Dopamine-P-hydroxylase

Methoxatin, now known as coenzyme PQQ, was originally obtained from methylotrophic bacteria but is now known to be a mammalian cofactor, for example, for lysyl oxidase and dopamine p-hydroxylase. The first synthesis of this rare compound was accomplished by the route outlined below. In the retrosynthetic analysis both of the heterocyclic rings were disconnected using directly keyed transforms. 

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

Nagaya T, Ishikawa N, Hata H. 1990. No change in serum dopamine-P-hydroxylase activity in workers exposed to trichloroethylene. Toxicol Lett 54 221-227. 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

Figure 8.5 The synthetic pathway for noradrenaline. The hydroxylation of the amino acid, tyrosine, which forms dihydroxyphenylalanine (DOPA) is the rate-limiting step. Conversion of dopamine to noradrenaline is effected by the vesicular enzyme, dopamine-P-hydroxylase (DpH) after uptake of dopamine into the vesicles from the cell cytosol...

Because LCEC had its initial impact in neurochemical analysis, it is not, surprising that many of the early enzyme-linked electrochemical methods are of neurologically important enzymes. Many of the enzymes involved in catecholamine metabolism have been determined by electrochemical means. Phenylalanine hydroxylase activity has been determined by el trochemicaUy monitoring the conversion of tetrahydro-biopterin to dihydrobiopterin Another monooxygenase, tyrosine hydroxylase, has been determined by detecting the DOPA produced by the enzymatic reaction Formation of DOPA has also been monitored electrochemically to determine the activity of L-aromatic amino acid decarboxylase Other enzymes involved in catecholamine metabolism which have been determined electrochemically include dopamine-p-hydroxylase phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase . Electrochemical detection of DOPA has also been used to determine the activity of y-glutamyltranspeptidase The cytochrome P-450 enzyme system has been studied by observing the conversion of benzene to phenol and subsequently to hydroquinone and catechol... 

There are no proven pharmacotherapies for treatment of cocaine or amphetamine dependence. Disulfiram, however, shows some promise in randomized controlled trials for treating cocaine dependence at doses of 250 mg daily, especially in combination with CBT.45 Its mechanism of action for treating cocaine dependence is not known, but may be due to its inhibition of the dopamine P-hydroxylase enzyme that converts DA to NE in the brain. The resulting increase in DA levels may counter the DA-deficient state that is believed to underlie cocaine withdrawal and craving. 

As the result of a screening program examining microbial fermentation products for pharmacological activity (other than antibiotic activity), fusaric acid (10) was isolated from Fusarium oxysporum following the discovery that extracts were potent inhibitors of dopamine p-hydroxylase, and thus interfered with the biosynthesis in vivo of the pressor neurohormone, norepinephrine. To refine this lead, amidation of 10 via the acid chloride was carried out... 

For neurons that synthesize epinephrine or norepinephrine, dopamine P-hydroxylase is the next step in the biosynthetic pathway 213... 

Weinshilboum, R. M., Thoa, N. B., Johnson, D. G., Kopin, I. J. and Axelrod, J. Proportional release of norepinephrine and dopamine-P-hydroxylase from sympathetic nerves. Science 174 1349-1351,1971. 

Alaniz, R.C. et al., Dopamine P-hydroxylase deficiency impairs cellular immunity, Proc. Natl. Acad. Sci. USA, 96, 2274, 1999. 

Dopastin is an experimental antihypertensive agent which has been noted to potently inhibit copper-dependent dopamine p hydroxylase [100]. The pharmacological... 

An enzyme inhibitor of microbial origin with a simple structure, fusaric acid (XXXIV), is a hypotensive agent. This compound has been tested clinically as the free acid (29) and as the calcium salt (30) and is orally effective in man with a low incidence of side-effects. Dopamine-p-hydroxylase inhibitory action of this compound has been demonstrated in man (29). 

Introduction of chlorine or bromine into the 3- and/or 4- positions of the side chain yields more potent compounds in terms of hypotension in rats and dopamine p- hydroxylase inhibition (31. 32). The analog YP-279 (XXXV) is also hypotensive in rats but is said not to affect brain norepinephrine biosynthesis unlike fusaric acid or dibromofusaric acid (33-35). Fusaric acid amide (bupicomide, Sch 10595, XXXVI) is clinically effective at 300 to 1800 mg per day and is said to have hemodynamic effects similar to hydralazine (36. 37). The amide is... 

Copper is a component of many enzymes including amine oxidase, lysyl oxidase, ferroxidase, cytochrome oxidase, dopamine P-hydroxylase, superoxide dismutase and tyrosinase. This latter enzyme is present in melanocytes and is important in formation of melanin controlling the colour of skin, hair and eyes. Deficiency of tyrosinase in skin leads to albinism. Cu " ion plays an important role in collagen formation. 

Tyrosinase is a monooxygenase which catalyzes the incorporation of one oxygen atom from dioxygen into phenols and further oxidizes the catechols formed to o-quinones (oxidase action). A comparison of spectral (EPR, electronic absorption, CD, and resonance Raman) properties of oxy-tyrosinase and its derivatives with those of oxy-Hc establishes a close similarity of the active site structures in these proteins (26-29). Thus, it seems likely that there is a close relationship between the binding of dioxygen and the ability to "activate" it for reaction and incoiporation into organic substrates. Other important copper monooxygenases which are however of lesser relevance to the model studies discussed below include dopamine p-hydroxylase (16,30) and a recently described copper-dependent phenylalanine hydroxylase (31). 

Transition metal hydroperoxo species are well established as important intermediates in the oxidation of hydrocarbons (8,70,71). As they relate to the active oxygenating reagent in cytochrome P-450 monooxygenase, (porphyrin)M-OOR complexes have come under recent scmtiny because of their importance in the process of (poiphyrin)M=0 formation via 0-0 cleavage processes (72-74). In copper biochemistry, a hydroperoxo copper species has been hypothesized as an important intermediate in the catalytic reaction of the copper monooxygenase, dopamine P-hydroxylase (75,76). A Cu-OOH moiety has also been proposed to be involved in the disproportionation of superoxide mediated by the copper-zinc superoxide dismutase (77-78). Thus, model Cun-OOR complexes may be of... 

Diliberto. E. J., Jr., Kaufman, S. Lack of inhibition of dopamine-p-hydroxylase by superoxide dismutase. In Superoxide and Superoxide Dismutases (Michelson, A. M., McCord, J. M Fridovich, I., eds.), London-New York-San Francisco, Academic Press, 1977, pp. 407-408... 

Dopamine-p-hydroxylase (from bovine adrenal medulla) [9013-38-1] Mr -290,000 [EC. 

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