ba-1968-0077.ch073. 
  3. ^ S Friedman, S Kaufman (1966). "An Electron Paramagnetic Resonance Study of 3, 4-Dihydroxyphenylethylamine beta-Hydroxylase.". The Journal of Biological Chemistry. 241 (10): 2256–2259. 
  4. ^ ST Prigge, RE Mains, BA Eipper, LM Amzel (2000). "New insights into copper monooxygenases and peptide amidation: structure, mechanism and function.". Cellular and Molecular Life Sciences. 57: 1236–1259. doi:10.1007/pl00000763. 
  5. ^ 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). doi:10.1371/journal.pone.0026509. 
  6. ^ 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. doi:10.1097/jcp.0b013e31825ddbe6. 
  7. ^ 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. doi:10.1038/jhg.2012.40. 
  8. ^ 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 Pediatrics. 42 (2): 123–129. 
  9. ^ 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. doi:10.1007/s00439-011-0989-6. 
  10. ^ 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). doi:10.1186/1471-2350-11-162. 
  11. ^ Goldstein M, Anagnoste B, Lauber E, McKeregham MR (1964). "Inhibition of dopamine-beta-hydroxylase by Disulfiram.". Life Sci 3 (7): 763–7. doi:10.1016/0024-3205(64)90031-1. PMID 14203977. 
  12. ^ Goldstein M, Lauber E, McKeregham MR (1964). "Inhibition of dopamine-beta-hydroxylase by tropolone and other chelating agents.". Biochem Pharmacol 13 (7): 1103–6. doi:10.1016/0006-2952(64)90109-1. PMID 14201135. 
  13. ^ Stanley WC et al. (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. 
  14. ^ S Townes, C Titone, RC Rosenberg (1990). "Inhibition of dopamine beta-hydroxylase by bidentate chelating agents.". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1037 (2): 240–247. doi:10.1016/0167-4838(90)90174-E. 
  15. ^ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754. 

Further reading[edit]

  • 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[edit]