Dopamine beta-hydroxylase explained

dopamine beta-monooxygenase
Ec Number:1.14.17.1
Cas Number:9013-38-1
Go Code:0004500
Align:right

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

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.[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 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

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]

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 the phenylethylamine skeleton: a benzene ring with a two-carbon side chain that terminates in an amino group.[2]

Assays for DBH activity in human serum and cerebrospinal fluid

DBH activity in human serum could be estimated by a spectrophotometric method [5] or with the aid of Ultra high performance liquid chromatography with Photo Diode Array detector (UHPLC-PDA).[6] 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.[7]

Expression quantitative trait loci (eQTLs) at DBH loci

Genetic variants such as single-nucleotide polymorphisms(SNPs)[8] [9] 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 [10] and rs1989787 [11] were shown to affect transcription of this gene. Mutations identified in dopamine beta hydroxylase deficiency[12] and non-synonymous SNPs such as rs6271 in this gene were found to cause defective secretion of the protein from the endoplasmic reticulum.[13]

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.[14] [15] [16]

DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism[17] and smoking,[18] attention deficit hyperactivity disorder,[19] schizophrenia,[20] and Alzheimer's disease.[21] Inadequate DBH is called dopamine beta hydroxylase deficiency.

The proximal promoter SNPs rs1989787 and rs1611115 were found to be associated with cognition in schizophrenia subjects.[22] Further these SNPs (rs1989787;rs1611115) and a distal promoter variant 19bp Ins/Del(rs141116007) were associated with scores of Abnormal Involuntary Movement Scale in tardive dyskinesia positive schizophrenia subjects.[22] Of the three variants, the proximal promoter SNP(rs1611115) was associated with Positive and Negative Syndrome Scale(PANSS) scores in tardive dyskinesia positive schizophrenia subjects.[22] The main effect of a putative splice variant in Dopamine beta-hydroxylase namely rs1108580 was found to be associated with Working memory Processing speed in a north Indian Schizophrenia case control study where the G/G genotype of that single-nucleotide polymorphism(SNP) was found to have lower cognitive scores than those with A/A and A/G genotypes. Furthermore the same SNP was associated with Emotion accuracy in healthy controls.[23]

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.

However, a crystal structure was also put forward in 2016.[24]

Regulation and inhibition

This protein may use the morpheein model of allosteric regulation.[25]

Inhibitors

Types of dopamine beta-hydroxylase inhibition!!HYD!HP!QCA!IQCA!BI!IAAhttps://pubchem.ncbi.nlm.nih.gov/compound/Imidazoleacetic-acid
CompetitiveAscorbateAscorbateAscorbateAscorbateAscorbateAscorbate
UncompetitiveTyramineTyramine
MixedTyramineTyramineTyramineTyramine
Ascorbate is cofactor; tyramine is substitute for dopamine, DBH's namesake substrate

DBH is inhibited by disulfiram,[26] tropolone,[27] and, most selectively, by nepicastat.[28]

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;https://pubchem.ncbi.nlm.nih.gov/compound/Imidazoleacetic-acid IAA). HYD, QCA, and IAA are allosteric competitive.[29]

Nomenclature

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

Other names in common use include:

Further reading

External links

Notes and References

  1. Rush RA, Geffen LB . Dopamine beta-hydroxylase in health and disease . Critical Reviews in Clinical Laboratory Sciences . 12 . 3 . 241–77 . 1980 . 6998654 . 10.3109/10408368009108731 .
  2. Book: Kaufman S, Bridgers WF, Baron J . Oxidation of Organic Compounds. The Mechanism of Action of Dopamine β-Hydroxylase . Advances in Chemistry . 77 . 172–176 . 1968 . 10.1021/ba-1968-0077.ch073 . 0-8412-0078-5 .
  3. Friedman S, Kaufman S . An electron paramagnetic resonance study of 3,4-dihydroxyphenylethylamine beta-hydroxylase . The Journal of Biological Chemistry . 241 . 10 . 2256–9 . May 1966 . 10.1016/S0021-9258(18)96614-7 . 4287853 . free .
  4. Prigge ST, Mains RE, Eipper BA, Amzel LM . New insights into copper monooxygenases and peptide amidation: structure, mechanism and function . Cellular and Molecular Life Sciences . 57 . 8–9 . 1236–59 . August 2000 . 11028916 . 10.1007/pl00000763 . 12738480 . 11146793 .
  5. Nagatsu T, Udenfriend S. Photometric Assay of Dopamine-β-Hydroxylase Activity in Human Blood. Clinical Chemistry . 18 . 9 . 980–983 . 1972 . 10.1093/clinchem/18.9.980. 5052101 . free .
  6. Punchaichira TJ, Deshpande SN, Thelma BK. Determination of Dopamine-β-hydroxylase Activity in Human Serum Using UHPLC-PDA Detection. Neurochemical Research . 43 . 12 . 2324–2332 . 2018 . 30357655 . 10.1007/s11064-018-2653-1. 53024826.
  7. Matsui H, Kato T, Yamamoto C, Fujita K, Nagatsu T. Highly sensitive assay for dopamine-beta-hydroxylase activity in human cerebrospinal fluid by high performance liquid chromatography-electrochemical detection: properties of the enzyme. Journal of Neurochemistry . 37 . 2 . 289–296 . 1981 . 7264660 . 10.1111/j.1471-4159.1981.tb00454.x . 42736106.
  8. Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF . A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus. American Journal of Human Genetics . 68 . 2 . 515–22 . 2001 . 11170900 . 1235285. 10.1086/318198 .
  9. Punchaichira TJ, Prasad S, Deshpande SN, Thelma BK . Deep sequencing identifies novel regulatory variants in the distal promoter region of the dopamine-beta-hydroxylase gene . Pharmacogenetics and Genomics . 26 . 7 . 311–23 . 2016 . 26959714 . 10.1097/FPC.0000000000000214. 205601803 .
  10. Chen Y, Wen G, Rao F, Zhang K, Wang L, Rodriguez-Flores JL, Sanchez, AP, Mahata M, Taupenot L, Sun P, Mahata SK, Tayo B, Schork NJ, Ziegler MG, Hamilton BA, O'Connor DT. Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure . Journal of Hypertension . 28 . 1 . 76–86 . 2010 . 20009769 . 2860271 . 10.1097/HJH.0b013e328332bc87 .
  11. Chen Y, Zhang K, Wen G, Rao F, Sanchez AP, Wang L, Rodriguez-Flores JL, Mahata M, Mahata SK, Waalen J, Ziegler MG, Hamilton BA, O'Connor DT . Human dopamine beta-hydroxylase promoter variant alters transcription in chromaffin cells, enzyme secretion, and blood pressure . American Journal of Hypertension . 24 . 1 . 24–32 . 2011 . 20814407 . 4906639 . 10.1038/ajh.2010.186 .
  12. Kim CH, Leung A, Huh YH, Yang E, Kim DJ, Leblanc P, Ryu H, Kim K, Kim DW, Garland EM, Raj SR, Biaggioni I, Robertson D, Kim KS. Norepinephrine deficiency is caused by combined abnormal mRNA processing and defective protein trafficking of dopamine beta-hydroxylase. Journal of Biological Chemistry . 286 . 11 . 9196–204 . 2011 . 21209083 . 3059068. 10.1074/jbc.M110.192351 . free.
  13. Punchaichira TJ, Dey SK, Mukhopadhyay A, Kundu S, Thelma BK. Characterization of SNPs in the dopamine-beta-hydroxylase gene providing new insights into its structure-function relationship . Neurogenetics . 18 . 3 . 155–168 . 2017 . 28707163 . 10.1007/s10048-017-0519-3 . 5259134 .
  14. Book: Glennon RA . Lemke TL, Williams DA, Roche VF, Zito W . Foye's principles of medicinal chemistry . 2013 . Wolters Kluwer Health/Lippincott Williams & Wilkins . Philadelphia, US . 9781609133450 . 646–648 . 7th . https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase&pg=PA646 . 11 September 2015 . Phenylisopropylamine stimulants: amphetamine-related agents . 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. . 8 March 2024 . https://web.archive.org/web/20240308024354/https://books.google.com/books?id=Sd6ot9ul-bUC&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase&pg=PA646#v=onepage&q=substituted%20derivatives%20substituents%20hydroxyamphetamine%20flavin%20monooxygenase&f=false . live .
  15. Taylor KB . Dopamine-beta-hydroxylase. Stereochemical course of the reaction . J. Biol. Chem. . 249 . 2 . 454–458 . January 1974 . 10.1016/S0021-9258(19)43051-2 . 4809526 . 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. . free . 7 October 2018 . https://web.archive.org/web/20181007182156/http://www.jbc.org/content/249/2/454.full.pdf . live .
  16. Horwitz D, Alexander RW, Lovenberg W, Keiser HR . Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity . Circ. Res. . 32 . 5 . 594–599 . May 1973 . 4713201 . 10.1161/01.RES.32.5.594 . 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. . free .
  17. Mutschler J, Abbruzzese E, Witt SH, Dirican G, Nieratschker V, Frank J, Grosshans M, Rietschel M, Kiefer F . 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 . August 2012 . 22760354 . 10.1097/jcp.0b013e31825ddbe6 .
  18. 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 . Association between dopamine beta hydroxylase rs5320 polymorphism and smoking behaviour in elderly Japanese . Journal of Human Genetics . 57 . 6 . 385–90 . June 2012 . 22513716 . 10.1038/jhg.2012.40 . free .
  19. Bhaduri N, Sinha S, Chattopadhyay A, Gangopadhyay PK, Singh M, Mukhopadhyay KK . Analysis of polymorphisms in the dopamine beta hydroxylase gene: association with attention deficit hyperactivity disorder in Indian children . Indian Pediatrics . 42 . 2 . 123–9 . February 2005 . 15767706 .
  20. Cubells JF, Sun X, Li W, Bonsall RW, McGrath JA, Avramopoulos D, Lasseter VK, Wolyniec PS, Tang YL, Mercer K, Pulver AE, Elston RC . Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia . Human Genetics . 130 . 5 . 635–43 . November 2011 . 21509519 . 10.1007/s00439-011-0989-6 . 3193571.
  21. 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 . 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 . 2010 . 21070631 . 10.1186/1471-2350-11-162 . 2994840 . free .
  22. Punchaichira TJ, Mukhopadhyay A, Kukshal P, Bhatia T, Deshpande SN, Thelma BK . Association of regulatory variants of dopamine β-hydroxylase with cognition and tardive dyskinesia in schizophrenia subjects . Journal of Psychopharmacology . 358–369 . 2020 . 34 . 3 . 31913053 . 10.1177/0269881119895539 . 7150076 .
  23. Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN. Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort. Molecular Neurobiology . 2023 . 60 . 12 . 6826–6839 . 37493923 . 10.1007/s12035-023-03496-4 . 260162784 .
  24. Vendelboe TV, Harris P, Zhao Y, Walter TS, Harlos K, Omari KE, Christensen HM. The crystal structure of human dopamine β-hydroxylase at 2.9 Å resolution. Science Advances. 2 . 4. e1500980. 2016 . 27152332 . 4846438. 10.1126/sciadv.1500980 . 2016SciA....2E0980V.
  25. Selwood T, Jaffe EK . Dynamic dissociating homo-oligomers and the control of protein function . Archives of Biochemistry and Biophysics . 519 . 2 . 131–43 . March 2012 . 22182754 . 3298769 . 10.1016/j.abb.2011.11.020 .
  26. Goldstein M, Anagnoste B, Lauber E, Mckeregham MR . Life Sciences . 3 . 7 . 763–7 . July 1964 . 14203977 . 10.1016/0024-3205(64)90031-1 . Inhibition of dopamine- β -hydroxylase by disulfiram .
  27. Goldstein M, Lauber E, Mckereghan MR . Biochemical Pharmacology . 13 . 7 . 1103–6 . July 1964 . 14201135 . 10.1016/0006-2952(64)90109-1 . The inhibitionof dopamine-β-hydroxylase by tropolone and other chelating agents .
  28. Stanley WC, Li B, Bonhaus DW, Johnson LG, Lee K, Porter S, Walker K, Martinez G, Eglen RM, Whiting RL, Hegde SS . 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 . August 1997 . 9283721 . 1564872 . 10.1038/sj.bjp.0701315 .
  29. Townes S, Titone C, Rosenberg RC . Inhibition of dopamine beta-hydroxylase by bidentate chelating agents . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1037 . 2 . 240–7 . February 1990 . 2306475 . 10.1016/0167-4838(90)90174-E .

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