Dopamine beta hydroxylase
Dopamine β-hydroxylase (DBH) is an enzyme that converts dopamine to norepinephrine.
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.
DBH is inhibited by disulfiram,[2] tropolone,[3] and, most selectively, by nepicastat.[4]
Mechanism
Based on the observations of what happens when there's no substrate, or oxygen, the following steps seem to constitute the hydroxylation reaction.[5][6]
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
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.[8]
Structure
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.[9]
Biological Functions
DBH is in the catecholamine biosynthetic pathway. DBH has been shown to be associated with decision making and addictive behaviors such as alcohol[10] and smoking,[11] attention deficit hyperactivity disorder,[12] and also with neurological diseases such as Schizophrenia[13] and Alzheimer's.[14]
Regulation
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
See also
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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. Unknown parameter
|unused_data=ignored (help) - ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
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)
| ||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||