Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-mortem brain material from control and Parkinson's disease patients was examined to elucidate further the neurochemistry of this disease and to determine the mechanism of action of L-dopa as a therapeutic agent. The activities of L-aromatic amino acid decarboxylase (dopa D), tyrosine hydroxylase, monoamine oxidase and catechol-O-methyl transferase were examined; in addition the tissue levels of dopa, 3-O-methyldopa, dopamine (DA) and homovanillic acid (HVA) were determined. In the non-dopa-treated Parkinsonian patients, the greatest decreases were detected for striatal DA and dopa D, with homovanillic acid and tyrosine hydroxylase levels showing a lesser change. The activities of monoamine oxidase and catechol-O-methyl transferase in the striatal nuclei were not different from the controls. The putamen was consistently the most severely affected region. Dopa and 3-O-methyldopa were detectable in all brain areas only in those patients treated with L-dopa shortly before death. The mean concentrations of DA in the striatum of these patients were 1) 9 to 15 times higher than those in non-dopa-treated patients, 2) related to the time before death of the last dose of L-dopa and 3) greater in the striatum of patients clinically classified as "good responders" as compared to "poor responders." Although L-dopa therapy increased homovanillic acid levels in all brain areas, a preferential increase was observed in the striatum. It was concluded that L-dopa's principal therapeutic effects in Parkinson's disease are consistent with its transformation to DA in the striatum.
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PMID:The neurochemistry of Parkinson's disease: effect of L-dopa therapy. 0 Apr 89

The audiogenic seizure-inducing drug H13/04 was found to elicit opposing effects on the in vivo accumulation of 5-HTP (5-hydroxytryptophan) and DOPA (3,4-dihydroxyphenylalanine) in the brain following inhibition of L-amino acid decarboxylase. In strains of mice that normally do not exhibit audiogenic seizures, H13/04 retarded the accumulation of 5-HTP in the telencephalon, diencephalon and brainstem and enhanced the accumulation DOPA in the diencephalon and brainstem. The duration of the biochemical action of H13/04-correlated with the duration of the behavioral effect. When H13/04 is administered to strains of mice with a genetically-determined susceptibility to audiogenic seizures, but at an age when they are developing resistance to seizures, H13/04 does not alter the incidence of sound-induced seizures. The effect on the accumulation of 5-HTP and DOPA was similar to that noted in the genetically-resistant strain; a retardation of the accumulation of 5-HTP in the telencephalon and brainstem and an enhancement of DOPA accumulation in the brainstem. Since the rate of accumulation of 5-HTP and DOPA is a measure of the in vivo rates of tryptophan and tyrosine hydroxylase, respectively, the results may reflect changes in neural activity with consequent effects on the synthesizing enzymes. These results emphasize the usefulness of the drug in analyzing central mechanisms underlying audiogenic seizure activity and in studying functional properties and interactions of the central catechol-and indoleamine systems.
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PMID:Central action of a catechol-amide seizure-inducing agent: opposing effect on tyrosine and tryptophan hydroxylase activity in vivo. 0 34

Tyrosine hydroxylase (EC1.14.16.2), presumably the rate-limiting enzyme in the biosynthesis of catecholamines, is known to catalyze the hydroxylation of both phenylalanine and tyrosine. Using both an isolated enzyme preparation and a synaptosomal preparation, where some architectural integrity of the tissue has been preserved, we have attempted to evaluate the manner in which these two substrates are hydroxylated by rat brain tyrosine hydroxylase. In the presence of tetrahydrobiopterin the isolated enzyme catalyzes the hydroxylation of phenylalanine to 3,4-dihydroxyphenylalanine with the release of free tyrosine as an obligatory intermediate. In contrast, the rat brain striatal synaptosomal preparation in the presence of endogenous cofactor converts phenylalanine to 3,4-dihydroxyphenylalanine without the release of free tyrosine.
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PMID:Studies on phenylalanine and tyrosine hydroxylation by rat brain tyrosine hydroxylase. 0 89

Previous studies indicating the importance of catecholamine metabolism in neuroblastoma were briefly reviewed. Metabolic pathways were presented showing how the major urinary metabolites 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA) are formed from norepinephrine and from dopamine plus 3,4-dihydroxyphenylalanine (DOPA), respectively. For 289 neuroblastoma patients at the time of diagnosis, the urinary excretion of VMA was significantly elevated in 75%, and HVA was elevated in 80%. Periodic assay of these metabolites during the course of the disease revealed that the excretion trends were of prognostic value with 80-90% reliability. By contrast, when the excretion in only the initial urine specimens was considered, the survival rate was the same for patients with normal, and with significantly elevated, excretion. Review of the results of tracer studies aimed at elucidating the in vivo metabolic origins of the urinary metabolites suggested that a) in neuroblastoma, the catecholamines were largely inactivated by intracellular metabolism in the tumor cells; b) there was excess production and excretion of the norepinephrine precursors, DOPA and dopamine; and c) in the tumors of most neuroblastoma patients, the initial enzyme in catecholamine synthesis, tyrosine hydroxylase, had an activity comparable with that in normal adrenal glands. The importance of the metabolism of catecholamines in patients with neuroblastoma was stressed: a) The excretion of elevated levels of urinary catecholamine metabolites were useful in diagnosis and in following the course of the disease, and b) study of the catecholamine metabolism in these patients permitted examination of possible relationships between the activity of the enzymes involved in catecholamine synthesis and the malignancy of this tumor.
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PMID:Catecholamine metabolism in neuroblastoma. 1 Apr 50

An in vivo system has been used to investigate the ability of dopamine agonists and antagonists to alter dopamine synthesis by acting at what appear to be presynaptic dopamine receptors. In order to eliminate postsynaptically induced changes in dopamine synthesis caused by the effects of these drugs on the firing rate of dopamine neurons, gammabutyrolactone was administered to block impulse flow in the nigro-neostriatal pathway. The accumulation of Dopa in the rat striatum after administration of Dopa decarboxylase inhibitor was used as an index of striatal tyrosine hydroxylase activity. It was found that administration of the dopamine agonists, apomorphine or ET-495 [1-(2-pyrimidyl)-piperonyl-piperazine], modified the apparent activity of striatal tyrosine hydroxylase when impulse flow was blocked in dopamine neurons. This presynaptic effect of apomorphine could be prevented by low doses of loxapine haloperidol and spiroperidol. Chlorpromazine, fluphenazine, and thioridizine were much less effective than the butyrophenones in blocking the effects of apomorphine. Molindone and (+) butaclamol, but not (-) butaclamol, reversed the presynaptic agonist effects, pimozide was a weak blocker and clozapine had no effect at all. All these neuroleptics except (-) butaclamol caused a significant increase in Dopa accumulation when impulse flow was intact. Compared with haloperidol the phenothiazines and pimozide appeared less potent in reversing the presynaptic effects of apomorphine than in blocking the behavioral effects of this agonist. Possible functional significance of the presynaptic dopamine receptors are considered.
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PMID:Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors. 1 15

Postmortem changes in the activities of tyrosine hydroxylase, dopa decarboxylase, and dopamine-beta-hydroxylase were examined in various areas of rat brain. Tyrosine hydroxylase activity decreased in an exponential fashion with a half-time of two to four hours in caudate-putamen, substantia nigra, and locus ceruleus. Dopa decarboxylase activity remained within 20% of control values at five hours in these areas, but then decreased precipitously. Dopamine-beta-hydroxylase activity remained within 20% of control for at least 20 hours after death.
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PMID:Postmortem changes in brain catecholamine enzymes. 23 34

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.
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PMID:Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT. 23 55

The morphine (75 mg/kg i.p.) induced stimulation of motor activity in mice was significantly suppressed by small doses of central catecholamine (CA) receptor agonists, apomorphine (0.2 mg/kg) and clonidine (0.05 mg/kg). In the same dose, and at the same time interval as the behavioural stimulation was obtained, morphine did not significantly affect the in vivo rate of tyrosine hydroxylation in two dopamine (DA)-rich mouse brain regions, the corpus striatum and in the limbic system, or in the noradrenaline (NA)-rich, but DA-poor hemispheres, measured as the Dopa-accumulation during 30 min after inhibition of aromatic amino-acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015) 150 mg/kg. The apomorphine induced reduction in Dopa accumulation in the DA-rich brain regions was not significantly affected by morphine. The disappearance rate of brain NA after inhibition of tyrosine hydroxylase by alpha-methyltyrosine methylester (250 mg/kg), the utilization of NA, was accelerated by morphine, whereas that of DA was not affected. Clonidine (0.05 mg/kg) retarded selectively brain NA utilization, and also suppressed the morphine-induced increase in NA utilization. In conclusion, morphine's stimulation of motor activity in mice, an effect which previously has been found to be correlated with its dependence producing action, could be inhibited by apomorphine or clonidine in small doses which inhibit brain DA- and NA-neurons, respectively. Thus, we have now shown the psychomtor stimulation by two euphoriant and dependence-producing drugs, ethanol and morphine, to be suppressed by CA "autoreceptor" activation.
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PMID:Antagonism of morphine-induced central stimulation in mice by small doses of catecholamine-receptor agonists. 69 Jun 27

The synthesis and release of noradrenaline (NA) in the heart and submaxillary glands were studied in the rat following s.c. injections of oxymetazoline (50 mug/kg) or noradrenaline (500 mug/kg). NA release was evaluated from the decline in tissular specific radioactivity after administration of 3H-NA and NA synthesis by the estimation of the amounts of 3H-NA synthesized from 3H-tyrosine (TY) or 3H-Dopa, 30 min after the injection. Oxymetazoline treatment delayed the release of NA, the NA biological half-lives rising from 12 up to 36 hours in the heart and from 5.9 up to 21 hours in sub-maxillary glands. This inhibitory effect on NA release was interpreted as the consequence of the stimulation of alpha-adrenoreceptors. Thirty minutes after its injection, oxymetazoline increased both NA endogenous levels and 3H-NA amounts formed from 3H-TY: 3H-NA specific activities were not significantly altered. NA treatment led to an acceleration of NA release in the heart (NA biological half-life decreasing from 12 to 2.2 hours) but not in sub-maxillary glands. After injection of 3H-TY, the amounts of 3H-NA found in the heart and sub-maxillary glands were strongly reduced. Similar results were observed in the heart using 3H-Dopa as a precursor. These data are interpreted as the consequence of the removal of the newly synthesized 3H-NA by exogenous NA. The results obtained with oxymetazoline point out a dissociation between the NA release which is reduced and the NA synthesis which is unaltered. This indicates that NA synthesis rate by sympathetic nerve terminals is not immediately regulated by its release intensity. These data do not support the end-product feedback inhibition hypothesis according to which tyrosine hydroxylase is regulated by the intraneuronal NA concentration.
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PMID:Effect of the activation of alpha-adrenoreceptors on the synthesis and release of noradrenaline by peripheral adrenergic nerves in vivo. 97 94

Several genes critical to the regulation of melanin production in mammals have recently been cloned and characterized. They map to the albino, brown, and slaty loci in mice, and encode proteins with similar structures and features, but with distinct catalytic capacities. The albino locus encodes tyrosinase, an enzyme with three distinct catalytic activities--tyrosine hydroxylase, 3,4-dihydroxyphenylalanine (DOPA) oxidase and DHI (5,6-dihydroxyindole) oxidase. The brown locus encodes TRP-1 (tyrosinase-related protein-1), which has the same, but greatly reduced, catalytic potential. The slaty locus encodes TRP-2, another tyrosinase related-protein, which has DOPAchrome tautomerase activity. In this study we have examined the enzymatic interactions of these proteins, and their regulation by a novel melanogenic inhibitor. We observed that tyrosinase activity is more stable in the presence of TRP-1 and/or TRP-2, but that the catalytic function of TRP-2 is not affected by the presence of TRP-1 or tyrosinase. Other factors also may influence melanogenesis and a unique melanogenic inhibitor suppresses tyrosinase and DOPAchrome tautomerase activities, but does not affect the spontaneous rate of DOPAchrome decarboxylation to DHI. The results demonstrate the catalytic functions of these proteins and how they stably interact within a melanogenic complex in the melanosome to regulate the quantity and quality of melanin synthesized by the melanocyte.
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PMID:Functional properties of cloned melanogenic proteins. 129 7


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