Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC1.14.17.1) that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the chemical reaction:
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 known 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.
Based on the observations of what happens when there is 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]
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]
Because it is difficult to obtain a stable crystal of dopamine beta-hydroxylase, its crystal structure is yet to be solved. However, an homology model based on the primary sequence and comparison to PHM is available.[16]
↑Rush RA, Geffen LB (1980). "Dopamine beta-hydroxylase in health and disease". Critical Reviews in Clinical Laboratory Sciences. 12 (3): 241–77. doi:10.3109/10408368009108731. PMID6998654.
↑ 2.02.1Kaufman S, Bridgers WF, Baron J (1968). "The Mechanism of Action of Dopamine beta-Hydroxylase". Advances in Chemistry. 77, chapter 73: 172–176. doi:10.1021/ba-1968-0077.ch073.
↑Friedman S, Kaufman S (May 1966). "An electron paramagnetic resonance study of 3,4-dihydroxyphenylethylamine beta-hydroxylase". The Journal of Biological Chemistry. 241 (10): 2256–9. PMID4287853.
↑Prigge ST, Mains RE, Eipper BA, Amzel LM (August 2000). "New insights into copper monooxygenases and peptide amidation: structure, mechanism and function". Cellular and Molecular Life Sciences. 57 (8–9): 1236–59. doi:10.1007/pl00000763. PMID11028916.
↑Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID15860375.
↑Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W. Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN9781609133450. Retrieved 11 September 2015. The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
↑Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction"(PDF). J. Biol. Chem. 249 (2): 454–458. PMID4809526. 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.
↑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. PMID4713201. 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.
↑Mutschler J, Abbruzzese E, Witt SH, Dirican G, Nieratschker V, Frank J, Grosshans M, Rietschel M, Kiefer F (August 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. PMID22760354.
↑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 (June 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. PMID22513716.
↑Bhaduri N, Sinha S, Chattopadhyay A, Gangopadhyay PK, Singh M, Mukhopadhyay KK (February 2005). "Analysis of polymorphisms in the dopamine beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children". Indian Pediatrics. 42 (2): 123–9. PMID15767706.
↑Goldstein M, Anagnoste B, Lauber E, Mckeregham MR (July 1964). "INHIBITION OF DOPAMINE-BETA-HYDROXYLASE BY DISULFIRAM". Life Sciences. 3 (7): 763–7. doi:10.1016/0024-3205(64)90031-1. PMID14203977.
↑Goldstein M, Lauber E, Mckereghan MR (July 1964). "THE INHIBITION OF DOPAMINE-BETA-HYDROXYLASE BY TROPOLONE AND OTHER CHELATING AGENTS". Biochemical Pharmacology. 13 (7): 1103–6. doi:10.1016/0006-2952(64)90109-1. PMID14201135.
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. PMID5846992.
Levin EY, Levenberg B, Kaufman S (1960). "The enzymatic conversion of 3,4-dihydroxyphenylethylamine to norepinephrine". J. Biol. Chem. 235: 2080&ndash, 2086.