HOME

TheInfoList



OR:

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
() that in humans is encoded by the DBH
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Dopamine beta-hydroxylase
catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
the conversion of dopamine to norepinephrine. The three substrates of the enzyme are
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
,
vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription di ...
(ascorbate), and O2. The
products Product may refer to: Business * Product (business), an item that can be offered to a market to satisfy the desire or need of a customer. * Product (project management), a deliverable or set of deliverables that contribute to a business solution ...
are
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, dehydroascorbate, and H2O. DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires
ascorbate Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription die ...
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 The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...
) 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 adrenal medulla, medulla of the adrenal glands in mammals. These cells serve a variety of functions such as serving as a response to ...
s of the
adrenal medulla The adrenal medulla () is the inner part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of chromaffin cells that secrete catecho ...
.


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 Spectrophotometry is a branch of electromagnetic spectroscopy concerned with the quantitative measurement of the reflection or transmission properties of a material as a function of wavelength. Spectrophotometry uses photometers, known as spe ...
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 Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
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 specific components in mixtures. The mixtures can origin ...
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 and bioinformatics, 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 ...
(SNPs) at DBH loci were found to be associated with DBH activity and are well known expression quantitative trait loci.
Allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
variants at two regulatory SNPs namely rs1611115 and rs1989787 were shown to affect transcription of this gene. Mutations identified in dopamine beta 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 A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, 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. Cate ...
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 ...
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 Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
and para-hydroxyamphetamine, producing
norephedrine Phenylpropanolamine (PPA), sold under many brand names, is a sympathomimetic agent used as a decongestant and appetite suppressant. It was once common in prescription drug, prescription and over-the-counter drug, over-the-counter cough and cold ...
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 use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
s, e.g., alcoholism and smoking,
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...
,
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
, and
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
. Inadequate DBH is called dopamine beta hydroxylase deficiency. The proximal promoter SNPs rs1989787 and rs1611115 were found to be associated with cognition in
schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
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 an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
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 an iatrogenic disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips, which occurs following treatment with medication. Additional mo ...
positive schizophrenia subjects. The main effect of a putative splice variant in Dopamine beta-hydroxylase namely rs1108580 was found to be associated with Working memory Processing speed in a north Indian
Schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
case control study where the G/G genotype of that
single-nucleotide polymorphism In genetics and bioinformatics, 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 ...
(SNP) was found to have lower cognitive scores than those with A/A and A/G genotypes. Furthermore the same SNP was associated with Emotion accuracy in healthy controls.


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 Morpheeins are proteins that can form two or more different homo-oligomers (morpheein forms), but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit di ...
model of
allosteric regulation In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the ...
.


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 Enzyme inhibition, inhibiting the enzyme aldehyde dehydrogenase (specifically ALD ...
, 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 aci

IAA). HYD, QCA, and IAA are allosteric competitive.


Nomenclature

The List of enzymes, 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


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