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)

Measurements on human brain samples of some enzymes concerned with neurotransmitter synthesis suggest serious losses with age. The most severe loss found was that in striatal tyrosine hydroxylase activity, the rate-controlling enzyme in the synthesis of dopamine. Cell counts in the substantia nigra where this dopaminergic tract originates suggest that the decrease in enzyme activity is partly due to cell loss, but must largely reflect decreased activity of residual cells. It is possible that this loss may account for some of the difficulties in movement seen in aged individuals and that it might be less if pigment formation in these cells could be inhibited.
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PMID:Aging and extrapyramidal function. 1 31

1. Four stereochemical isomers of tetrahydrobiopterin, i.e., 6-L-erythro-, 6-D-erythro-, 6-L-threo-, or 6-D-threo-1,2-dihydroxypropyltetrahydropterin, have been synthesized and used as cofactors for tyrosine hydroxylase (EC 1.14.18.-) purified from the soluble fraction of bovine adrenal medulla. The L-erythro- (the putative natural cofactor) and D-threo isomers showed a striking similarity in their cofactor activities for tyrosine hydroxylase; the remaining two isomeric tetrahydrobiopterins, D-erythro and L-threo isomers, also had very similar cofactor characteristics. 2. The Km values of the L-erythro and D-threo isomers as cofactor were found to be dependent on their concentrations. When their concentrations were below 100 muM, the Km values of the L-erythro and D-threo isomers were fairly low (about 20 muM). However, the Km values were markedly higher (about 150 muM) at concentrations above 100 muM. The same kinetic behavior was also observed with the tetrahydrobiopterin prepared from a natural source (bullfrog). In contrast, the Km value of the L-threo or D-erythro isomer was found to be independent of the concentration and remained constant throughout the concentration examined. 3. The Km values of tyrosine did not show much difference (from 20 muM to 30 muM) with respect to the structure of the four isomeric cofactors. At high concentrations tyrosine inhibited the enzymatic reaction with any one of the four tetrahydrobiopterin cofactors. 4. Oxygen at high concentrations was also inhibitory with any one of the four stereochemical isomers as cofactor. Approximate Km values for oxygen with the tetrahydrobiopterins as cofactor were 1-5%. 5. In contrast to the four isomers of tetrahydrobiopterin, when 6-methyltetrahydropterin or 6,7-dimethyltetrahydropterin was used as cofactor tyrosine or oxygen did no inhibit the enzymatic reaction at high concentrations, and the Km values toward the pterin cofactor, tyrosine, and oxygen were significantly higher than the Km values with the tetrahydrobiopterins as cofactor.
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PMID:Effects of stereochemical structures of tetrahydrobiopterin on tyrosine hydroxylase. 1 20

Using quantitative microfluorimetry in combination with tyrosine hydroxylase inhibition (H44/68) the concentration and turnover of noradrenaline (NA) and dopamine (DA) was studied in the subependymal layer (SEL) and the medial (MPZ) and lateral palisade zone (LPZ) of the rat median eminence during the 4- and 5- day vaginal estrous cycle. Significant cyclic variations were only found in SEL and LPZ. The NA turnover in SEL was high on proestrous and low on all other days of the 4-day estrous cycle, whereas in the 5-day estrous cycle the NA turnover in SEL started to increase already on the second day of diestrous to reach a peak in the afternoon of proestrous. At that time also the NA concentrations in SEL were increased, although significantly only in the 5-day cyclic rats. The DA turnover in LPZ was low on proestrous and high on all other days in both 4-and 5-day cyclic rats. Apart from the median eminence cyclic variations in catecholamine metabolism were only found in the medial preoptic area, where NA turnover was high on proestrous and low on estrous-diestrous. The present findings give further support for the existence of a facilitatory noradrenergic and inhibitory dopaminergic mechanism in the control of gonadotrophin release. Furthermore, it is suggested that an acceleration of reticulo-hypothalamic NA turnover precedes the retardation of tubero-infundibular DA turnover found on proestrous and that the time lag between initial NA activation and subsequent DA inactivation is longer in the 5-than in the 4-day estrous cycle.
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PMID:Catecholamine turnover alterations in discrete areas of the median eminence of the 4- and 5-day cyclic rat. 1 57

The decrease of tyrosine hydroxylase activity in adrenal homogenate in scurvy was recovered after the administration of ascorbic acid. The causes of the increase in the enzyme activity after the administration of ascorbic acid have been studied. 1. No significant elevation in the enzyme activity was observed after the administration of reserpine to the scortutic guinea pig. 2. A dose of metal chelating agent, alpha, alpha'-dipyridyl, prevented the ascorbic acid-induced or reserpine-induced increase in enzyme activity in the scorbutic and the non-scorbutic guinea pigs, respectively. 3. Tyrosine hydroxylase activity was partially recovered by the administration of FeSO4 to the scorbutic guinea pig. From these results, it became clear that the induction of tyrosine hydroxylase which was not observed in scurvy was due to the deficiency of Fe2+. These results suggested that ascorbic acid affected the induction of this enzyme via Fe2+.
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PMID:Role of ascorbic acid on tyrosine hydroxylase activity in the adrenal gland of guinea pig. 1 71

The synthesis of neurotransmitters in mammalian brain responds rapidly to changes in precursor availability. Serotonin synthesis depends largely on the brain concentrations of L-tryptophan, its precursor amino aicd. This relationship appears to be physiologic: when brain tryptophan levels vary because of insulin secretion or meal ingestion, corresponding alterations occur in the rate of serotonin formation. The ability of any food to modify brain tryptophan (and serotonin) depends on how its ingestion changes the serum concentration of not only tryptophan, but also several other large neutral amino acids that compete with tryptophan for uptake into the brain. Such precursor-induced changes in brain serotonin appear to be functionally important: animals having a reduced level of brain serotonin (caused by the chronic ingestion of a naturally tryptophan-poor diet, such as corn) demonstrate a heightened sensitivity to painful stimuli; this pain sensitivity can be acutely restored to normal values by a single injection of L-tryptophan, which rapidly elevates brain serotonin. The synthesis of catecholamines (e.g., dopamine, norepinephrine) in the brain also varies with the availability of the precursor amino acid L-tyrosine. Single injections of this amino acid increase brain tyrosine levels and accelerate brain catechol synthesis, while injections of a competing neutral amino acid (e.g., leucine, tryptophan) reduce brain tyrosine and its rate of conversion to dopa. The rate of catecholamine synthesis, however, appears to be influenced less by precursor levels than is serotonin formation: tyrosine hydroxylase, whcih catalyzes the rate-limiting step in catecholamine synthesis, responds strongly to end-product inhibition and to other controls that reflect variations in neuronal activity. The synthesis of acetylcholine in brain responds to substrate (choline) availability much like serotonin synthesis. Short-term alterations in brain choline levels are mirrored by similar changes in brain acetylcholine concentration. Variations in the daily dietary intake of choline also modify brain choline and acetylcholine. The relationship between choline availability and acetylchyoline synthesis has already foudn a cletween choline availability and acetylchyoline synthesis has already found a clinical application: choline has been used successfully in the treatment of tardive dyskinesia, a disorder of the central nervous system thought to reflect a deficiency in cholinergic transmission. These relationships between precursor availability from the periphery and brain neurotransmitter synthesis may ultimately provide the brain with information about peripheral metabolic state.
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PMID:Effects on the diet on brain neurotransmitters. 1 61

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

In an attempt to determine the mechanism of action of L-proly-L-leucyl-glycine amide (MIF-I) in the treatment of Parkinson's disease, various parameters of dopaminergic neuronal function were studied in rats. It was found that the active uptake of 3H-dopamine (3H-DA) by synaptosome-rich homogenates of the striatum of rats treated with MIF-I (1 mg/kg IP X 3, 24 hr intervals) was unaltered 1 hr after final treatment with MIF-I. Also, neither tyrosine hydroxylase nor dopa decarboxylase activity was altered in the striatum and substantia nigra of rats treated with MIF-I (20 mg/kg IP X 3, 24 hr intervals). Thus, vital functional processes associated with dopaminergic neurons apparently are not altered by MIF-I under the conditions studied. These findings illustrate the importance of concurrent DOPA administration in observing an effect of MIF-I on dopaminergic neuronal function.
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PMID:Effects of L-prolyl-L-leucyl-glycine amide (MIF-I) on dopaminergic neurons. 1 12

Subcutaneous administration of ACTH 1-24 to mice increased the incorporation of [3H]lysine into brain and liver proteins, an effect which resembled that due to footshock. Corticosterone administration did not mimic these effects. ACTH 4-10 increased the [3H]lysine incorporation into brain or liver. These results are consistent with ACTH mediating the effects of footshock. However, dexamethasone decreased the brain responses to both footshock and ACTH, but while the liver response to ACTH was blocked, the footshock response was only diminished. This suggests a neural component in the response of the liver and possibly the brain. Intraventricular administration of ACTH 1-24 or ACTH 4-10 (D-phe), but not ACTH 4-10, increased [3H]lysine incorporation into brain protein. These neurochemical responses parallelled a distinctive pattern of behavior characterized by stretching, yawning and excessive grooming. Treatment for 3 days with long-acting preparations of ACTH 4-10, ACTH 4-10 (D-phe) or ACTH 1-24 increased the conversion of [3H]tyrosine into dopamine but not norepinephrine, alpha-MSH, beta-MSH or LVP had no such effect. Similar treatment with ACTH 4-10 or ACTH 1-24 increased striatal tyrosine hydroxylase activity measured in vitro, but did not significantly alter the enzyme activity from other brain regions. We conclude that ACTH peptides can stimulate protein and dopamine metabolism in mouse brain and that LVP has no such effects.
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PMID:Neurochemical responses of mice to ACTH and lysine vasopressin. 1 13

Newborn rats were treated at 1 and 2 days after birth with 100 mg/kg 6-hydroxydopamine (60HDA), s.c. Testing on several operant behavioural tasks was begun at 6 months of age. On a fixed ratio 30 (FR 30) schedule of food reinforcement, the neonatal 60HDA treated rats responded at a significantly higher rate. Further analysis of the FR 30 response pattern indicated that the higher rate was due to a decrease in the amount of time spent pausing after the receipt of each reinforcer. The 60HDA treatment failed to alter the rat's behaviour during the extinction of the FR 30 response and on the progressive ratio or variable interval schedules of food reinforcement. Biochemical analysis of several brain areas at 9 months of age showed a decrease in noradrenaline (NA) levels in the cerebral cortex and hippocampus, while in the pons-medulla NA content was doubled. The tyrosine hydroxylase activity in these same brain areas was not significantly altered, but there appeared to be some decrease in the activity of this enzyme in the hippocampus. Comparison of the operant behavioural effects seen after various lesioning procedures in this and other studies, suggest the effects on FR performance are a result of destruction of NA neurons in the hippocampus and/or the apparent regeneration of neurons in the pons-medulla.
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PMID:Operant behavioural and neurochemical effects after neonatal 6-hydroxydopamine treatment. 1 45

Group-housed male C57BR/cdJ mice (victims) were exposed to attack for 10 min daily for up to 14 days by male Swiss-Webster mice, made aggressive by prolonged isolation. Their adrenal glands were analyzed for tyrosine hydroxylase (TH) and phenylethanolamine-N-methyltransferase (PNMT) activities and for norepinephrine (NE) and epinephrine (EPI) concentrations. TH was increased to 41 per cent above control after two exposures and remained elevated through 14 exposures to attack. PNMT was increased to 29 per cent above control after 2 days and increased further to 50 per cent above control after 14 days of attack. Both NE and EPI increased to 88 per cent and 51 per cent above control, respectively, after 7 days. In victim mice recuperating after 1 week of daily stress, EPI levels and PNMT activities were back to normal after 4 days whereas NE levels and TH activities returned to normal only after 1 week. Phenobarbital (40 mg/kg, i.m.) was effective in preventing the biochemical changes when given 2 h prior to each daily attack but was ineffective when given immediately after each daily stress.
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PMID:Alterations of mouse adrenal medullary catecholamines and enzymes in response to attack: effect of pre- and post-treatment with phenobarbital. 1 47


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