Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Tryptophan hydroxylase (TPH) carries out the 5-hydroxylation of L-Trp, which is the rate-limiting step in the synthesis of serotonin. We have prepared and characterized a stable N-terminally truncated form of human TPH that includes the catalytic domain (Delta90TPH). We have also determined the conformation and distances to the catalytic non-heme iron of both L-Trp and the tetrahydrobiopterin cofactor analogue L-erythro-7,8-dihydrobiopterin (BH2) bound to Delta90TPH by using 1H NMR spectroscopy. The bound conformers of the substrate and the pterin were then docked into the modeled three-dimensional structure of TPH. The resulting ternary TPH-BH2-L-Trp structure is very similar to that previously determined by the same methods for the complex of phenylalanine hydroxylase (PAH) with BH2 and L-Phe [Teigen, K., et al. (1999) J. Mol. Biol. 294, 807-823]. In the model, L-Trp binds to the enzyme through interactions with Arg257, Ser336, His272, Phe318, and Phe313, and the ring of BH2 interacts mainly with Phe241 and Glu273. The distances between the hydroxylation sites at C5 in L-Trp and C4a in the pterin, i.e., 6.1 +/- 0.4 A, and from each of these sites to the iron, i.e., 4.1 +/- 0.3 and 4.4 +/- 0.3 A, respectively, are also in agreement with the formation of a transient iron-4a-peroxytetrahydropterin in the reaction, as proposed for the other hydroxylases. The different conformation of the dihydroxypropyl chain of BH2 in PAH and TPH seems to be related to the presence of nonconserved residues, i.e., Tyr235 and Pro238 in TPH, at the cofactor binding site. Moreover, Phe313, which seems to interact with the substrate through ring stacking, corresponds to a Trp residue in both tyrosine hydroxylase and PAH (Trp326) and appears to be an important residue for influencing the substrate specificity in this family of enzymes. We show that the W326F mutation in PAH increases the relative preference for L-Trp as the substrate, while the F313W mutation in TPH increases the preference for L-Phe, possibly by a conserved active site volume effect.
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PMID:Conformation of the substrate and pterin cofactor bound to human tryptophan hydroxylase. Important role of Phe313 in substrate specificity. 1174 34

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

The neuroprotective effect of intermittent hypoxia on ferrous citrate (iron)-induced oxidative stress was investigated in the nigrostriatal dopaminergic system of rat brain. Female Wistar rats were subjected to 380 mm Hg in an altitude chamber for 15 h/day for 7, 14, or 28 days. Iron was locally infused in the substantia nigra of anesthetized rats. Seven days after infusion, lipid peroxidation was elevated in the infused substantia nigra and dopamine content and tyrosine hydroxylase-positive axons were decreased in the ipsilateral striatum in the normoxic rats. Intermittent hypoxic treatment prevented iron-induced oxidative injuries. Induction of the neuroprotection required 2 weeks. Intracerebroventricular infusion of L-buthionine-[S,R]-sulfoximine (L-BSO), which mimicked a reduced antioxidative condition, aggravated iron-induced oxidative injuries. Intermittent hypoxia ameliorated L-BSO-induced augmentation of iron-induced oxidative injuries. Basal GSH (glutathione) content, GSH/GSSG ratio, superoxide dismutase (SOD) and catalase activities in intact substantia nigra were not altered by intermittent hypoxia. Furthermore, intermittent hypoxia attenuated iron-induced reductions in GSH content, GSH/GSSG ratio, and SOD, iron-induced increase in catalase but had no effect on glutathione peroxidase. Our data suggest that intermittent hypoxia may protect the nigrostriatal dopaminergic system from iron-induced oxidative injuries. Moreover, antioxidative defensive systems may partially contribute to the neuroprotection by intermittent hypoxia.
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PMID:Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. 1235 74

Hodological, electrophysiological, and ablation studies indicate a role for the basal forebrain in telencephalic vocal control; however, to date the organization of the basal forebrain has not been extensively studied in any nonmammal or nonhuman vocal learning species. To this end the chemical anatomy of the avian basal forebrain was investigated in a vocal learning parrot, the budgerigar (Melopsittacus undulatus). Immunological and histological stains, including choline acetyltransferase, acetylcholinesterase, tyrosine hydroxylase, dopamine and cAMP-regulated phosphoprotein (DARPP)-32, the calcium binding proteins calbindin D-28k and parvalbumin, calcitonin gene-related peptide, iron, substance P, methionine enkephalin, nicotinamide adenine dinucleotide phosphotase diaphorase, and arginine vasotocin were used in the present study. We conclude that the ventral paleostriatum (cf. Kitt and Brauth [1981] Neuroscience 6:1551-1566) and adjacent archistriatal regions can be subdivided into several distinct subareas that are chemically comparable to mammalian basal forebrain structures. The nucleus accumbens is histochemically separable into core and shell regions. The nucleus taeniae (TN) is theorized to be homologous to the medial amygdaloid nucleus. The archistriatum pars ventrolateralis (Avl; comparable to the pigeon archistriatum pars dorsalis) is theorized to be a possible homologue of the central amygdaloid nucleus. The TN and Avl are histochemically continuous with the medial aspects of the bed nucleus of the stria terminalis and the ventromedial striatum, forming an avian analogue of the extended amygdala. The apparent counterpart in budgerigars of the mammalian nucleus basalis of Meynert consists of a field of cholinergic neurons spanning the basal forebrain. The budgerigar septal region is theorized to be homologous as a field to the mammalian septum. Our results are discussed with regard to both the evolution of the basal forebrain and its role in vocal learning processes.
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PMID:Organization of the avian basal forebrain: chemical anatomy in the parrot (Melopsittacus undulatus). 1245 5

The reaction mechanism for the formation of the hydroxylating intermediate in aromatic amino acid hydroxylases (i.e., phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase) was investigated by means of hybrid density functional theory. These enzymes use molecular oxygen to hydroxylate both the tetrahydrobiopterin cofactor and the aromatic amino acid. A mechanism is proposed in which dioxygen forms a bridging bond between the cofactor and iron. The product is an iron(II)-peroxy-pterin intermediate, and iron was found to be essential for the catalysis of this step. No stable intermediates involving a pterin radical cation and a superoxide ion O(2)(-) were found on the reaction pathway. Heterolysis of the O-O bond in the iron(II)-peroxy-pterin intermediate is promoted by one of the water molecules coordinated to iron and releases hydroxypterin and the high-valent iron oxo species Fe(IV)=O, which can carry out subsequent hydroxylation of aromatic rings. In the proposed mechanism, the formation of the bridging C-O bond is rate-limiting in the formation of Fe(IV)=O.
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PMID:Mechanism of dioxygen cleavage in tetrahydrobiopterin-dependent amino acid hydroxylases. 1250 69

The hypothalamic corticotropin-releasing hormone system and the sympathetic nervous system are anatomically and functionally interconnected and hormones of the hypothalamic-pituitary-adrenocortical axis contribute to the regulation of catecholaminergic systems. To investigate the role of glucocorticoids on activity of the adrenal gland, we analysed plasma and adrenal catecholamines, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression in rats injected with metyrapone or dexamethasone. Metyrapone-treated rats had significantly lower epinephrine and higher norepinephrine production than control rats. Metyrapone increased TH protein synthesis and TH mRNA expression whereas its administration did not affect PNMT mRNA expression. Dexamethasone restored plasma and adrenal epinephrine concentrations and increased PNMT mRNA levels, which is consistent with an absolute requirement of glucocorticoids for PNMT expression. Adrenal denervation completely abolished the metyrapone-induced TH mRNA expression. Blockage of cholinergic neurotransmission by nicotinic or muscarinic receptor antagonists did not prevent the metyrapone-induced rise in TH mRNA. Finally, pituitary adenylate cyclase activating polypeptide (PACAP) adrenal content was not affected by metyrapone. These results provide evidence that metyrapone-induced corticosterone depletion elicits transsynaptic TH activation, implying noncholinergic neurotransmission. This may involve neuropeptides other than PACAP.
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PMID:Metyrapone-induced glucocorticoid depletion modulates tyrosine hydroxylase and phenylethanolamine N-methyltransferase gene expression in the rat adrenal gland by a noncholinergic transsynaptic activation. 1253 65

The amino acid ligands to the active site iron in the aromatic amino acid hydroxylase tyrosine hydroxylase are two histidines and a glutamate. This 2-histidine-1-carboxylate motif has been found in a number of other metalloenzymes which catalyze a variety of oxygenase reactions. As a probe of the plasticity of this metal binding site, each of the ligands in TyrH has been mutated to glutamine, glutamate, or histidine. The H336E and H336Q enzymes show dramatic decreases in iron affinity but retain substantial activity for both tyrosine hydroxylation and tetrahydropterin oxidation. The H331E enzyme shows a lesser decrease in iron affinity and is unable to hydroxylate tyrosine. Instead, this enzyme oxidizes tetrahydropterin in the absence of added tyrosine. The E376H enzyme has no significant activity, while the E376Q enzyme hydroxylates tyrosine at about 0.4% the wild-type rate. When dopamine is bound to either the H336Q or H331E enzymes, the position of the long wavelength charge-transfer absorbance band is consistent with the change in the metal ligand. In contrast, the H336E enzyme does not form a stable binary complex with dopamine, while the E376H and E376Q enzymes catalyze dopamine oxidation.
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PMID:Characterization of metal ligand mutants of tyrosine hydroxylase: insights into the plasticity of a 2-histidine-1-carboxylate triad. 1259 May 96

NMR spectroscopy and X-ray crystallography have provided important insight into structural features of phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH). Nevertheless, significant problems such as the substrate specificity of PAH and the different susceptibility of TH to feedback inhibition by l-3,4-dihydroxyphenylalanine (l-DOPA) compared with dopamine (DA) remain unresolved. Based on the crystal structures 5pah for PAH and 2toh for TH (Protein Data Bank), we have used molecular docking to model the binding of 6(R)-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) and the substrates phenylalanine and tyrosine to the catalytic domains of PAH and TH. The amino acid substrates were placed in positions common to both enzymes. The productive position of tyrosine in TH.BH4 was stabilized by a hydrogen bond with BH4. Despite favorable energy scores, tyrosine in a position trans to PAH residue His290 or TH residue His336 interferes with the access of the essential cofactor dioxygen to the catalytic center, thereby blocking the enzymatic reaction. DA and l-DOPA were directly coordinated to the active site iron via the hydroxyl residues of their catechol groups. Two alternative conformations, rotated 180 degrees around an imaginary iron-catecholamine axis, were found for DA and l-DOPA in PAH and for DA in TH. Electrostatic forces play a key role in hindering the bidentate binding of the immediate reaction product l-DOPA to TH, thereby saving the enzyme from direct feedback inhibition.
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PMID:Modeled ligand-protein complexes elucidate the origin of substrate specificity and provide insight into catalytic mechanisms of phenylalanine hydroxylase and tyrosine hydroxylase. 1263 Dec 67

Iron-induced oxidative injuries in locus coeruleus (LC), a major source of noradrenergic projections in the central nervous system (CNS), were investigated in chloral-hydrate anesthetized rats. Local infusion of iron dose-dependently elevated lipid peroxidation of iron-infused LC seven days after infusion. At the same time, norepinephrine content in the hippocampus ipsilateral to the iron-infused LC was decreased in a concentration-dependent manner. Our immunostaining study demonstrated reduced tyrosine hydroxylase-positive neurons in the iron-infused LC, indicating a reduction of neuron number by iron infusion. The involvement of apoptosis in iron-induced oxidative injuries was studied. An abrupt increase in cytosolic cytochrome c content was demonstrated in the infused LC 48 hours after iron infusion. TUNEL-positive cells, an indication of apoptosis, were detected in the iron-infused LC. In an attempt to prevent iron-induced neurotoxicity, vitamin D3, an active metabolite of vitamin D, was systemically administered. Iron-induced increases in cytosolic cytochrome c and TUNEL-positive cells were reduced by this treatment. Furthermore, systemic administration of vitamin D3 attenuated iron-induced oxidative injuries in the infused LC. Our data suggest that local infusion of iron in LC induced oxidative stress and resulted in programmed cell death in the LC-hippocampal noradrenergic system. Furthermore, vitamin D3 may be neuroprotective and therapeutic in attenuating iron-induced neurotoxicity in CNS.
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PMID:Systemic vitamin D3 attenuated oxidative injuries in the locus coeruleus of rat brain. 1285 23

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86


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