Dopamine-beta-hydroxylase
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Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
() that in humans is encoded by the DBH
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine. The three substrates of the enzyme are dopamine,
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...
(ascorbate), and O2. The
products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...
are
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
,
dehydroascorbate Dehydroascorbic acid (DHA) is an oxidized form of ascorbic acid (vitamin C). It is actively imported into the endoplasmic reticulum of cells via glucose transporters. It is trapped therein by reduction back to ascorbate by glutathione and ot ...
, and H2O. DBH is a 290 kDa copper-containing
oxygenase An oxygenase is any enzyme that oxidizes a substrate by transferring the oxygen from molecular oxygen O2 (as in air) to it. The oxygenases form a class of oxidoreductases; their EC number is EC 1.13 or EC 1.14. Discoverers Oxygenases were disco ...
consisting of four identical subunits, and its activity requires 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 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 cell Chromaffin cells, also called pheochromocytes (or phaeochromocytes), are neuroendocrine cells found mostly in the medulla of the adrenal glands in mammals. These cells serve a variety of functions such as serving as a response to stress, monito ...
s of the adrenal medulla.


Mechanism of catalysis

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 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 Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...
using
High-performance liquid chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
with Electrochemical detector(HPLC-ECD) was also described earlier.


Expression quantitative trait loci (eQTLs) at DBH loci

Genetic variants such as
single-nucleotide polymorphisms In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(SNPs) at DBH loci were found to be associated with DBH activity and are well known
expression quantitative trait loci Expression quantitative trait loci (eQTLs) are genomic loci that explain variation in expression levels of mRNAs. Distant and local, trans- and cis-eQTLs, respectively An expression quantitative trait is an amount of an mRNA transcript or a p ...
.
Allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
variants at two regulatory SNPs namely rs1611115 and rs1989787 were shown to affect transcription of this gene. Mutations identified in
dopamine beta hydroxylase deficiency Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine. Dopamine is released, as a ...
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 A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...
and
trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to th ...
biosynthesis. It also participates in the metabolism of
xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
s related to these substances; for example, the human DBH enzyme catalyzes the beta-hydroxylation of amphetamine and para-hydroxyamphetamine, producing
norephedrine Phenylpropanolamine (PPA) is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It was commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to contro ...
and para-hydroxynorephedrine respectively. DBH has been implicated as correlating factor in conditions associated with decision making and
addictive drug Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use of ...
s, e.g., alcoholism and smoking,
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
,
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
, and Alzheimer's disease. Inadequate DBH is called
dopamine beta hydroxylase deficiency Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase. It is characterized by increased amounts of serum dopamine and the absence of norepinephrine (NE) and epinephrine. Dopamine is released, as a ...
. The proximal promoter SNPs rs1989787 and rs1611115 were found to be associated with cognition in
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
subjects. Further these SNPs (rs1989787;rs1611115) and a distal promoter variant 19bp Ins/Del(rs141116007) were associated with scores of Abnormal Involuntary Movement Scale in
Tardive dyskinesia Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
positive schizophrenia subjects. Of the three variants, the proximal promoter SNP(rs1611115) was associated with Positive and Negative Syndrome Scale(PANSS) scores in
Tardive dyskinesia Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
positive schizophrenia subjects.


Structure

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

This protein may use the morpheein model of allosteric regulation.


Inhibitors

DBH is inhibited by
disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of ...
,
tropolone Tropolone is an organic compound with the chemical formula . It is a pale yellow solid that is soluble in organic solvents. The compound has been of interest to research chemists because of its unusual electronic structure and its role as a ligan ...
, and, most selectively, by 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 A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...
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


Further reading

* *


External links


GeneReviews/NIH/NCBI/UW entry on Dopamine Beta-Hydroxylase Deficiency
* {{Use dmy dates, date=April 2017 EC 1.14.17 Copper enzymes Enzymes of known structure Biology of attention deficit hyperactivity disorder Amphetamine