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

Immunocytochemical localization of the neurotransmitter synthesizing enzymes, tyrosine and tryptophan hydroxylase, was used to determine whether the noradrenergic neurons in the nucleus locus coeruleus of the rat are innervated by serotonergic (5-HT) neurons. Specific antibodies were prepared to tyrosine hydroxylase, purified from the bovine adrenal medulla, and tryptophan hydroxylase, purified from rat midbrain. These were localized by both light and electron microscopy by the use of the peroxidase-antiperoxidase method. In the nucleus locus coeruleus, tyrosine hydroxylase was contained in the cytoplasm, proximal axons, and dendrites of intrinsic neurons. Tryptophan hydroxylase, on the other hand, was only contained within processes surrounding the perikarya and dendrites of the catecholaminergic neurons. The processes labeled with tryptophan hydroxylase were unmyelinated, ranged in size from 0.1 to 1.4 micron, and consisted of terminal varicosities separated by intervaricose segments. Although in close approximation to noradrenergic neurons, these processes, presumably axons, rarely formed synatic contacts with thickened membrane specializations. In processes, tryptophan hydroxylase was associated with subcellular organelles which had size and distribution of microtubules, and small and large synaptic vesicles. These observations provide a morphological basis to support the hypothesis that the activity of noradrenergic neurons may be modulated by a direct action of 5-HT neurons.
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PMID:A serotonergic innervation of noradrenergic neurons in nucleus locus coeruleus: demonstration by immunocytochemical localization of the transmitter specific enzymes tyrosine and tryptophan hydroxylase. 1 25

4, 14 and 28 days old rats were exposed to hypoxic environment of 6% O2-94% N2 for 30 min. Tyrosine hydroxylase and tryptophan hydroxylase activity was studied in different brain regions (hemispheres, striatum, midbrain and brainstem in vivo by measuring the accumulation of dihydroxyphenylalanine (Dopa) and 5-hydroxytryptophan (5-HTP) respectively, after inhibition of aromatic L-amino acid decarobyxlase with NSD 1015. Tyrosine and tryptophan levels in the different brain regions were measured simultaneously. The tyrosine and tryptophan levels in the various brain parts were generally not influenced during exposure to hypoxia. Tyrosine hydroxylase activity decreased in most areas in the 4 and 14 days old rats, and all brain areas studied in the 28 days old rats. Tryptophan hydroxylase activity decreased markedly in all brain areas at all ages studied. It is concluded that the enzymes tyrosine hydroxylase as well as tryptophan hydroxylase seem to be equally affected during hypoxia in the different brain regions studied.
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PMID:Regional changes in monoamine synthesis in the developing rat brain during hypoxia. 4 6

Tryptophan hydroxylase (tryptophan, tetrahydropteridine: oxygen oxidoreductase (5-hydroxylating) EC 1.14.16.4) purified from the neoplastic murine mast cells by hydroxylapatite chromatography following ammonium sulfate fractionation showed maximum activity at pH 6.0 in the presence of 2-mercaptoethanol, 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetra-hydropteridine and Fe2+, and pH 7.6 to 8.0 in the absence of addED Fe2+. The Km values were 38.5 muM and 22.2 muM for tryptophan, 298 muM and 204 muM for 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetra-hydropteridine, and 6.45% for oxygen in either presence or absence of added Fe-2+, respectively. From kinetic data the reaction mechanism of tryptophan hydroxylation appears to be of the sequential, rather than the ping-pong, type. Tryptophan hydroxylase from mast cells was considerably inhibited by o-phenanthroline like phenylalanine hydroxylase as well as tyrosine hydroxylase from other sources, and its Ki was between 1.2 muM and 4.53 muM. It was found that the inhibition by o-phenanthroline was competitive with respect to both tryptophan and 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine, but not molecular oxygen under the assay conditions employed.
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PMID:Further studies on tryptophan hydroxylase from neoplastic murine mast cells. 23 36

The present study compared the activities of some of the monoamine synthesizing enzymes in several brain regions, the retina as well as adrenal gland of albino Sprague-Dawley (SD) and Long-Evans hooded (LE) rats. Brainstem, hypothalamic and retinal tyrosine hydroxylase (TH) activity were significantly higher in LE than in SD. In addition to higher enzyme activity, a larger number of TH-immunoreactive perikarya as well as a higher concentration of TH-immunoreactive processes were observed in the retina of LE rats. There was no strain difference in TH activity of caudate nucleus (CN) and substantia nigra (SN). In contrast to brain regions and retina, adrenal TH activity was markedly higher in SD than in LE animals. Aromatic L-amino acid decarboxylase (AADC) activity of both the brainstem and adrenal gland in the LE strain was lower than in SD animals. No differences in the AADC activity of hypothalamus, SN and CN were found between LE and SD strains. Phenylethanolamine N-methyltransferase (PNMT) activity of the hypothalamus, retina and adrenal gland of LE strains was significantly lower than in SD rats. In spite of the difference in the enzyme activity, there were no marked morphological changes observed in PNMT-immunostaining patterns between the retina of LE and SD rats. Tryptophan hydroxylase activity of both the brainstem and hypothalamus did not exhibit strain differences.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Strain differences between albino and pigmented rats in monoamine-synthesizing enzyme activities of brain, retina and adrenal gland. 196 57

A cDNA clone for rabbit tryptophan hydroxylase was used as a probe to identify human tryptophan hydroxylase gene fragments in a panel of hamster-human somatic cell hybrids and determine its chromosomal location in man. A single locus was identified for tryptophan hydroxylase on chromosome 11. Tryptophan hydroxylase is a member of the superfamily of pterin-dependent aromatic amino acid hydroxylases which includes tyrosine hydroxylase, located at 11p15.5-p15, and phenylalanine hydroxylase, located at 12q22-q24.1 in human. The locations of these genes and the evolutionary distance between their sequences suggest that at least three distinct genetic events have occurred during the evolution of the aromatic amino acid hydroxylase superfamily: two sequential gene duplications giving rise to the three distinct hydroxylase loci, and a translocation which separated the tryptophan and tyrosine hydroxylase loci on chromosome 11 from the phenylalanine hydroxylase locus on chromosome 12.
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PMID:Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases. 288 73

Tryptophan hydroxylase (TPH) activity was measured in various rat brain regions after administering large doses of methamphetamine (METH). After four sequential doses of METH (15 mg/kg), given every 6 hr, TPH activity was decreased (to approximately 10% of control) in both the neostriatum and hippocampus. The depression of enzyme activity persisted for at least 30 days. When compared with the depression of neostriatal tyrosine hydroxylase activity, the depression of neostriatal and hippocampal TPH activity occurred sooner and was more pronounced. The depression of TPH activity was dependent on the number of doses and the amount of drug administered. Five days after one to two doses of METH, a transient recovery was observed but when four doses were given, the enzyme was depressed. No decrease in TPH activity was observed in brain areas containing serotonergic cell bodies. Agents which prevent the METH-induced decrease of neostriatal tyrosine hydroxylase activity, i.e., haloperidol, alpha-methyl-p-tyrosine and gamma-aminobutyric acid transaminase inhibitors also prevented the decrease in TPH activity caused by METH. In addition, fluoxetine, an inhibitor of 5-hydroxytryptamine re-uptake, prevented the METH-induced decrease in neostriatal and hippocampal TPH activity but did not alter the decrease in nenostriatal tyrosine hydroxylase activity.
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PMID:Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. 610 22

A recently developed technique of immunoautoradiography on nitrocellulose transfers of serial frozen sections was used to determine tryptophan hydroxylase concentration in selected areas of the adult rat brain following neonatal 6-hydroxydopamine destruction of nigrostriatal dopamine neurons. Particular attention was paid to the neostriatum, known to be serotonin-hyperinnervated under these conditions, and to the nucleus raphe dorsalis, containing the cell bodies of origin for these nerve terminals. The hippocampus was also investigated as a territory of structurally intact serotonin innervation arising primarily from the nucleus raphe medianus. Tryptophan hydroxylase protein was measured at successive transverse levels across the entire caudorostral extent of all these regions. Similar measurements of tyrosine hydroxylase protein across the substantia nigra and the neostriatum verified the disappearance of the nigrostriatal dopamine neurons. The average tryptophan hydroxylase tissue concentration in the dorsal third of the serotonin-hyperinnervated neostriatum was up by 36% above control, i.e. significantly less than the number of its serotonin axon terminals or varicosities. This was therefore indicative of a lowering of the tryptophan hydroxylase protein content per serotonin ending. Interestingly, a tight correlation between the respective level-by-level concentrations of tryptophan hydroxylase and tyrosine hydroxylase protein in the control neostriatum allowed the prediction the tryptophan hydroxylase concentration after dopamine denervation with a serotonin hyperinnervation. Tryptophan hydroxylase concentration was also significantly reduced in both the nucleus raphe dorsalis and nucleus raphe medianus, notably at those raphe dorsalis levels known to give rise to the serotonin hyperinnervation of neostriatum. It is hypothesized that the lower steady-state level of tryptophan hydroxylase inside the terminals and cell bodies of hyperinnervating serotonin neurons was the result of a feedback inhibition of the synthesis of the enzyme by its end-product, presumably because of the increased amount of serotonin in these terminals.
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PMID:Changes in steady-state levels of tryptophan hydroxylase protein in adult rat brain after neonatal 6-hydroxydopamine lesion. 767 79

The present study demonstrates the effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) on turnover of dopamine and serotonin (5-HT) in rat striatum during continuous infusion of the amino acids tyrosine and tryptophan. By monitoring with microdialysis, it was found that the increase in dopamine and homovanillic acid (HVA) concentrations in rat striatal extracellular fluid (ECF) induced by 6R-BH4 was further enhanced by the continuous infusion of tyrosine at a relatively low dose (1 mumol/min/kg) as compared with the concentration which saturates tyrosine hydroxylation. This dose of tyrosine alone did not induce the elevation of dopamine and HVA concentrations in ECF. In contrast, though the concentration of 5-HT and 5-HIAA in striatal ECF was gradually increased by tryptophan infusion, 6R-BH4 had no further effect. Although the higher output of dopamine into ECF was induced by the dialytic perfusion of 6R-BH4 via the microdialysis probe into striatum, tyrosine infusion had no further effect on dopamine concentration in the dialysates. The in vivo measurement of DOPA accumulation during NSD 1015 perfusion suggests that the enhancement of dopamine concentration in ECF induced by tyrosine infusion and 6R-BH4 might be attributable to an increase in tyrosine hydroxylase activity in striatum. Tryptophan hydroxylase was also activated by tryptophan infusion and/or 6R-BH4, however, it did not induce an increase in 5-HT concentration in striatal ECF.
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PMID:Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the extracellular levels of dopamine and serotonin in the rat striatum: a microdialysis study with tyrosine or tryptophan infusion. 790 18

Tryptophan hydroxylase (TPH) catalyzes the rate-limiting and committed step in serotonin biosynthesis. Within this enzyme, two distinct domains have been hypothesized to exist, an amino-terminal regulatory domain and a carboxyl-terminal catalytic domain. In the present experiments, the functional boundary between the putative domains was defined using deletion mutagenesis. A full-length cDNA clone for rabbit TPH was engineered for expression in bacteria. Five amino-terminal deletions were constructed using PCR, i.e., Ndelta50, Ndelta60, Ndelta90, Ndelta106, and Ndelta116 (referring to the number of amino acids deleted from the amino terminus). Enzymatic activity was determined for each mutant after expression in bacteria. Whereas deletion of 116 amino acids (Ndelta116) abolished enzyme activity, all of the other amino-terminal deletions exhibited increased specific activity relative to the recombinant wild-type TPH. The ability of the cyclic AMP-dependent protein kinase (PKA) to phosphorylate members of the deletion series was also examined. Deletion of the first 60 amino-terminal residues abolished the ability of the enzyme to serve as a substrate for PKA, yet the native and Ndelta50 enzymes were phosphorylated. Moreover, a serine-58 point mutant (S58A) was not phosphorylated by PKA. In conclusion, the first 106 amino acids comprise a regulatory domain that is phosphorylated by PKA at serine-58. In addition, the boundary between regulatory and catalytic domains is analogous to the domain structure observed for the related enzyme tyrosine hydroxylase.
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PMID:Amino-terminal analysis of tryptophan hydroxylase: protein kinase phosphorylation occurs at serine-58. 932 3

Tryptophan hydroxylase (TPH) catalyzes the rate-limiting step in the synthesis of serotonin and participates (in a non-rate-limiting fashion) in melatonin biosynthesis. In rabbit, TPH exists as a tetramer of four identical 51007 dalton (444 amino acids) protein subunits. An intersubunit binding domain responsible for tetramer formation of TPH was identified by assessing the role of a carboxyl terminal leucine heptad and 4-3 hydrophobic repeat. These repeats are conserved in all of the aromatic amino acid hydroxylases and have been shown to be required for the assembly of tyrosine hydroxylase tetramers. Polymerase chain reaction was utilized to create three TPH carboxyl terminal deletions (C delta8, C delta12 and C delta17) that sequentially remove members of the leucine heptad and 4-3 hydrophobic repeat. Each deletion and full-length recombinant TPH was expressed in bacteria to obtain soluble enzyme extracts for subsequent activity and structural analysis. It was found that removal of 8, 12 or 17 amino acids from the carboxyl terminus of TPH did not significantly alter enzymatic activity when compared to full-length recombinant TPH. However, the macromolecular structure of the deletions was dramatically affected as determined by dimeric and monomeric profiles on size exclusion chromatography. It can be concluded that amino acids 428-444 (the C-terminal 17 amino acids) comprise an intersubunit binding domain that is required for tetramer formation of TPH, but that tetramer assembly is not essential for full enzymatic activity.
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PMID:Carboxyl terminal deletion analysis of tryptophan hydroxylase. 939 22


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