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)

1. The mechanism of action of trimipramine, a clinically efficacious tricyclic antidepressant, is not well understood. In order to investigate whether it might affect the activities of different enzymes involved in biogenic amine metabolism we have undertaken a comparative study of it along with amitriptyline. 2. Neither trimipramine nor amitriptyline, at concentrations up to 1 mM, exhibited any significant effect on phenylalanine hydroxylase, tyrosine hydroxylase, L-aromatic amino acid decarboxylase, dopamine-beta-hydroxylase, phenylethanolamine-N-methyltransferase, catechol-O-methyltransferase, phenylsulfotransferase or tyrosine aminotransferase. 3. Monoamine oxidase, however, was inhibited by both drugs with the greatest effect being on MAO-B. The inhibition was reversible, non-competitive and relatively weak.
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PMID:Effect of trimipramine, an atypical tricyclic antidepressant, on the activities of various enzymes involved in the metabolism of biogenic amines. 197 1

Catecholamines (adrenaline, noradrenaline and dopamine) are potent inhibitors of phenylalanine 4-monooxygenase (phenylalanine hydroxylase, EC 1.14.16.1). The amines bind to the enzyme by a direct coordination to the high-spin (S = 5/2) Fe(III) at the active site (charge transfer interaction), as seen by resonance Raman and EPR spectroscopy. Experimental evidence is presented that a group with an apparent pKa value of about 5.1 (20 degrees C) is involved in the interaction between the catecholamine and the enzyme. The high-affinity binding of L-noradrenaline to phenylalanine hydroxylase, as studied by equilibrium microdialysis (anaerobically) and ultrafiltration (aerobically), shows positive cooperativity (h = 1.9); at pH 7.2 and 20 degrees C the rat enzyme binds about 0.5 mol L-noradrenaline/mol subunit with a half-maximal binding (S50) at 0.25 microM L-noradrenaline. No binding to the ferrous form of the enzyme was observed. The affinity decreases with decreasing pH, by phosphorylation and by preincubation of the enzyme with the substrate L-phenylalanine, while it increases after alkylation of the enzyme with the activator N-ethylmaleimide. Preincubation of the enzyme with L-phenylalanine also leads to a complete loss of the cooperativity of L-noradrenaline binding (h = 1.0). The many similarities in binding properties of the inhibitor L-noradrenaline and the activator/substrate L-phenylalanine makes it likely that the cooperative interactions of these effectors are due to their binding to the same site. The high-affinity of catecholamines to phenylalanine hydroxylase is a valuable probe to study the active site of this enzyme and is also relevant for the homologous enzyme tyrosine hydroxylase, which is purified as a stable catecholamine-Fe(III) complex.
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PMID:Cooperative homotropic interaction of L-noradrenaline with the catalytic site of phenylalanine 4-monooxygenase. 222 40

PH8 monoclonal antibody has previously been shown to react with all three aromatic amino acid hydroxylases, being particularly useful for immunohistochemical staining of brain tissue [Haan, Jennings, Cuello, Nakata, Chow, Kushinsky, Brittingham & Cotton (1987) Brain Res. 426, 19-27]. Western-blot analysis of liver extracts showed that PH8 reacted with phenylalanine hydroxylase from a wide range of vertebrate species. The epitope for antibody PH8 has been localized to the human phenylalanine hydroxylase sequence between amino acid residues 139 and 155. This highly conserved region of the aromatic amino acid hydroxylases has 11 out of 17 amino acids identical in phenylalanine hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase.
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PMID:A monoclonal antibody to aromatic amino acid hydroxylases. Identification of the epitope. 246 4

RNA amplification with transcript sequencing (RAWTS) is a rapid and sensitive method of direct sequencing that involves complementary DNA synthesis, polymerase chain reaction (PCR) with a primer or primers containing a phage promoter, transcription from the phage promoter, and reverse transcriptase-mediated sequencing. By means of RAWTS, it was possible to sequence each of four tissue-specific human messenger RNAs (blue pigment, factor IX, phenylalanine hydroxylase, and tyrosine hydroxylase) in four cell types examined (white blood cells, liver, K562 erythroleukemia cells, and chorionic villus cells). These results indicate that there is a basal rate of transcription, splicing, and polyadenylation of tissue-specific mRNAs in adult and embryonic tissues. In addition to revealing sequence information, it is possible to generate a desired in vitro translation product by incorporating a translation initiation signal into the appropriate PCR primer. RAWTS can be used to obtain novel mRNA sequence information from other species as illustrated with a segment of the catalytic domain of factor IX. In general, the ability to obtain mRNA sequences rapidly across species boundaries should aid both the study of protein evolution and the identification of sequences crucial for protein structure and function.
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PMID:Access to a messenger RNA sequence or its protein product is not limited by tissue or species specificity. 279 88

p-Chlorophenylalanine was administered to rats to inhibit hepatic phenylalanine hydroxylase activity. Two days later, phenylalanine injection was noted to produce substantial increases in serum phenylalanine levels, and relatively modest increments in serum tyrosine levels. Rats injected with p-chlorophenylalanine 2 days earlier showed a normal light-induced activation of retinal tyrosine hydroxylase activity in vivo, measured as dihydroxyphenylalanine accumulation following pharmacologic inhibition in vivo of aromatic L-amino acid decarboxylase activity. In addition, tyrosine injection into p-chlorophenylalanine-treated rats in the light produced anticipated increments in retinal tyrosine hydroxylation rate, showing the enzyme to be functionally normal. The acute administration of phenylalanine (62.5-500 mg/kg i.p.) to p-chlorophenylalanine-treated rats produced dose-related increments in retinal phenylalanine. In vivo tyrosine hydroxylation rate in retina was normal at all doses below 300 mg/kg. However, at the highest dose (500 mg/kg), when retinal phenylalanine levels were almost 5-times normal tyrosine hydroxylation rate consistently fell (to about half-normal values). These results demonstrate that very large elevations in tissue phenylalanine levels do not stimulate tyrosine hydroxylation in vivo, and that at extremely high levels phenylalanine inhibits tyrosine hydroxylation rate.
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PMID:In vivo tyrosine hydroxylation rate in retina: effects of phenylalanine and tyrosine administration in rats pretreated with p-chlorophenylalanine. 257

The substrates of dihydropteridine reductase (EC 1.6.99.7), quinonoid 7,8-dihydro(6 H)pterins, are unstable and decompose in various ways. In attempting to prepare a more stable substrate, 6,6,8-trimethyl-5,6,7,8-tetrahydro(3 H)pterin was synthesised and the quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin derived from it is extremely stable with a half-life in 0.1 M Tris/HCl (pH 7.6, 25 degrees C) of 33 h. Quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin is not a substrate for dihydropteridine reductase but it is reduced non-enzymically by NADH at a significant rate and it is a weak inhibitor of the enzyme: I50 200 microM, pH 7.6, 25 degrees C when using quinonoid 6-methyl-7,8-dihydro(6 H)pterin as substrate. 6,6,8-Trimethyl-5,6,7,8-tetrahydropterin is a cofactor for phenylalanine hydroxylase (EC 1.14.16.1) with an apparent Km of 0.33 mM, but no cofactor activity could be detected with tyrosine hydroxylase (EC 1.14.16.2). Its phenylalanine hydroxylase activity, together with the enhanced stability of quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin, suggest that it may have potential for the treatment of variant forms of phenylketonuria.
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PMID:Reduced 6,6,8-trimethylpterins. Preparation, properties and enzymic reactivities with dihydropteridine reductase, phenylalanine hydroxylase and tyrosine hydroxylase. 285 23

The effects of lead, a known neurotoxin on the metabolism of a vital tetrahydrobiopterin cofactor for the hydroxylation enzymes tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase, have been investigated. Reduced availability of this pteridine has the potential to reduce the level of the neurotransmitters noradrenaline, adrenaline and 5-hydroxytryptophan in the brain. Using the rat as a model, increases in tetrahydrobiopterin concentration and in the activity of dihydropteridine reductase, an enzyme involved in tetrahydrobiopterin metabolism, were observed after exposure to lead via the drinking water. Possible explanations for this increased level of tetrahydrobiopterin relate to alterations in the balance between synthesis and salvage of this co-factor.
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PMID:Neurotoxic action of lead: effect on tetrahydrobiopterin metabolism in the rat. 286 Oct 54

Screening of a rat liver cDNA expression library constructed in the vector lambda gt11 with an affinity purified antiserum to rat phenylalanine hydroxylase has resulted in the isolation of two clones which contain the complete coding region (1362 base pairs) of phenylalanine hydroxylase and the entire 3'-untranslated region (562 base pairs). From the nucleotide sequence we deduced the amino acid sequence of the enzyme. The molecular weight is 51,632 (452 amino acids). The rat enzyme is highly homologous to human phenylalanine hydroxylase. The two proteins differ in only 36 amino acids (92% homology), many of which are conservative changes. A dot matrix computer program was used to analyze regions of homology with the amino acid sequence of rat tyrosine hydroxylase. Considerable homology was detected from amino acid 140 in the rat enzyme to the C terminus, but little or no homology was apparent in the N-terminal region. The cDNA clone was used to determine the levels of phenylalanine hydroxylase mRNA in rat tissues using RNA blot hybridization. Two mRNA species were detected, with approximate lengths of 2,000 and 2,400 nucleotides, which appear to derive from use of alternate polyadenylation signals. No difference in mRNA size was found in rats which have different phenylalanine hydroxylase alleles. The kidney was found to contain about 10% of the mRNA found in the liver, and no phenylalanine hydroxylase mRNA was detected in rat brain. Reuber H4 hepatoma cells were also analyzed for phenylalanine hydroxylase mRNA. The parental cells contained mRNA species of the same sizes as in rat liver. Incubation in 10(-6) M hydrocortisone for 24 h resulted in an 18-fold increase in the mRNA level. Mutant hepatoma cells which express very little phenylalanine hydroxylase contained less than 5% of the parental mRNA, but the gene still responded to hydrocortisone.
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PMID:Isolation and sequence of a cDNA clone which contains the complete coding region of rat phenylalanine hydroxylase. Structural homology with tyrosine hydroxylase, glucocorticoid regulation, and use of alternate polyadenylation sites. 286 38

As reported previously [Vulliet et al. (1985) FEBS Lett. 182 335-339], tyrosine hydroxylase purified from rat pheochromocytoma is phosphorylated at an identical site (site A) by cyclic AMP-dependent protein kinase, the calmodulin-dependent multiprotein kinase and protein kinase C, while the calmodulin-dependent multiprotein kinase also phosphorylates another unique site (site C). Preparations of tyrosine hydroxylase purified from this source are also contaminated with traces of a fourth protein kinase which phosphorylates another unique site (site E). We have isolated tryptic peptides containing each of these sites and determined their amino acid sequences. By comparison of these data with the known cDNA sequence for rat tyrosine hydroxylase, we have been able to identify these sites as Ser-8 (site E), Ser-19 (site C), and Ser-40 (site A). In some preparations of tyrosine hydroxlyase, cyclic AMP-dependent protein kinase also phosphorylated a secondary site which was identified as ser-153. All of these phosphorylation sites are in the amino-terminal region, where there is no significant homology with the closely related enzyme, phenylalanine hydroxylase. Our data also establish that the initiator methionine is removed by post-translational processing to leave pro-2 as the amino-terminus of the mature protein. The significance of these results for the mechanism of action of extracellular signals on catecholamine biosynthesis is discussed.
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PMID:Identification of four phosphorylation sites in the N-terminal region of tyrosine hydroxylase. 287 40

Tetrahydrobiopterin (THB) analogues with 6-alkoxymethyl substituents, 3a-j, where the substituents were straight- and branched-chain alkyl ranging from methyl to octyl, have been synthesized by the Taylor method from pyrazine ortho amino nitriles by guanidine cyclization, hydrolysis in aqueous NaOH, and catalytic hydrogenation over Pt in trifluoroacetic acid (TFA). The best of these compounds, 3b, is an excellent cofactor for phenylalanine hydroxylase, tyrosine hydroxylase (V = 154% of THB), and tryptophan hydroxylase, does not destablize the binding of substrate (Kmtyr = 23 microM), and is recycled by dihydropteridine reductase (V = 419% of THB). The compounds are being evaluated as cofactor replacements in biopterin-deficiency diseases.
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PMID:Synthetic analogues of tetrahydrobiopterin with cofactor activity for aromatic amino acid hydroxylases. 287 18


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