Dopamine-beta-hydroxylase

Dopamine-beta-hydroxylase

Dopamine beta-hydroxylase (dopamine beta-monooxygenase)
Identifiers
1.14.17.1
RNA expression pattern

Dopamine β-hydroxylase (DBH) is an enzyme that converts dopamine to norepinephrine.

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.

DBH is inhibited by disulfiram,[2] tropolone,[3] and, most selectively, by nepicastat.[4]

Mechanism

Based on the observations of what happens when there's no substrate, or oxygen, the following steps seem to constitute the hydroxylation reaction.[5][6]

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.[7]

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.[8]

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.[9]

Biological Functions

DBH is in the catecholamine biosynthetic pathway. DBH has been shown to be associated with decision making and addictive behaviors such as alcohol[10] and smoking,[11] attention deficit hyperactivity disorder,[12] and also with neurological diseases such as Schizophrenia[13] and Alzheimer's.[14]

Regulation

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 [15]

See also

References

External links

  • GeneReviews/NIH/NCBI/UW entry on Dopamine Beta-Hydroxylase Deficiency
  • Medical Subject Headings (MeSH)