Dopamine beta-monooxygenase

Dopamine beta-monooxygenase, also known as dopamine beta-hydroxylase, is an is_associated_with::enzyme that in humans is encoded by the DBH is_associated_with::gene. Dopamine beta-monooxygenase catalyzes the is_associated_with::chemical reaction:



The 3 substrates of this enzyme are is_associated_with::3,4-dihydroxyphenethylamine, is_associated_with::ascorbate, and O2, whereas its 3 products are is_associated_with::noradrenaline, is_associated_with::dehydroascorbate, and H2O.

This enzyme belongs to the family of is_associated_with::oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with reduced ascorbate as one donor, and incorporation of one atom of oxygen into the other donor. This enzyme participates in is_associated_with::tyrosine metabolism. It has 3 cofactors: is_associated_with::copper, PQQ, and is_associated_with::Fumarate.

DBH is a 290 kDa copper-containing is_associated_with::oxygenase consisting of four identical subunits, and its activity requires is_associated_with::ascorbate as a cofactor.

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



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.

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.

Clinical significance
DBH primarily contributes to is_associated_with::catecholamine and is_associated_with::trace amine biosynthesis. DBH has been implicated as correlating factor in conditions associated with decision making and is_associated_with::addictive drugs, e.g., alcoholism and smoking, is_associated_with::attention deficit hyperactivity disorder, is_associated_with::schizophrenia, and is_associated_with::Alzheimer's disease. Inadequate DBH is called is_associated_with::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 discovered. However, a model based on the primary sequence and comparison to PHM is available.

Regulation and inhibition
This protein may use the is_associated_with::morpheein model of is_associated_with::allosteric regulation.

Inhibitors
DBH is inhibited by is_associated_with::disulfiram, is_associated_with::tropolone, and, most selectively, by is_associated_with::nepicastat.

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.

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