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)

A recently described new form of hyperphenylalaninemia is characterized by the excretion of 7-substituted isomers of biopterin and neopterin and 7-oxo-biopterin in the urine of patients. It has been shown that the 7-substituted isomers of biopterin and neopterin derive from L-tetrahydrobiopterin and D-tetrahydroneopterin and are formed during hydroxylation of phenylalanine to tyrosine with rat liver dehydratase-free phenylalanine hydroxylase. We have now obtained identical results using human phenylalanine hydroxylase. The identity of the pterin formed in vitro and derived from L-tetrahydrobiopterin as 7-(1',2'-dihydroxypropyl)pterin was proven by gas-chromatography mass spectrometry. Tetrahydroneopterin and 6-hydroxymethyltetrahydropterin also are converted to their corresponding 7-substituted isomers and serve as cofactors in the phenylalanine hydroxylase reaction. Dihydroneopterin is converted by dihydrofolate reductase to the tetrahydro form which is biologically active as a cofactor for the aromatic amino acid monooxygenases. The 6-substituted pterin to 7-substituted pterin conversion occurs in the absence of pterin-4a-carbinolamine dehydratase and is shown to be a nonenzymatic process. 7-Tetrahydrobiopterin is both a substrate (cofactor) and a competitive inhibitor with 6-tetrahydrobiopterin (Ki approximately 8 microM) in the phenylalanine hydroxylase reaction. For the first time, the formation of 7-substituted pterins from their 6-substituted isomers has been demonstrated with tyrosine hydroxylase, another important mammalian enzyme which functions in the hydroxylation of phenylalanine and tyrosine.
 ...
PMID:7-substituted pterins in humans with suspected pterin-4a-carbinolamine dehydratase deficiency. Mechanism of formation via non-enzymatic transformation from 6-substituted pterins. 135 46

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.
 ...
PMID:Catecholamines in human keratinocyte differentiation. 776 65

Pseudomonas aeruginosa possesses a multigene operon that includes phenylalanine hydroxylase (PhhA; phenylalanine 4-monooxygenase, EC 1.14.16.1). phhA encodes PhhA (M(r) = 30,288), phhB (M(r) = 13,333) encodes a homologue of mammalian 4 alpha-carbinolamine dehydratase/homeodomain protein transregulator, and phhC encodes an aromatic aminotransferase (M(r) = 43,237). The reading frames specifying phhB and phhC overlap by 2 bases. The P. aeruginosa PhhA appears to contain iron and is pterin dependent. Unlike the multimeric mammalian hydroxylase, the native P. aeruginosa enzyme is a monomer. The P. aeruginosa PhhA is homologous with mammalian PhhA, tryptophan hydroxylase, and tyrosine hydroxylase. Expression of PhhA from its native promoter required phhB. This may suggest a positive regulatory role for phhB, consistent with the dual catalytic and regulatory roles of the corresponding mammalian homologue.
 ...
PMID:Pseudomonas aeruginosa possesses homologues of mammalian phenylalanine hydroxylase and 4 alpha-carbinolamine dehydratase/DCoH as part of a three-component gene cluster. 810 17

A novel pterin intermediate, in addition to the expected 4a-hydroxytetrahydrobiopterin (4a-OH-BH4) and quinonoid dihydrobiopterin, was generated during catalytic turnover of tyrosine hydroxylase (TH) with tetrahydrobiopterin as the cofactor. Based on chromatographic, spectroscopic and stability properties its structure is proposed to be similar to the product formed by the non-enzymic conversion of synthetic 4a-OH-BH4 [Bailey, Rebrin, Boerth and Ayling (1995) J. Am. Chem. Soc. 117, 10203-10211]. This compound was tentatively described as a 4a-adduct of a side-chain hydroxy group, i.e. the O2', 4a-cyclic-tetrahydrobiopterin (4a-Cyc-BH4). The intermediate generated in the TH reaction has a UV spectrum which is similar to that of 4a-OH-BH4, but elutes with a longer retention time (tR = 1.69 min compared with 1.06 min) on reversed-phase chromatography. Its conversion into quinonoid dihydrobiopterin is catalysed by pterin-4a-carbinolamine dehydratase (EC 4.2.1.96), although 4a-OH-BH4 is the preferred substrate for that enzyme. A precursor-product relationship was demonstrated between 4a-OH-BH4 and the putative 4a-Cyc-BH4 intermediate. The apparent stability of this compound is dependent on pH as well as on the nature of the buffer ions. At pH 8.0 a large amount was generated in Hepes and Tris, but little in phosphate buffer. At pH 7.0 in Hepes (standard assay conditions) and Tris buffer the putative 4a-Cyc-BH4, but no 4a-OH-BH4, was observed. None of the intermediates was observed at pH 6.0. The accumulation of these intermediates in the absence of dehydratase has important implications for the assay of TH and phenylalanine hydroxylase activities, and is also compatible with a possible physiological role of the dehydratase in the synthesis of catecholamines in vivo.
 ...
PMID:Characterization of a novel pterin intermediate formed in the catalytic cycle of tyrosine hydroxylase. 892 Oct 4

Human epidermal melanocytes hold the full capacity for autocrine de novo synthesis/regulation/recycling of the essential cofactor 6-tetrahydrobiopterin (6BH(4)) for conversion of L-phenylalanine via phenylalanine hydroxylase to L-tyrosine and for production of L-Dopa via tyrosine hydroxylase to initiate both pigmentation and catecholamine synthesis in these neural crest-derived cells. Earlier we have demonstrated pterin-4a-carbinolamine dehydratase (PCD) mRNA and enzyme activities in epidermal melanocytes and keratinocytes. This protein dimerises also the transcription factor hepatocyte nuclear factor 1 (HNF-1), leading to activation of multiple genes. This study demonstrates for the first time DCoH/HNF-1 alpha expression and transcriptional activity in human epidermal melanocytes in vitro and in situ and identified tyrosinase, the key enzyme for pigmentation, as a new transcriptional target. Specific binding of DCoH/HNF-1 complex to the human tyrosinase promoter was confirmed by gel shift analysis. These results provide a novel mechanism in the regulation of skin pigmentation.
 ...
PMID:In situ and in vitro evidence for DCoH/HNF-1 alpha transcription of tyrosinase in human skin melanocytes. 1256 7

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.
 ...
PMID:Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. 1949 Nov 46

Inborn errors of monoamine neurotransmitter biosynthesis and degradation belong to the rare inborn errors of metabolism. They are caused by monogenic variants in the genes encoding the proteins involved in (1) neurotransmitter biosynthesis (like tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC)), (2) in tetrahydrobiopterin (BH4) cofactor biosynthesis (GTP cyclohydrolase 1 (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), sepiapterin reductase (SPR)) and recycling (pterin-4a-carbinolamine dehydratase (PCD), dihydropteridine reductase (DHPR)), or (3) in co-chaperones (DNAJC12). Clinically, they present early during childhood with a lack of monoamine neurotransmitters, especially dopamine and its products norepinephrine and epinephrine. Classical symptoms include autonomous dysregulations, hypotonia, movement disorders, and developmental delay. Therapy is predominantly based on supplementation of missing cofactors or neurotransmitter precursors. However, diagnosis is difficult and is predominantly based on quantitative detection of neurotransmitters, cofactors, and precursors in cerebrospinal fluid (CSF), urine, and blood. This review aims at summarizing the diverse analytical tools routinely used for diagnosis to determine quantitatively the amounts of neurotransmitters and cofactors in the different types of samples used to identify patients suffering from these rare diseases.
 ...
PMID:Analysis of Catecholamines and Pterins in Inborn Errors of Monoamine Neurotransmitter Metabolism-From Past to Future. 3140 45