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Attributes of Peripheral Dopamine and Dopamine Receptors
Published in Nira Ben-Jonathan, Dopamine, 2020
The homeostasis of catecholamines is covered in great detail in Chapter 1. Here we recapitulate some of the salient features that are especially pertinent to peripheral catecholamines. The three catecholamines, DA, NE, and Epi, are synthesized by four sequential enzymes (Figure 1.1). The first enzyme, tyrosine hydroxylase (TH), converts tyrosine to dihydroxyphenylalanine (Dopa) by inserting an OH group on the ring. Tyrosine circulates at a concentration of 1–1.5 mg/dL and enters the cells by an active transport. TH serves as the rate-limiting step and is expressed in a number of peripheral organs and tissues. The second enzyme, Dopa decarboxylase (DDC; also known as aromatic L-amino acid decarboxylase), generates DA from Dopa by removing the carboxyl group from the side chain and is widely expressed. Dopa can also become available to catecholamine-producing cells from the circulation. Cells that express the third enzyme, dopamine β-hydroxylase (DBH), which inserts an OH group on the side chain, can synthesize NE as a final product. Expression of phenylethanolamine N-methyl-transferase (PNMT), which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to NE, enables the production of Epi. Within the adrenals, the high concentration of cortisol, which diffuses from the zona fasciculata of the cortex to the adrenal medulla, enhances PNMT expression. This accounts for the fact that in the normal human adrenal medulla, about 80% of the catecholamine content is Epi, while only 20% is NE.
Genetic Disorders of the Autonomic Nervous System
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
No cases of deficiency in phenylethanolamine N-methyltransferase (PNMT) have yet been reported. The major reason to suspect that some individuals have this disorder is that individuals with DBH deficiency, with absence of noradrenaline and adrenaline, have now been recognized. Presumably, if individuals can survive in the absence of both these neurotransmitters, they should also be able to survive in the absence of adrenaline alone. This presupposes that PNMT’s sole action is to convert noradrenaline into adrenaline, a traditional view that has been challenged by the finding that some PNMT-containing neurons in the medulla oblongata do not contain DBH; this could mean that in some sites it might act on a different substrate to produce a hitherto unrecognized product.
Overview
Published in Stephen W. Carmichael, Susan L. Stoddard, The Adrenal Medulla 1986 - 1988, 2017
Stephen W. Carmichael, Susan L. Stoddard
Phenylethanolamine N-methyltransferase (PNMT) is the enzyme that converts norepinephrine to epinephrine. The complete nucleotide and deduced amino acid sequence of bovine PMNT was reported by Baetge, Suh and Joh (1986) and Batter, D’Mello, Turzai et al. (1988). The human enzyme has also been sequenced (Baetge, Behringer, Messing et al., 1988; Kaneda, Ichinose, Kobayashi et al., 1988).
Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland
Published in Clinical and Experimental Hypertension, 2020
Diogo Nóbrega Catelas, Maria Paula Serrão, Patricio Soares-Da-Silva
Another relevant observation concerning the adrenal medulla is that related to the marked effect of nepicastat upon EPI levels, when compared to that upon NE tissue levels, which is in line with the fact that the activity of phenylethanolamine N-methyltransferase (PNMT; the enzyme that catalyzes the conversion of NE to AD) is 1 order of magnitude higher than the activity of DβH (24). Taking this into account, we would expect higher basal values of EPI than those of NE, which we found and has also been previously described (25). Indeed, tissue levels in the adrenal medulla were threefold those of NE tissue levels in vehicle-treated rats and, as mentioned, inhibition of DβH activity (93% and 80% decrease 4 h and 8 h postdrug administration) in the nepicastat-treated rats resulted in a more marked reduction in EPI tissue levels than in NE tissue levels. This is probably related to the sequence of events and the time at which each of them is occurring; the first consequence of the nepicastat-induced inhibition of DβH activity is the decrease in NE availability for its subsequent conversion through phenyl-N-methyltransferase to AD, whereas when this second step takes place DβH activity is already recovering from inhibition by nepicastat.
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Catecholamines are a group of compounds that are each structurally made up of a catechol group and an amine. Catecholamines act as hormones in the periphery, and as neurotransmitters in the CNS. The predominant catecholamines in the brain are dopamine, norepinephrine, and epinephrine. Catecholamines are derived mainly from l-tyrosine. Tyrosine hydroxylase mediates the oxidation of l-tyrosine to l-DOPA, which is the rate-limiting step in catecholamine biosynthesis. DOPA decarboxylase catalyzes the removal of the carboxyl group from DOPA to form dopamine. Dopamine is oxidized by dopamine β-hydroxylase to form norepinephrine. Finally, a methyl group is transferred to norepinephrine by phenylethanolamine N-methyltransferase (PNMT) to form epinephrine. Hiroi and coworkers described an alternative dopamine biosynthetic pathway mediated by human CYP2D6 that involves the hydroxylation of tyramine (Figure 3) (Hiroi et al. 1998). CYP2D-mediated synthesis of dopamine from tyramine in the brain has been shown in vitro and in vivo (Bromek et al. 2010, 2011). In rats, only three of the six isoforms of CYP2D enzymes are capable of forming dopamine from tyramine (CYP2D2, 2D4, and 2D18), and these are less efficient than human CYP2D6. Therefore, it has been assumed that CYP2D-mediated dopamine biosynthesis is greater in humans (Bromek et al. 2010). Human CYP2D6 is expressed in neuronal and glial cells of diverse brain regions (Table 1).
Factors contributing to development and resolution of dysglycemia in patients with pheochromocytomas and catecholamine-secreting paragangliomas
Published in Annals of Medicine, 2023
Lin Zhao, Ting Zhang, Xu Meng, Zenglei Zhang, Yi Zhou, Hua Fan, Yecheng Liu, Xianliang Zhou, Huadong Zhu
The enzyme phenylethanolamine-N-methyl transferase is responsible for conversion of norepinephrine to epinephrine in the adrenal glands. This enzyme is unique to the adrenal gland, brain, and organ of Zuckerkandl. Consequently, the adrenal medulla secretes the catecholamines predominantly as epinephrine [18]. As epinephrine exerts a heavier impact on glucose metabolism when compared to norepinephrine, dysglycemia may be more likely to occur in patients with PHEOs. Therefore, clinicians should screen for dysglycemia in patients with PHEOs. Besides, many of our patients who had dysglycemia did not have elevated BMI, this suggests that if dysglycemia is present in surprisingly lean patients, the presence of PPGLs should be vigilant.