|, DBM, Dopamine beta-monooxygenase, dopamine beta-hydroxylase, Dopamine β-hydroxylase, ORTHYP1|
Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC 18.104.22.168) that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.
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.
- 1 Mechanism of catalysis
- 2 Assays for DBH activity in human serum and Cerebrospinal fluid
- 3 Clinical significance
- 4 Structure
- 5 Regulation and inhibition
- 6 Nomenclature
- 7 References
- 8 Further reading
- 9 External links
Mechanism of catalysis
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
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.
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.
Assays for DBH activity in human serum and Cerebrospinal fluid
DBH activity in human serum could be estimated by a spectrophotometric method  or with the aid of Ultra high performance liquid chromatography with Photo Diode Array detector (UHPLC-PDA). 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.
Expression quantitative trait loci (eQTLs) at DBH loci
Genetic variants such as single-nucleotide polymorphisms(SNPs) 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  and rs1989787  were shown to affect transcription of this gene. Mutations identified in Dopamine beta hydroxylase deficiency  and non-synonymous SNPs such as rs6271 in this gene were found to cause defective secretion of the protein from the endoplasmic reticulum.
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.
DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism and smoking, attention deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease. Inadequate DBH is called dopamine beta hydroxylase deficiency.
The proximal promoter(genetics) SNPs rs1989787 and rs1611115 were found to be associated with cognition in Schizophrenia subjects. Further these SNPs and a distal promoter variant 19bp Ins/Del(rs141116007) were important in Tardive dyskinesia and Positive and Negative Syndrome Scale(PANSS) scores in schizophrenia subjects. .
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.
Regulation and inhibition
|Ascorbate is cofactor; tyramine is substitute for dopamine, DBH's namesake substrate
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.
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)
- 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
- GRCh38: Ensembl release 89: ENSG00000123454 - Ensembl, May 2017
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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.
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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.
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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.
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