DBH

Official Full Name

dopamine beta-hydroxylase

Organism

Homo sapiens

GeneID

1621

Background

The protein encoded by this gene is an oxidoreductase belonging to the copper type II, ascorbate-dependent monooxygenase family. The encoded protein, expressed in neuroscretory vesicles and chromaffin granules of the adrenal medulla, catalyzes the conversion of dopamine to norepinephrine, which functions as both a hormone and as the main neurotransmitter of the sympathetic nervous system. The enzyme encoded by this gene exists exists in both soluble and membrane-bound forms, depending on the absence or presence, respectively, of a signal peptide. Mutations in this gene cause dopamine beta-hydroxylate deficiency in human patients, characterized by deficits in autonomic and cardiovascular function, including hypotension and ptosis. Polymorphisms in this gene may play a role in a variety of psychiatric disorders. [provided by RefSeq, Aug 2017]

Synonyms

DBM; ORTHYP1;

Bio Chemical Class

Paired donor oxygen oxidoreductase

Protein Sequence

MPALSRWASLPGPSMREAAFMYSTAVAIFLVILVAALQGSAPRESPLPYHIPLDPEGSLELSWNVSYTQEAIHFQLLVRRLKAGVLFGMSDRGELENADLVVLWTDGDTAYFADAWSDQKGQIHLDPQQDYQLLQVQRTPEGLTLLFKRPFGTCDPKDYLIEDGTVHLVYGILEEPFRSLEAINGSGLQMGLQRVQLLKPNIPEPELPSDACTMEVQAPNIQIPSQETTYWCYIKELPKGFSRHHIIKYEPIVTKGNEALVHHMEVFQCAPEMDSVPHFSGPCDSKMKPDRLNYCRHVLAAWALGAKAFYYPEEAGLAFGGPGSSRYLRLEVHYHNPLVIEGRNDSSGIRLYYTAKLRRFNAGIMELGLVYTPVMAIPPRETAFILTGYCTDKCTQLALPPSGIHIFASQLHTHLTGRKVVTVLVRDGREWEIVNQDNHYSPHFQEIRMLKKVVSVHPGDVLITSCTYNTEDRELATVGGFGILEEMCVNYVHYYPQTQLELCKSAVDAGFLQKYFHLINRFNNEDVCTCPQASVSQQFTSVPWNSFNRDVLKALYSFAPISMHCNKSSAVRFQGEWNLQPLPKVISTLEEPTPQCPTSQGRSPAGPTVVSIGGGKG

Open

Disease

Heart failure, Post-traumatic stress disorder

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Dopamine beta-hydroxylase (DbH) is a key copper-dependent oxidase that converts dopamine to norepinephrine. This function is essential for the metabolic pathways of noradrenergic neurons in both the sympathetic and central nervous systems. DbH is a tetrameric protein comprised of two non-covalently connected dimers, each of which binds two copper ions. These copper sites, termed as "Cu-His" and "Cu-Met," have separate functions in electron transfer during catalysis, giving the enzyme a high substrate selectivity and catalytic efficiency. The stringent reliance on copper ions emphasizes the significance of this structural characteristic in function.

Figure 1: Diagrammatic overview of noradrenergic neurons illustrating neurotransmitter synthesis, release, and the biosynthetic pathway of norepinephrine, highlighting key enzymes like tyrosine hydroxylase (rate-limiting), DDC, and DbH. Figure 1. Schematic representations of noradrenergic neurons and neurotransmitter synthesis. (Gonzalez-Lopez E, et al., 2019)

Soluble and Membrane-Bound Forms

DbH has two forms: soluble and membrane-bound. This variability is the consequence of varied signal peptide processing. The membrane-bound form is found on the synaptic vesicle membrane in neurons and has a direct role in norepinephrine release into the synaptic cleft. In contrast, the soluble form is released into the extracellular space and detectable in blood. DbH is extensively glycosylated, with post-translational changes in the endoplasmic reticulum and Golgi apparatus that improve its stability, catalytic activity, and secretion efficiency. DbH secretion and activity are dynamically regulated by physiological stress, making it an ideal model for researching neurotransmitter balance.

Gene Regulation and Tissue Specificity

The expression of the DbH gene is strictly controlled and tissue-specific. The promoter region includes critical components such as glucocorticoid and cAMP response elements, which react to brain activity, stress signals, and metabolic changes. Transcription factors such as Phox2a and Phox2b are critical for maintaining DbH expression in noradrenergic neurons and adrenal medullary cells. DbH activity is carefully tuned by variables other than transcriptional control, including substrate concentration, copper ion availability, and post-translational modifications. Copper deficiency, for example, might affect DbH catalytic performance, resulting in disturbances in norepinephrine synthesis—a process that may be involved in some neurodegenerative illnesses.

Physiological and Pathophysiological Roles

DbH's involvement goes beyond norepinephrine production, regulating a variety of physiological and pathologic processes. During sympathetic nervous system activation, increased DbH activity promotes norepinephrine release, which contributes to blood pressure rise and heart rate acceleration. This reaction is especially strong under stress, allowing for quick adaptability to environmental changes. DBH dysfunction has been linked to a variety of illnesses. Reduced DbH activity may result in lower norepinephrine levels, which may contribute to mental illnesses including depression and ADHD. Conversely, increased DbH activity has been associated with anxiety disorders and post-traumatic stress disorder (PTSD). Furthermore, DbH has been linked to inflammation control, with studies indicating overexpression in specific inflammatory illnesses, suggesting a function in regulating immune responses via sympathetic activity.

Insights from Genetic Knockout Models

DbH-knockout mice research has shown that the enzyme is critical for embryonic development and physiological control. These animals have full norepinephrine insufficiency, which results in permanent cardiovascular and neurological impairments. Supplementing with norepinephrine precursors will only partly restore these capabilities. These results provide light on DbH's important roles and lay the groundwork for future research into treatment methods for linked disorders.

Future Perspectives and Therapeutic Potential

DbH is a crucial enzyme with a variety of biological roles, including neurotransmitter metabolism and immunological control. Its intricate structure, sophisticated regulation mechanisms, and diverse pathogenic connections make it a valuable study topic in neurology and biochemistry. Future research into the molecular underpinnings of DbH and its role in illnesses holds the potential for creating novel therapeutic methods, opening the door for better diagnosis and treatment of linked conditions.

References:

Gonzalez-Lopez E, Vrana KE. Dopamine beta-hydroxylase and its genetic variants in human health and disease. J Neurochem. 2020 Jan;152(2):157-181.
Dey SK, Saini M, et al. Dopamine β hydroxylase as a potential drug target to combat hypertension. Expert Opin Investig Drugs. 2020 Sep;29(9):1043-1057.

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