Dopamine beta-hydroxylase

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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 chemical reaction:

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

The three substrates of this enzyme are 3,4-dihydroxyphenethylamine, ascorbate, and O2, whereas its three products are noradrenaline, 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 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.

Mechanism of catalysis

dopamine beta-monooxygenase
Identifiers
EC number 1.14.17.1
CAS number Template:CAS
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Based on the observations of what happens when there's no substrate, or oxygen, the following steps seem to constitute the hydroxylation reaction.[2][3]

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.[4]

Human biosynthesis pathway for trace amines and catecholamines[5][6]
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In humans, catecholamines and phenethylaminergic trace amines are derived from the amino acid phenylalanine.

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.[2]

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.[7][8][9]

DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism[10] and smoking,[11] attention deficit hyperactivity disorder,[12] schizophrenia,[13] and Alzheimer's disease.[14] Inadequate DBH is called dopamine beta hydroxylase deficiency.

Structure

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.[15]

Experimental DBH structural model based upon in silico prediction and physiochemical validation[15]

Regulation and inhibition

File:DBH inhibitors.png
Types of dopamine beta-hydroxylase inhibition by: hydralazine(HYD); 2-hydrazinopyridine(HP); 2-quinoline-carboxylic acid (QCA); l-isoquinolinecarboxylic acid (IQCA); 2,2'-biimidazole(BI); and imidazole-4-acetic acid(IAA) with respect to ascorbate (cofactor) and tyramine (substitute for dopamine, DBH's substrate).

This protein may use the morpheein model of allosteric regulation.[16]

Inhibitors

DBH is inhibited by disulfiram,[17] tropolone,[18] and, most selectively, by nepicastat.[19]

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.[20]

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

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Further reading

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External links

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