Dopamine-/J-hydroxylase

It is possible to deplete the brain of both DA and NA by inhibiting tyrosine hydroxylase but while NA may be reduced independently by inhibiting dopamine jS-hydroxylase, the enzyme that converts DA to NA, there is no way of specifically losing DA other than by destruction of its neurons (see below). In contrast, it is easier to augment DA than NA by giving the precursor dopa because of its rapid conversion to DA and the limit imposed on its further synthesis to NA by the restriction of dopamine S-hydroxylase to the vesicles of NA terminals. The activity of the rate-limiting enzyme tyrosine hydroxylase is controlled by the cytoplasmic concentration of DA (normal end-product inhibition), presynaptic dopamine autoreceptors (in addition to their effect on release) and impulse flow, which appears to increase the affinity of tyrosine hydroxylase for its tetrahydropteridine co-factor (see below). 

An alternative approach for the synthesis of the (/ )-(-)-6-[ F]FNE enantiomer was described by Lui et al. Here 6-[ F]FDA was converted into (/ )-(-)-6-[ F]FNE enzymatically by dopamine jS-hydroxylase with an optical purity of at least 90%. Compared to the aforementioned synthesis approach, the enzymatic method offers the advantage of avoiding the enantiomeric resolution [157]. 

As a first step toward a dopamine-jS-hydroxylase mimic, basket-shaped receptor 17 was functionalized with two sets of bis-[2-(3,5-dimethyl-l-pyra-zolyl)ethyl]amine ligands to give compound 35 (see Scheme 5). Reaction of 35 with Cu(C104,)2-6H20 yielded complex 36 which was fully characterized [39], Ligand system 35 binds dopamine derivative 37 and phloroglucinol (1,3,5-trihydroxybenzene) with association constants of = 60 and 3500 respectively. The affinity of the Cu(I) analogon of 36 for 37 was very similar to that of 36 itself and amounted to Ka = 60 M L Resorcinol is bound in the cavity of the Cu(I) complex with a Xj-value of 2(XX) M". ... 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

Analysis of dopamine-jS-hydroxylase activity in plasma can not be used to make a definitive diagnosis, as approximately 4% of the population have very low plasma activities. Support for such a diagnosis can come from examining the noradrenaline dopamine ratio in plasma. This is markedly reduced in this condition. Deficiencies of the MAO isoforms have been confirmed from enzymatic analysis of fibroblasts (MAO-A) or platelets (MAO-B). 

Copper has an essential role in a number of enzymes, notably those involved in the catalysis of electron transfer and in the transport of dioxygen and the catalysis of its reactions. The latter topic is discussed in Section 62.1.12. Hemocyanin, the copper-containing dioxygen carrier, is considered in Section 62.1.12.3.8, while the important role of copper in oxidases is exemplified in cytochrome oxidase, the terminal member of the mitochondrial electron-transfer chain (62.1.12.4), the multicopper blue oxidases such as laccase, ascorbate oxidase and ceruloplasmin (62.1.12.6) and the non-blue oxidases (62.12.7). Copper is also involved in the Cu/Zn-superoxide dismutases (62.1.12.8.1) and a number of hydroxylases, such as tyrosinase (62.1.12.11.2) and dopamine-jS-hydroxylase (62.1.12.11.3). Tyrosinase and hemocyanin have similar binuclear copper centres. 

Several diverse metal centres are involved in the catalysis of monooxygenation or hydroxylation reactions. The most important of these is cytochrome P-450, a hemoprotein with a cysteine residue as an axial ligand. Tyrosinase involves a coupled binuclear copper site, while dopamine jS-hydroxylase is also a copper protein but probably involves four binuclear copper sites, which are different from the tyrosinase sites. Putidamonooxin involves an iron-sulfur protein and a non-heme iron. In all cases a peroxo complex appears to be the active species. 

Maneb possesses chelating properties, allowing it to possibly interfere with a number of enzyme systems that contain metals such as zinc, copper, and iron (e.g., dopamine jS-hydroxylase). It is also capable of inhibiting sulfhydryl-containing enzymes and some other enzyme systems involved in glucose metabolism. 

Figure 12.4. Pathways in the metabolism of L-dopa (1) and its major decarboxylated product dopamine (2). Major (heavy arrows) and minor (light arrows) reactions are indicated. AD, aldehyde dehydrogenase AAD, aromatic L-amino acid decarboxylase COMT, catechol-O-methyltransferase DH, dopamine jS-hydroxylase MAO, monoamine oxidase PNMT, phenylethanolamine-N-methyl-transferase.

Neuromodulatory transmitter inputs to MOB. Darkfield photomicrographs showing the distribution of cholinergic (a), noradrenergic (b), and serotonergic (c) fibers revealed respectively with immunohistochemistry for choline acetyltransferase (ChAT), dopamine-jS-hydroxylase (DBH), and serotonin (5-HT). Reprinted from Handbook of Chem. Neuroanat. Integrated Sys. CNS, Vol. 12, Part III, Chapter III, The Olfactory System, M. Shipley et al., pp. 469-573, 1996, with permission from Elsevier, Ltd... 

Tyrosine is the precursor for the synthesis of the hormone and neurotransmitter noradrenalin which is formed from dopamine (3,4-dihydroxyphenylethanolamine) by the vitamin C-requiring dopamine j8-mono-oxygenase (also called dopamine-jS-hydroxylase) in the adrenal medulla as shown in Figure 5.14. 

Both the above hydroxylations seem to involve the recycling of tetrahydrobiopterin which may require ascorbic acid. Recently it has been suggested that dopamine-jS-hydroxylase (DBH) works in tandem with semidehydroascorbate reductase (SDR) in order to recycle the vitamin and oxidise NADHj as in Figure 5.15. 

Since the phenylethylamines 312 produced by these decarboxylases are substrates for systems containing dopamine jS-hydroxylase (EC 1.14.17.1), the availability of 7>R and 3S isotopically labeled samples of the aromatic amino acids has allowed the stereochemistry of the hydroxylation of dopamine 313 to yield norepinephrine 314 to be studied (Scheme 83). It was shown that the 3-pro-S hydrogen, Hg, was lost from phenylalanine 297a in the process and that the hydroxylation yielding 314 therefore occurred with retention of configuration (319). 

C9H17N3O3, Mr 215.25, needles, mp. 116-119°C, pK, 5.1, [oId 246" (C2H5OH). D. is isolated from cultures of a Pseudomonas strain and is an inhibitor of dopamine jS-hydroxylase it exhibits hypotensive activity and inhibits the germination of barley. 

For example, 4-hydroxy benzyl cyanide is an IMBI that can inhibit dopamine jS-hydroxylase. Inhibition of this enzyme decreases production of epinephrine and it is hoped that this IMBI will turn out to be useful in reducing sympathetic tone (Baldoni, Villafranca and Mallettee, 1980). 

It was argued [1256] that provided the tropolones did not act simply as metal ion scavangers (as in the case, for example, with ethylene diamine tetra-cetic acid [1258]), since chelation with metal ions undoubtedly underlies the antifungal properties [1259, 1260] of the thujaplicins and their congeners, then they should be able to compete with the catecholamines for the active enzymic site. The results showed that some of the tropolones, including the two thujaplicins, did in fact act in this way. Presumably the inhibition [1261] of dopamine jS-hydroxylase by y-thujaplicin occurs by a similar mechanism. 

Tyramine is oxidized to octopamine by dopamine-jS hydroxylase causing hydroxylation of the carbon atom of its side chain. Octopamine is converted to / -hydroxymandelic acid either directly or after being methylated to AT-methyloctopamine. The introduction of an OH group in the meta or para position in the nucleus of / - and m-tyramine respectively leads in vitro to the production of dopamine it is not known if... 

Biologically the most important metabolic pathway for dopamine is the hydroxylation of its side chain giving noradrenaline. The reaction is catalysed by dopamine-jS-hydroxylase. A -acetylation of dopamine gives N acetyldopamine, 336,i836) powerful inhibitor of dopa-decarboxylase. (768) jV-methylation gives epinine(= A -methyldopamine) which has not so far been shown to occur in man, this may be subsequently hydroxylated in vitro to give adrenaline. Dopamine is deaminated oxidatively to... 

The morphology of the carotid body resembles chromaffin tissues expressing catecholamines. Now it is fairly established that carotid bodies express dopamine and norepinephrine, whereas there is no convincing evidence for epinephrine. Type I cells from a variety of species express tyrosine hydroxylase (TH) and dopamine jS hydroxylase (DBH), the enzymes responsible for the synthesis of dopamine (DA) and norepinephrine (NE), respectively (10,20,91). In addition, nerve fibers (of sensory as well as autonomic origin) and ganghon cells also show TH immunoreactivity (91). The actions of DA and NE are terminated by a reuptake mechanism involving specific transporters. However, evidence for DA and/or NE transporters in the carotid body is lacking. 

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