Dopamine beta-hydroxylase

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DBH
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Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC 1.14.17.1) that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes

the conversion of dopamine to norepinephrine.

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

The three

dehydroascorbate, and H2O
.

DBH is a 290 kDa copper-containing

ascorbate as a cofactor.[5]

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.[6][7]

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.[8]

Substrate specificity

Biosynthetic pathways for catecholamines and trace amines in the human brain[9][10][11]
The image above contains clickable links
In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid L-phenylalanine.

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.[6]

Assays for DBH activity in human serum and cerebrospinal fluid

DBH activity in human serum could be estimated by a

spectrophotometric method [12] or with the aid of Ultra high performance liquid chromatography with Photo Diode Array detector (UHPLC-PDA).[13] 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.[14]

Expression quantitative trait loci (eQTLs) at DBH loci

Genetic variants such as

single-nucleotide polymorphisms(SNPs)[15][16] 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 [17] and rs1989787 [18] were shown to affect transcription of this gene. Mutations identified in dopamine beta hydroxylase deficiency[19] and non-synonymous SNPs such as rs6271 in this gene were found to cause defective secretion of the protein from the endoplasmic reticulum.[20]

Clinical significance

DBH primarily contributes to

para-hydroxynorephedrine respectively.[21][22][23]

DBH has been implicated as correlating factor in conditions associated with decision making and

addictive drugs, e.g., alcoholism[24] and smoking,[25] attention deficit hyperactivity disorder,[26] schizophrenia,[27] and Alzheimer's disease.[28] 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.[29] 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.[29] 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.[29] 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.[30]

Structure

Experimental DBH structural model based upon in silico prediction and physiochemical validation[31]

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.[31]

However, a crystal structure was also put forward in 2016.[32]

Regulation and inhibition

This protein may use the morpheein model of allosteric regulation.[33]

Inhibitors

Types of dopamine beta-hydroxylase inhibition[clarification needed][citation needed]
HYD[a] HP[b] QCA[c] IQCA[d] BI[e] IAA[f][1]
Competitive Ascorbate Ascorbate Ascorbate Ascorbate Ascorbate Ascorbate
Uncompetitive Tyramine Tyramine
Mixed Tyramine Tyramine Tyramine Tyramine
Ascorbate is cofactor; tyramine is substitute for dopamine, DBH's namesake substrate
  1. ^ hydralazine
  2. ^ 2-hydrazinopyridine
  3. ^ 2-quinoline-carboxylic acid
  4. ^ l-isoquinolinecarboxylic acid
  5. ^ 2,2'-biimidazole
  6. ^ imidazole-4-acetic acid

DBH is inhibited by disulfiram,[34] tropolone,[35] and, most selectively, by nepicastat.[36]

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;[2] IAA). HYD, QCA, and IAA are allosteric competitive.[37]

Nomenclature

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000123454 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000889 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. PMID 6998654
    .
  6. ^
    ISBN 0-8412-0078-5
    .
  7. PMID 4287853
    .
  8. S2CID 12738480
    .
  9. PMID 19948186
    .
  10. PMID 15860375
    .
  11. PMID 24374199
    .
  12. PMID 5052101
    .
  13. S2CID 53024826
    .
  14. S2CID 42736106
    .
  15. PMID 11170900
    .
  16. S2CID 205601803
    .
  17. PMID 20009769
    .
  18. PMID 20814407
    .
  19. PMID 21209083
    .
  20. S2CID 5259134
    .
  21. ISBN 9781609133450. Archived
    from the original on 8 March 2024. 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.
  22. PMID 4809526. Archived
    (PDF) from the original on 7 October 2018. 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.
  23. PMID 4713201
    . 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.
  24. PMID 22760354
    .
  25. PMID 22513716
    .
  26. PMID 15767706
    .
  27. PMID 21509519
    .
  28. PMID 21070631
    .
  29. ^
    PMID 31913053
    .
  30. S2CID 260162784
    .
  31. ^
    PMID 22028891
    .
  32. PMID 27152332
    .
  33. PMID 22182754
    .
  34. PMID 14203977
    .
  35. PMID 14201135
    .
  36. PMID 9283721
    .
  37. PMID 2306475
    .

Further reading

External links

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