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 pigmented subclone of Cloudman S91 melanoma cells, PS1-wild type, can grow in medium lacking tyrosine. This ability is conferred by phenylalanine hydroxylase activity, and not by tryptophan hydroxylase, tyrosine hydroxylase or tyrosinase activities, although the latter activity is also present in these cells. Conversion of phenylalanine to tyrosine was measured in living cells by chromatographic identification of the metabolites of [14C]phenylalanine and in cell extracts using a sensitive assay for phenylalanine hydroxylase. Phenylalanine hydroxylase activity in melanoma cell extracts was identified by its inhibition with p-chlorophenylalanine and not with 6-fluorotryptophan, 3-iodotyrosine, phenylthiourea, tyrosine or tryptophan; and by adsorption with antiserum prepared against purified rat liver phenylalanine hydroxylase, and migration of immunoprecipitable activity with authentic phenylalanine hydroxylase subunits in sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
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PMID:Phenylalanine hydroxylase in melanoma cells. 2 86

The effect of copper on the concentrations of o- and m-tyrosines in the serum of guinea pigs was studied in vivo. When guinea pigs were fed the normal diet and 0.1% CuSO4 solution as a drinking water for 13 d, the concentrations of o- and m-tyrosines in the serum increased more significantly than that of guinea pigs fed normal diet and water without copper. Phenylalanine hydroxylase in the liver and kidney, and tyrosine hydroxylase in the brain and adrenal were not activated by the administration of copper to guinea pigs. The administration of copper caused an abnormal accumulation of copper in the liver, but not in the kidney, adrenal and brain, and significantly depressed the ascorbic acid content in various organs including the liver, kidney, brain and adrenal. The results obtained suggest that o- and m-tyrosines may be also formed nonenzymatically in vivo, in addition to the formation by the participation of enzymes such as phenylalanine and tyrosine hydroxylases.
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PMID:[The effect of copper on o- and m-tyrosine content in the serum of guinea pigs]. 168 10

Phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TYH) are mixed-function oxidases that share many characteristic biochemical and immunological properties. The recent cloning and sequencing of full-length cDNAs for both human PAH and rat TYH allow detailed comparison of their primary structures. There is a high degree of homology between PAH and TYH on nucleic acid and amino acid levels. The pattern of homology suggests that these molecules are comprised of a homologous core containing the determinants for enzymatic activity and a nonhomologous region that contributes to substrate specificity and regulation. The degree of homology also suggests that these two proteins evolved from a common ancestor.
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PMID:Homology between phenylalanine and tyrosine hydroxylases reveals common structural and functional domains. 241 78

Phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH) are consecutive enzymes in the metabolic pathway leading to the production of catecholamine neurotransmitters. A comparison of recently available sequence data of these enzymes in the rat indicates about 70% homology in the 3' coding regions. We have localized TH by in situ hybridization to human chromosome region 11p15. Consideration of this assignment and that of PAH to chromosome 12, together with the known distribution of other pairs of related genes on these two chromosomes, provides convincing evidence of their ancestral relationship and suggests a role for gene duplication in the diversification of metabolic pathways in the vertebrate ancestors of mammals.
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PMID:Localization of the human tyrosine hydroxylase gene to 11p15: gene duplication and evolution of metabolic pathways. 287 99

Phenylalanine hydroxylase activity measured in leucocytes and fibroblasts by the fluorometric method is nonspecific and can be released by other aromatic hydroxylases. Investigations with the inhibitors p-Cl-phenylalanine, 3-I-tyrosine and 6-F-tryptophan made evident that these results may be caused by the tryptophan hydroxylase and the tyrosine hydroxylase. Phenylalanine hydroxylase activities in leucocytes could also not be measured by radiochemical investigations with [3-14C] phenylalanine (scanner and liquid scintillation technique).
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PMID:[Detection of phenylalanine hydroxylase activity in leukocytes and fibroblasts]. 667 Sep 99

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

Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a family of tetrahydropterin-dependent aromatic amino acid hydroxylases. It has been proposed that each hydroxylase is composed of a conserved C-terminal catalytic domain and an unrelated N-terminal regulatory domain. Of the three, only tyrosine hydroxylase is activated by heparin and binds to heparin-Sepharose. A series of N-terminal deletion mutants of tyrosine hydroxylase has been expressed in Escherichia coli to identify the heparin-binding site. The mutants lacking the first 32 or 68 amino acids bind to heparin-Sepharose. The mutant lacking 76 amino acids binds somewhat to heparin-Sepharose and the proteins lacking 88 or 128 do not bind at all. Therefore, an important segment of the heparin-binding site must be composed of the region from residues 76 to 90. All of the deletion mutants are active, and the Michaelis constants for pterins and tyrosine are similar among all the mutant and wild-type enzymes.
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PMID:Deletion mutants of tyrosine hydroxylase identify a region critical for heparin binding. 779 35

Phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase constitute a family of tetrahydropterin-dependent aromatic amino acid hydroxylases. Comparison of the amino acid sequences of these three proteins shows that the C-terminal two-thirds are homologous, while the N-terminal thirds are not. This is consistent with a model in which the C-terminal two-thirds constitute a conserved catalytic domain to which has been appended discrete regulatory domains. To test such a model, two mutant proteins have been constructed, expressed in Escherichia coli, purified, and characterized. One protein contains the first 158 amino acids of rat tyrosine hydroxylase. The second lacks the first 155 amino acid residues of this enzyme. The spectral properties of the two domains suggest that their three-dimensional structures are changed only slightly from intact tyrosine hydroxylase. The N-terminal domain mutant binds to heparin and is phosphorylated by cAMP-dependent protein kinase at the same rate as the holoenzyme but lacks any catalytic activity. The C-terminal domain mutant is fully active, with Vmax and Km values identical to the holoenzyme; these results establish that all of the catalytic residues of tyrosine hydroxylase are located in the C-terminal 330 amino acids. The results with the two mutant proteins are consistent with these two segments of tyrosine hydroxylase being two separate domains, one regulatory and one catalytic.
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PMID:Expression and characterization of catalytic and regulatory domains of rat tyrosine hydroxylase. 810 13

Phenylalanine hydroxylase (PheOH) catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of phenylalanine. Mutations in the human PheOH gene cause phenylketonuria, a common autosomal recessive metabolic disorder that in untreated patients often results in varying degrees of mental retardation. We have determined the crystal structure of human PheOH (residues 118-452). The enzyme crystallizes as a tetramer with each monomer consisting of a catalytic and a tetramerization domain. The tetramerization domain is characterized by the presence of a domain swapping arm that interacts with the other monomers forming an antiparallel coiled-coil. The structure is the first report of a tetrameric PheOH and displays an overall architecture similar to that of the functionally related tyrosine hydroxylase. In contrast to the tyrosine hydroxylase tetramer structure, a very pronounced asymmetry is observed in the phenylalanine hydroxylase, caused by the occurrence of two alternate conformations in the hinge region that leads to the coiled-coil helix. Examination of the mutations causing PKU shows that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains. Their effects on the structural and cellular stability of the enzyme are discussed.
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PMID:Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. 964 59

Phenylalanine hydroxylase (PAH) is a tetrahydrobiopterin and non-heme iron-dependent enzyme that hydroxylates L-Phe to l-Tyr using molecular oxygen as additional substrate. A dysfunction of this enzyme leads to phenylketonuria (PKU). The conformation and distances to the catalytic iron of both L-Phe and the cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) simultaneously bound to recombinant human PAH have been estimated by (1)H NMR. The resulting bound conformers of both ligands have been fitted into the crystal structure of the catalytic domain by molecular docking. In the docked structure L-Phe binds to the enzyme through interactions with Arg270, Ser349 and Trp326. The mode of coordination of Glu330 to the iron moiety seems to determine the amino acid substrate specificity in PAH and in the homologous enzyme tyrosine hydroxylase. The pterin ring of BH2 pi-stacks with Phe254, and the N3 and the amine group at C2 hydrogen bond with the carboxylic group of Glu286. The ring also establishes specific contacts with His264 and Leu249. The distance between the O4 atom of BH2 and the iron (2.6(+/-0.3) A) is compatible with coordination, a finding that is important for the understanding of the mechanism of the enzyme. The hydroxyl groups in the side-chain at C6 hydrogen bond with the carbonyl group of Ala322 and the hydroxyl group of Ser251, an interaction that seems to have implications for the regulation of the enzyme by substrate and cofactor. Some frequent mutations causing PKU are located at residues involved in substrate and cofactor binding. The sites for hydroxylation, C4 in L-Phe and C4a in the pterin are located at a distance of 4.2 and 4.3 A from the iron moiety, respectively, and at 6.3 A from each other. These distances are adequate for the intercalation of iron-coordinated molecular oxygen, in agreement with a mechanistic role of the iron moiety both in the binding and activation of dioxygen and in the hydroxylation reaction.
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PMID:The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase: implications for the catalytic mechanism. 1061 Jul 98


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