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Ascorbate as an Enzyme Cofactor
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Margreet C.M. Vissers, Andrew B. Das
Dopamine β-hydroxylase is found in the chromaffin granules of the adrenal medulla and sympathetic neurons, where it catalyzes the hydroxylation of the catecholamine neurotransmitter dopamine to generate norepinephrine (Table 5.1 and Figure 5.5) [250]. The reaction proceeds in two distinct steps; ascorbate-mediated reduction of Cu2+ in the enzyme active site followed by Cu+-mediated activation of oxygen to hydroxylate dopamine to the norepinephrine product (Figure 5.5). Ascorbate is consumed stoichiometrically in this reaction cycle with equimolar production of semidehydroascorbate and dopamine [251–254]. The Km for ascorbate is ∼0.6 mM [243,251], and the adrenals and neurons supporting this activity contain 10–20 mM ascorbate, the highest concentrations in the body [5,36,37,49,51]. These tissues accumulate ascorbate very efficiently and retain their content when plasma supply is limited [114], suggesting adaptation to ensure ongoing optimal dopamine β-hydroxylase activity.
Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Requirement 2 is a difficult one to fulfill in light of the ubiquitous nature of many of the body’s enzymes. In this regard adrenomedullary enzymes are especially instructive. The four enzymes responsible for the sequential conversion of tyrosine to epinephrine have been characterized5-7 and are shown in Figure 2. Dopa decarboxylase is widely distributed in mammalian tissues such as brain, liver, kidney, lung, adrenal medulla, and sympathetic nerve endings. In addition to the adrenal medulla, tyrosine hydroxylase and dopamine-β-hydroxylase are found in adrenergic nerves and thus in organs such as heart and spleen. Of the four enzymes, only phenylethanolamine-N-methyltransferase (PNMT) is found exclusively in the adrenal medulla (a small amount is found in the brain stem) and thus radiolabeled inhibitors of this enzyme represent perhaps the most feasible approach to developing a scanning agent for the adrenal medulla.
Autonomic Neuropathy and the Heart in Diabetes
Published in Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla, Heart Dysfunction in Diabetes, 2019
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla
Previous studies53 have examined NE turnover in the control and diabetic hearts 8 weeks after streptozotocin injection. The disappearance of the specific activity of cardiac NE followed first-order kinetics over the time period examined (1 to 8 hr after the injection of 3H-NE); the slope of the 3H-NE disappearance curve in the diabetic group was steeper than that in the control group indicating higher turnover rate in diabetic rats. An increased turnover of cardiac NE stores should be accompanied by an increased synthesis if NE levels are to be maintained at a high level. Table 3 shows that diabetic hearts had, in fact, higher activities of synthetic enzymes responsible for NE formation. Both tyrosine hydroxylase as well as dopa decarboxylase activities were found to be increased in diabetic hearts. Such an increase in the enzyme activities did not appear to be due to a denser sympathetic innervation as a result of the decrease in total ventricular mass because higher activities were still apparent in diabetic animals when the values were expressed per heart instead of per gram weight. Recently, the activity of dopamine β-hydroxylase, the final enzyme in the synthesis of NE, was found to be lower in diabetic heart.54 It is possible that an increased exocytotic release of this enzyme as a result of very high sympathetic activity depletes this enzyme in the heart. This view is substantiated by the fact that dopamine (β-hydroxylase is increased in plasma obtained from diabetic rats.55
Functional role of ascorbic acid in the central nervous system: a focus on neurogenic and synaptogenic processes
Published in Nutritional Neuroscience, 2022
Morgana Moretti, Ana Lúcia S. Rodrigues
Ascorbic acid (vitamin C) is a water-soluble vitamin that exerts numerous essential cellular and molecular functions, including neuronal neuromodulation and regulation of CNS homeostasis [1]. Ascorbic acid is a reducing agent, and several physiological functions of this compound depend on its redox property [2]. Aside from its antioxidant effects [3] and its ability to act as a cofactor for the collagen biosynthesis enzymes lysyl hydroxylase and prolyl hydroxylase [4], ascorbate (the dominant form at physiological pH) is required as a cofactor for several enzymes that play an important role in the central nervous system. For example, it is a cofactor of dopamine β-hydroxylase, the enzyme that catalyzes the conversion of dopamine into norepinephrine [5]. Ascorbate is also an essential cofactor for the synthesis of many neuropeptides [6]. Moreover, it is involved in the formation of the myelin sheath by Schwann cells [7,8], and regulates the sodium-potassium ATPase enzyme [9,10]. Studies also demonstrated that ascorbate can modulate acetylcholine release in synaptic vesicles from rat brain synaptosomes [11] and cultured adrenal chromaffin cells [12].
Dopamine β hydroxylase as a potential drug target to combat hypertension
Published in Expert Opinion on Investigational Drugs, 2020
Sanjay Kumar Dey, Manisha Saini, Pankaj Prabhakar, Suman Kundu
Such attempts during the last few years include the development of inhibitors of mineralocorticoid receptor, antagonists of vasopeptidases, aldosterone synthase, and soluble epoxide hydrolase, activators of natriuretic peptide A and vasoactive intestinal peptide receptor 2, inhibitors of aminopeptidase A, intestinal Na+/H+ exchanger 3 inhibitors, activators of key players of the angiotensin-converting enzyme 2, angiotensin (1–7), Mas receptor axis, vaccines against angiotensin II and its type 1 receptor among others [4]. Nevertheless, there have been no new class of drugs of late which can utilize body’s own BP lowering mechanism with fewer side effects, desired systolic and diastolic BP (SBP and DBP) and the ability to combat resistant hypertension. Dopamine β hydroxylase (DBH), a key enzyme of the dopaminergic pathway, is involved in the sympathetic nervous system (SNS) and plays a central role in regulating BP through dopaminergic receptors [17]. This enzyme is explored in this review as a novel drug target to treat hypertension, including resistant, portal, and pulmonary hypertension. We review the current research progress and available inhibitors of DBH with their advantage and disadvantages. We also outlined a direction for utilizing existing as well as new in silico, in vitro, ex vivo, and in vivo tools for rapid identification and validation of novel inhibitors of DBH.
Chemical pharmacotherapy for the treatment of orthostatic hypotension
Published in Expert Opinion on Pharmacotherapy, 2019
Approximately one-third of patients with persistent OH have nOH, which is a cardinal manifestation of sympathetic adrenergic failure [34]. NOH results from deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic postganglionic nerve terminals. This can occur at the level of the central or the peripheral nervous system. Congenital adrenergic failure occurs in dopamine β-hydroxylase deficiency. Central adrenergic failure occurs in diseases such as multiple system atrophy (MSA) that destroy brain stem or spinal cord pathways that mediate sympathetic outflow. Ganglionic adrenergic failure occurs in diseases such as autoimmune autonomic ganglionopathy in patients with α3-ganglionic neuronal acetylcholine receptor antibodies which interrupt sympathetic neurotransmission in the sympathetic chain ganglia. Peripheral adrenergic failure occurs in diseases that impair postganglionic sympathetic neurons innervating vascular adrenoceptors. Examples include PAF, Parkinson’s disease (PD), Lewy body dementia, amyloid autonomic neuropathy, and diabetic autonomic neuropathy.