Dopamine beta-hydroxylase

Last updated
DBH
4zel.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DBH , DBM, Dopamine beta-monooxygenase, dopamine beta-hydroxylase, Dopamine β-hydroxylase, ORTHYP1
External IDs OMIM: 609312 MGI: 94864 HomoloGene: 615 GeneCards: DBH
EC number 1.14.17.1
Orthologs
SpeciesHumanMouse
Entrez

1621

13166

Ensembl

ENSG00000123454

ENSMUSG00000000889

UniProt

P09172

Q64237

RefSeq (mRNA)

NM_000787

NM_138942

RefSeq (protein)

NP_000778

NP_620392

Location (UCSC) Chr 9: 133.64 – 133.66 Mb Chr 2: 27.06 – 27.07 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
dopamine beta-monooxygenase
Identifiers
EC no. 1.14.17.1
CAS no. 9013-38-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Search
PMC articles
PubMed articles
NCBI proteins

Dopamine beta-hydroxylase (DBH), also known as dopamine beta-monooxygenase, is an enzyme (EC 1.14.17.1) that in humans is encoded by the DBH gene. Dopamine beta-hydroxylase catalyzes the conversion of dopamine to norepinephrine.

Contents

Dopamine is converted to norepinephrine by the enzyme dopamine b-hydroxylase; ascorbic acid serves as a cofactor Dopamine beta-monooxygenase reaction.svg
Dopamine is converted to norepinephrine by the enzyme dopamine β-hydroxylase; ascorbic acid serves as a cofactor

The three substrates of the enzyme are dopamine, vitamin C (ascorbate), and O2. The products are norepinephrine, dehydroascorbate, and H2O.

DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires ascorbate as a cofactor. [5]

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 cells 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. [6] [7]

In the absence of oxygen, dopamine or other substrates, the enzyme and ascorbate mixture produces reduced enzyme and dehydroascorbate. Exposing the reduced enzyme to oxygen and dopamine results in oxidation of the enzyme and formation of noradrenaline and water, and this step doesn't require ascorbate. DBH mechanism.png
In the absence of oxygen, dopamine or other substrates, the enzyme and ascorbate mixture produces reduced enzyme and dehydroascorbate. Exposing the reduced enzyme to oxygen and dopamine results in oxidation of the enzyme and formation of noradrenaline and water, and this step doesn't require ascorbate.

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. [8]

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. [6]

Assays for DBH activity in human serum and cerebrospinal fluid

DBH activity in human serum could be estimated by a spectrophotometric method [12] or with the aid of Ultra high performance liquid chromatography with Photo Diode Array detector (UHPLC-PDA). [13] 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. [14]

Expression quantitative trait loci (eQTLs) at DBH loci

Genetic variants such as single-nucleotide polymorphisms(SNPs) [15] [16] 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 [17] and rs1989787 [18] were shown to affect transcription of this gene. Mutations identified in dopamine beta hydroxylase deficiency [19] and non-synonymous SNPs such as rs6271 in this gene were found to cause defective secretion of the protein from the endoplasmic reticulum. [20]

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. [21] [22] [23]

DBH has been implicated as correlating factor in conditions associated with decision making and addictive drugs, e.g., alcoholism [24] and smoking, [25] attention deficit hyperactivity disorder, [26] schizophrenia, [27] and Alzheimer's disease. [28] Inadequate DBH is called dopamine beta hydroxylase deficiency.

The proximal promoter SNPs rs1989787 and rs1611115 were found to be associated with cognition in schizophrenia subjects. [29] 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 positive schizophrenia subjects. [29] Of the three variants, the proximal promoter SNP(rs1611115) was associated with Positive and Negative Syndrome Scale(PANSS) scores in tardive dyskinesia positive schizophrenia subjects. [29] 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 case control study where the G/G genotype of that single-nucleotide polymorphism(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. [30]

Structure

Experimental DBH structural model based upon in silico prediction and physiochemical validation Models for Oligomer Structures of DBH.png
Experimental DBH structural model based upon in silico prediction and physiochemical validation

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. [31]

However, a crystal structure was also put forward in 2016. [32]

Regulation and inhibition

This protein may use the morpheein model of allosteric regulation. [33]

Inhibitors

Types of dopamine beta-hydroxylase inhibition[ clarification needed ][ citation needed ]
HYD [lower-alpha 1] HP [lower-alpha 2] QCA [lower-alpha 3] IQCA [lower-alpha 4] BI [lower-alpha 5] IAA [lower-alpha 6]
Competitive AscorbateAscorbateAscorbateAscorbateAscorbateAscorbate
Uncompetitive TyramineTyramine
MixedTyramineTyramineTyramineTyramine
Ascorbate is cofactor; tyramine is substitute for dopamine, DBH's namesake substrate
  1. ↑ hydralazine
  2. ↑ 2-hydrazinopyridine
  3. ↑ 2-quinoline-carboxylic acid
  4. ↑ l-isoquinolinecarboxylic acid
  5. ↑ 2,2'-biimidazole
  6. ↑ imidazole-4-acetic acid

DBH is inhibited by disulfiram, [34] tropolone, [35] and, most selectively, by nepicastat. [36]

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. [37]

Nomenclature

The systematic name of this enzyme class is 3,4-dihydroxyphenethylamine, ascorbate:oxygen oxidoreductase (beta-hydroxylating).

Other names in common use include:

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.

<span class="mw-page-title-main">Phenylpropanolamine</span> Sympathomimetic agent

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 control urinary incontinence in dogs.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">Phenylacetone</span> Chemical compound

Phenylacetone, also known as phenyl-2-propanone, is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. It is a mono-substituted benzene derivative, consisting of an acetone attached to a phenyl group. As such, its systematic IUPAC name is 1-phenyl-2-propanone.

<span class="mw-page-title-main">4-Hydroxyamphetamine</span> Group of stereoisomers

4-Hydroxyamphetamine (4HA), also known as hydroxyamfetamine, hydroxyamphetamine, oxamphetamine, norpholedrine, para-hydroxyamphetamine, and α-methyltyramine, is a drug that stimulates the sympathetic nervous system.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">21-Hydroxylase</span> Human enzyme that hydroxylates steroids

Steroid 21-hydroxylase is a protein that in humans is encoded by the CYP21A2 gene. The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on the substrate acted upon and the chemical process performed. Biochemically, this enzyme is involved in the biosynthesis of the adrenal gland hormones aldosterone and cortisol, which are important in blood pressure regulation, sodium homeostasis and blood sugar control. The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively, within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in the enzyme may cause congenital adrenal hyperplasia.

<span class="mw-page-title-main">Steroid 11β-hydroxylase</span> Protein found in mammals

Steroid 11β-hydroxylase, also known as steroid 11β-monooxygenase, is a steroid hydroxylase found in the zona glomerulosa and zona fasciculata of the adrenal cortex. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene. The enzyme is involved in the biosynthesis of adrenal corticosteroids by catalyzing the addition of hydroxyl groups during oxidation reactions.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, most commonly sold under the brand name Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults, and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours. In the United Kingdom, it is usually less preferred to methylphenidate for the treatment of children.

<span class="mw-page-title-main">Kynurenine 3-monooxygenase</span> Enzyme

In enzymology, a kynurenine 3-monooxygenase (EC 1.14.13.9) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Peptidylglycine alpha-amidating monooxygenase</span> Protein-coding gene in the species Homo sapiens

Peptidyl-glycine alpha-amidating monooxygenase is an enzyme that catalyzes the conversion of glycine amides to amides and glyoxylate.

<span class="mw-page-title-main">Dopamine beta hydroxylase deficiency</span> Medical condition

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 false neurotransmitter, in place of norepinephrine. Other names for norepinephrine include noradrenaline (NA) and noradrenalin. This condition is also sometimes referred to as "norepinephrine deficiency". Researchers of disorders such as schizophrenia are interested in studying this disorder, as patients with these specific diseases can have an increase in the amount of dopamine in their system and yet do not show other symptoms of DβH deficiency.

<span class="mw-page-title-main">Monooxygenase DBH-like 1</span> Protein-coding gene in the species Homo sapiens

DBH-like monooxygenase protein 1, also known as monooxygenase X, is an enzyme that in humans is encoded by the MOXD1 gene.

<i>p</i>-Hydroxynorephedrine Chemical compound

p-Hydroxynorephedrine (PHN), or 4-hydroxynorephedrine, is the para-hydroxy analog of norephedrine and an active sympathomimetic metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced from both p-hydroxyamphetamine and norephedrine.

<span class="mw-page-title-main">4-Hydroxyphenylacetone</span> Chemical compound

4-Hydroxyphenylacetone is the para-hydroxy analog of phenylacetone, an inactive metabolite of amphetamine in humans. When it occurs as a metabolite of amphetamine, it is produced directly from the inactive metabolite phenylacetone.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000889 - Ensembl, May 2017
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  29. 1 2 3 Punchaichira TJ, Mukhopadhyay A, Kukshal P, Bhatia T, Deshpande SN, Thelma BK (2020). "Association of regulatory variants of dopamine β-hydroxylase with cognition and tardive dyskinesia in schizophrenia subjects". Journal of Psychopharmacology. 34 (3): 358–369. doi:10.1177/0269881119895539. PMC   7150076 . PMID   31913053.
  30. ↑ Punchaichira TJ, Kukshal P, Bhatia T, Deshpande SN (2023). "Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort". Molecular Neurobiology. 60 (12): 6826–6839. doi:10.1007/s12035-023-03496-4. PMID   37493923. S2CID   260162784.
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