Dopamine beta-hydroxylase

Based on the observations of what happens when there is 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 β-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 β-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. == 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. 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 β-hydroxylase deficiency. == Structure ==

and physiochemical validation It was difficult to obtain a stable crystal of dopamine β-hydroxylase. Hence an homology model based on the primary sequence and comparison to PHM is available. == Regulation and inhibition ==

This protein may use the morpheein model of allosteric regulation. Inhibitors DBH is inhibited by disulfiram, tropolone, and, most selectively, by nepicastat. It is also inhibited by etamicastat and zamicastat. 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 (β-hydroxylating). Other names in common use include: • dopamine β-monooxygenase • dopamine β-hydroxylase • membrane-associated dopamine β-monooxygenase (MDBH) • soluble dopamine β-monooxygenase (SDBH) • dopamine-B-hydroxylase • 3,4-dihydroxyphenethylamine β-oxidase • 4-(2-aminoethyl) pyrocatechol β-oxidase • dopa β-hydroxylase • dopamine β-oxidase • dopamine hydroxylase • phenylamine β-hydroxylase • (3,4-dihydroxyphenethylamine) β-mono-oxygenase == References ==