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)

A selection procedure was devised for neurons and related cells that depends upon the ability of the cells to synthesize certain amine neurotransmitters. The rationale for selection is that tyrosine is an essential amino acid for most mammalian cells and that three enzymes from mammalian sources can catalyze the synthesis of tyrosine: phenylalanine hydroxylase (EC 1.14.16.1), tyrosine hydroxylase (EC 1.14.16.2), and tryptophan hydroxylase (EC 1.14.16.4). Tyrosine hydroxylase is found predominantly in adrenergic neurons and related cells that synthesize dopamine, norepinephrine, and epinephrine, and tryptophan hydroxylase in cells synthesizing serotonin or melatonin. Only 1 out of 70,000 uncloned mouse neuroblastoma cells grew well in the absence of tyrosine. Approximately 50% of the cell lines obtained by selection had tyrosine hydroxylase activity. This selection procedure thus provides a simple means of obtaining cell lines of neural origin on the basis of their ability to synthesize putative transmitters.
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PMID:Selection for neuroblastoma cells that synthesize certain transmitters. 415 49

A number of proteins were tested as potential substrates for purified rabbit liver calmodulin-dependent glycogen synthase kinase. It was found that liver phenylalanine hydroxylase and several brain proteins including tyrosine hydroxylase, microtubule-associated protein 2, and synapsin I were readily phosphorylated. Brain tubulin was very poorly phosphorylated. These results suggest that calmodulin-dependent glycogen synthase kinase may be a more general protein kinase involved in the regulation of several cellular Ca2+-dependent functions.
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PMID:Substrate specificity of liver calmodulin-dependent glycogen synthase kinase. 614 5

A new microbial inhibitor for rat-liver phenylalanine hydroxylase (L-phenylalanine, tetrahydropteridine: oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1) was isolated from a culture medium of Fomes tasmanicus, and its structure was determined as 3,4-dihydroxystyrene. This compound inhibited the enzyme by 50% at a concentration of 5 X 10(-6) M and 5 X 10(-7) M, respectively, without or with preincubation at 25 degrees C for 15 min. Without preincubation, dihydroxystyrene inhibited phenylalanine hydroxylase noncompetitively with phenylalanine and a pteridine cofactor, 6,7-dimethyltetrahydropterin, and uncompetitively with oxygen. A change in kinetic properties of the inhibition was observed when the enzyme was preincubated with dihydroxystyrene; the degree of inhibition was increased, and the purely noncompetitive-type inhibition with phenylalanine changed to a mixed-type inhibition. A study concerning the structure-inhibitory activity relationship using several compounds similar to dihydroxystyrene, indicated that the catechol structure is essential and that the structure of the aliphatic side-chain affects the inhibitory potency. A similar degree of inhibition was observed using 6,7-dimethyl- or 6-methyltetrahydropterin or tetrahydrobiopterin as a cofactor. Dihydroxystyrene also inhibited other pteridine-dependent monooxygenases, tyrosine hydroxylase (EC 1.14.16.2) and tryptophan hydroxylase (EC 1.14.16.4), indicating that dihydroxystyrene is a general inhibitor for pteridine-dependent monooxygenases.
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PMID:3,4-dihydroxystyrene, a novel microbial inhibitor for phenylalanine hydroxylase and other pteridine-dependent monooxygenases. 614 5

The effects of experimental hyperphenylalaninemia on catecholamine and serotonin synthesis in brain at a later stage of brain development were investigated. A group of 35-day-old rats treated with normal chow supplemented with 5% Phe + 0.4% alpha-methylphenylalanine, alpha MP, for the previous 10 days showed decreases in dopa, norepinephrine, and epinephrine versus controls. A group treated with a normal diet supplemented with 0.4% alpha MP showed similar decreases and these differences could be attributed to the presence of the phenylalanine hydroxylase and tyrosine hydroxylase inhibitor, alpha MP, rather than the hyperphenylalaninemia condition. No differences in dopamine were observed. Serotonin and 5-hydroxyindoleacetic acid (5HIAA) were decreased 50% in the HyPhe condition and were unaffected in the presence of alpha MP alone, indicating that the decreases in serotonin and 5HIAA were due to the increases in phenylalanine rather than the presence of the inhibitor. These abnormalities in serotonin metabolism at later stages of brain development may be relevant to early discontinuation of dietary therapy in the PKU patient and implies a role in tryptophan supplementation to increase intracerebral serotonin values.
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PMID:Effect of experimental hyperphenylalaninemia on biogenic amine synthesis at later stages of brain development. 661 90

Phenylalanine hydroxylase was shown to be inhibited by oudenone and its derivatives in vitro. At a concentration of 2.3 x 10(-3) M, oudenone inhibited phenylalanine hydroxylase by 50%, and some of the oudenone derivatives showed more potent inhibition. The kinetic data have shown that the inhibition by oudenone is competitive with a tetrahydropterin cofactor (6,7-dimethyltetrahydropterin, DMPH4) and noncompetitive with phenylalanine and oxygen. Among 12 oudenone derivatives, there was no parallel structure-activity relationship between the inhibitory effect for phenylalanine hydroxylase and that for tyrosine hydroxylase. A derivative of oudenone, [compound No. 142; 2-(3,4-dihydroxyphenyl)-1-oxopropyl)cyclohexan-1,3-dione] showed the most potent inhibition among the oudenone derivatives. It inhibited phenylalanine hydroxylase by 50% at a concentration of 1.8 x 10(-5) M. This inhibition was a mixed type with either a tetrahydropterin cofactor, DMPH4, or with the substrate phenylalanine, which was different from the inhibition by oudenone. However, the same noncompetitive inhibition was shown toward oxygen.
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PMID:Inhibition of phenylalanine hydroxylase, a pterin-requiring monooxygenase, by oudenone and its derivatives. 709 1

The synaptic connections of amacrine cells synthesizing or accumulating serotonin in the retina of the cane toad, Bufo marinus, were studied by using preembedding double-labeling electron-microscopic immunocytochemistry. The binding sites of an anti-serotonin antibody were revealed by the diaminobenzidine reaction, whilst a colloidal gold-conjugated secondary antibody was used to detect an antibody to phenylalanine hydroxylase. Since the latter antibody recognizes tryptophan 5-hydroxylase, one of the synthesizing enzymes for serotonin, as well as tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis, the double labeling of the present study enabled us to identify three groups of labeled profiles at the ultrastructural level. The profiles of serotonin-synthesizing amacrine cells contained both diaminobenzidine reaction product and colloidal gold particles, whilst those of serotonin-accumulating and dopaminergic amacrine cells contained only diaminobenzidine reaction product or colloidal gold particles, respectively. The synapses of serotonin-synthesizing or serotonin-accumulating amacrine cells were distributed all through the inner plexiform layer of the retina. The profiles of serotonin-synthesizing amacrine cells predominantly received synapses from, and made synapses onto, unlabeled amacrine cell dendrites. They also received synapses from, and made synapses onto, bipolar cell terminals. They also made synapses onto presumed ganglion cell dendrites. However, the profiles of serotonin-accumulating cells made synapses only with unlabeled amacrine cell processes. There were close contacts between the profiles of serotonin-synthesizing and serotonin-accumulating amacrine cells. No synaptic relationships were observed between dopaminergic and serotonin-synthesizing or serotonin-accumulating amacrine cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synaptic circuitry of serotonin-synthesizing and serotonin-accumulating amacrine cells in the retina of the cane toad, Bufo marinus. 771 93

Human keratinocytes have the capacity to synthesize catecholamines from L-tyrosine, which in turn is produced from L-phenylalanine via phenylalanine hydroxylase. This enzyme activity is controlled by the supply of the essential cofactor/electron donor (6R)5,6,7,8 tetrahydrobiopterin (6-BH4). Undifferentiated keratinocytes express high levels of the rate-limiting enzymes for the de novo synthesis of 6-BH4, i.e., GTP-cyclohydrolase-1, and for its recycling, i.e., 4a-hydroxytetrahydrobiopterin dehydratase. As a consequence of 6-BH4 synthesis, phenylalanine hydroxylase is activated, yielding L-tyrosine, which in the presence of excess 6-BH4 turns on the biosynthesis of catecholamines via the rate-limiting enzyme tyrosine hydroxylase. Therefore, undifferentiated keratinocytes contain high levels of the catecholamine system yielding sufficient levels of norepinephrine and epinephrine, required for the induction of beta-2-adrenoceptors. Stimulation of beta-2-adrenoceptors by epinephrine causes a rise in intracellular calcium via extracellular influx. This event corresponds with keratinocyte differentiation. In differentiated keratinocytes, all enzyme activities involved in 6-BH4, L-tyrosine, and epinephrine biosynthesis are decreased, resulting in significantly lower levels of epinephrine and a concomitant decrease in the expression of beta-2-adrenoceptors. These data strongly suggest a connection between catecholamine biosynthesis, beta-2-adrenoceptor expression, calcium flux, and the differentiation of keratinocytes in human epidermis.
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PMID:Catecholamines in human keratinocyte differentiation. 776 65

We report the isolation and the organization of the gene encoding human tryptophan hydroxylase (TPH) and an analysis of the corresponding mRNAs. The gene spans a region of 29 kilobases, which contains at least 11 exons and a variably spliced 5'-untranslated region (5'-UTR). The sequence of the coding region and the majority of the positions of the intron-exon boundaries of human TPH gene are very similar to those encoding human tyrosine hydroxylase and phenylalanine hydroxylase, the other members of the aromatic amino acid hydroxylase family. Phylogenetic analysis evidences the early divergence and the independent evolution of the three hydroxylase types. TPH cDNA cloning and anchored polymerase chain reaction revealed a diversity of the TPH mRNA, which is restricted to the 5'-UTR. Four TPH mRNA species were detected by Northern blot with pineal gland and carcinoid tumor RNAs. These messengers are transcribed from a single transcriptional initiation site, and their diversity results from differential splicing of three intron-like regions and of three exons located in the 5'-UTR. Analysis by S1 nuclease protection revealed that the intron-like regions in the 5'-UTR are mostly unspliced and that TPH mRNA species where the three intron-like regions are eliminated are present at low level in pineal gland and not detectable in carcinoid tumors.
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PMID:The human tryptophan hydroxylase gene. An unusual splicing complexity in the 5'-untranslated region. 787 15

Around 50 min after adult ecdysis, a significant increase in DOPA content is observed in Drosophila melanogaster. This increase, which is followed by increases of other catecholamine sclerotizing precursors, parallels the visually observable pigmentation and hardening of the adult cuticle. Since this DOPA concentration developmental profile is correlated with cuticle formation, we have analyzed the involvement of aromatic amino acid hydroxylases in this process by determining the same profile in mutant strains affecting these hydroxylations, either directly (defects in the genes coding for these hydroxylases), or indirectly (defects in genes involved in the biosynthesis of the essential pterin cofactor, tetrahydrobiopterin). The altered profiles of the pterin biosynthesis defective strains Pu2/SM1 and cn prc4/cn prm2b showed that some pterin is required for these metabolic changes. Meanwhile the altered profiles of the Hnr3 and ple/TM3 strains directly implicate the phenylalanine and tyrosine hydroxylase enzymes. An analysis of the phenylalanine hydroxylase protein presence during the period of the first 3 h post adult ecdysis in thorax plus abdomen extracts has shown that although the protein is present during the complete developmental period, no changes in the cross reacting material amounts are observed.
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PMID:A genetic analysis of aromatic amino acid hydroxylases involvement in DOPA synthesis during Drosophila adult development. 791 53

The lysine residues at positions 194 and 198 in phenylalanine hydroxylase have been shown to react with a photoaffinity label which is an analog of phenyltetrahydropterin (Gibbs, B. S., and Benkovic, S. J. (1991) Biochemistry 30, 6795-6802), in a manner suggesting that these lysine residues are involved in tetrahydrobiopterin binding. The related enzyme tyrosine hydroxylase has a lysine at position 241 which, given the 75% identity between its C-terminal 330 amino acids and those of phenylalanine hydroxylase, corresponds to lysine194 of phenylalanine hydroxylase. Site-directed mutagenesis was used to alter lysine241 of tyrosine hydroxylase to alanine. Steady-state kinetic parameters were measured for wild-type and K241A tyrosine hydroxylase. No kinetic parameter differed between the wild-type and K241A enzymes, including Vmax values, Michaelis constants for tetrahydrobiopterin, 6-methyl-tetrahydropterin, and tyrosine, and the inhibition constants for norepinephrine. These results show that lysine241 is not required for tetrahydrobiopterin binding to tyrosine hydroxylase.
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PMID:Lysine241 of tyrosine hydroxylase is not required for binding of tetrahydrobiopterin substrate. 809 96


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