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)

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by a variety of agents. Previous workers have found that cyclic AMP-dependent protein kinase and calcium-stimulated protein kinases activate tyrosine hydroxylase. We wanted to determine whether cyclic GMP might also be involved in the regulation of tyrosine hydroxylase activity. We found that treatment of rat PC12 cells with sodium nitroprusside (an activator of guanylate cyclase), 8-bromocyclic GMP, forskolin (an activator of adenylate cyclase), and 8-bromocyclic AMP all produced an increase in tyrosine hydroxylase activity measured in vitro or an increased conversion of [14C]tyrosine to labeled catecholamine in situ. Sodium nitroprusside also increased the relative synthesis of cyclic GMP in these cells. In the presence of MgATP, both cyclic GMP and cyclic AMP increased tyrosine hydroxylase activity in PC12 cell extracts. The heat-stable cyclic AMP-dependent protein kinase inhibitor failed to attenuate the activation produced in the presence of cyclic GMP. It eliminated the activation produced in the presence of cyclic AMP. Sodium nitroprusside also increased tyrosine hydroxylase activity in vitro in rat corpus striatal synaptosomes and bovine adrenal chromaffin cells. In all cases, the cyclic AMP-dependent activation of tyrosine hydroxylase was greater than that of the cyclic GMP-dependent second messenger system. These results indicate that both cyclic GMP and cyclic AMP and their cognate protein kinases activate tyrosine hydroxylase activity in PC12 cells.
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PMID:Activation of tyrosine hydroxylase in PC12 cells by the cyclic GMP and cyclic AMP second messenger systems. 287 73

Incubation of cultured bovine adrenal medullary cells in Na+-free sucrose medium or in Na+-free Cs+ medium enhanced the synthesis of 14C-catecholamines from [14C]tyrosine about two- to threefold or sixfold, respectively. The increment of 14C-catecholamine synthesis produced by Na+-free medium was partially dependent on the presence of Ca2+ in the medium. Dibutyryl cyclic AMP also stimulated the synthesis of 14C-catecholamines in adrenal medullary cells, and the effects of Na+ removal and dibutyryl cyclic AMP (5 mM) on the synthesis were almost additive. The intracellular pH measured by using a weak acid 5,5-dimethyloxazolidine-2,4-dione was 7.14 in control cells and when Na+ was replaced by sucrose or Cs+, it shifted down to 6.56 or 5.66, respectively. The fall in intracellular pH and the stimulation of 14C-catecholamine synthesis were similarly dependent on the concentration of Na+ in the medium. The optimal pH of soluble tyrosine hydroxylase was 5.5-6.0 both in control cells and in cells incubated in Na+-free medium. These results suggest that removal of extracellular Na+ increases the synthesis of catecholamines, at least in part, by shifting the intracellular pH toward the optimal pH of tyrosine hydroxylase.
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PMID:Intracellular pH and catecholamine synthesis in cultured bovine adrenal medullary cells: effect of extracellular Na+ removal. 289 Jul 12

Activation of rat pheochromocytoma tyrosine hydroxylase by limited tryptic proteolysis was investigated. The modifications produced upon the enzyme's structure were analyzed with the use of sodium dodecyl sulfate/polyacrylamide gel electrophoresis and tyrosine hydroxylase activity was measured all through the digestion. During the proteolysis the activity of tyrosine hydroxylase was elevated threefold at the same time as a 56-kDa tryptic fragment was formed. When the enzyme was phosphorylated, at its N-terminal region, by a kinase copurified with tyrosine hydroxylase, the major 56-kDa species did not appear to be phosphorylated on the autoradiograph, suggesting that it was derived from the native subunit by cleavage of the N-terminal of the protein. The reactivity of the 2/40/15 anti-(tyrosine hydroxylase) monoclonal antibody with the N-terminal of tyrosine hydroxylase was also investigated, using the Western-blot technique. This antibody reacted with the 62-kDa hydroxylase subunit but not with the 60-kDa tryptic fragment; the amino acid sequences of these two species showed that the 60-kDa fragment lacked the first 16 N-terminal amino acids of the native molecule. These results suggest that the N-terminal region of tyrosine hydroxylase is apparently responsible for an inhibition of the hydroxylase activity and that the first N-terminal amino acids of the hydroxylase are necessary for the recognition of the enzyme by its antibody.
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PMID:Role of the N-terminus of rat pheochromocytoma tyrosine hydroxylase in the regulation of the enzyme's activity. 289 26

Tyrosine hydroxylase activity is reversibly modulated by the actions of a number of protein kinases and phosphoprotein phosphatases. A previous report from this laboratory showed that low-molecular-weight substances present in striatal extracts lead to an irreversible loss of tyrosine hydroxylase activity under cyclic AMP-dependent phosphorylation conditions. We report here that ascorbate is one agent that inactivates striatal tyrosine hydroxylase activity with an EC50 of 5.9 microM under phosphorylating conditions. Much higher concentrations (100 mM) fail to inactivate the enzyme under nonphosphorylating conditions. Isoascorbate (EC50, 11 microM) and dehydroascorbate (EC50, 970 microM) also inactivated tyrosine hydroxylase under phosphorylating but not under nonphosphorylating conditions. In contrast, ascorbate sulfate was inactive under phosphorylating conditions at concentrations up to 100 mM. Since the reduced compounds generate several reactive species in the presence of oxygen, the possible protecting effects of catalase, peroxidase, and superoxide dismutase were examined. None of these three enzymes, however, afforded any protection against inactivation. We also examined the effects of ascorbate and its congeners on the activity of tyrosine hydroxylase purified to near homogeneity from a rat pheochromocytoma. This purified enzyme was also inactivated by the same agents that inactivated the impure corpus striatal enzyme. Under conditions in which ascorbate almost completely abolished enzyme activity, we found no indication for significant proteolysis of the purified enzyme as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We also found that pretreatment of PC12 cells in culture for 4 h with 1 mM ascorbate, dehydroascorbate, or isoascorbate (but not ascorbate sulfate) also decreased tyrosine hydroxylase activity 25-50%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inactivation of tyrosine hydroxylase activity by ascorbate in vitro and in rat PC12 cells. 290 63

The B16/C3 murine melanoma is a pigmented tumor that is rich in the copper-containing enzyme, tyrosinase. This enzyme, which converts tyrosine to melanin precursors, is largely associated with membrane fractions of cells and exists in a number of discrete isozymic forms ranging in molecular mass from 58,000 to 150,000 daltons and pI from 3.4 to 5.2. One of these isozymes (Mr = 58,000, pI 3.4) has been purified to homogeneity. The purified enzyme catalyzes the hydroxylation of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) and the conversion of L-DOPA to dopaquinone. Ascorbic acid, tetrahydrofolate, and dopamine can serve as cofactors in the hydroxylase reaction. The Michaelis constants for the purified enzyme were 7 X 10(-4) M for L-tyrosine and 6 X 10(-4) M for L-DOPA. The Vmax for L-DOPA was much greater than the Vmax for L-tyrosine indicating that tyrosine hydroxylation is rate-limiting in melanin precursor biosynthesis. Two putative copper chelators, phenylthiourea and diethyldithiocarbamide inhibited both the tyrosine hydroxylase and L-DOPA oxidase activities of the enzyme. Phenylthiourea was a noncompetitive inhibitor while diethyldithiocarbamide was a competitive inhibitor indicating that these agents act by different mechanisms. When digested with proteases and glycosidases, higher molecular weight forms of tyrosinase co-migrated with the purified enzyme in isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggesting that the isozyme was derived from larger precursors. Thus, post-translational processing of tyrosinase may underlie isozyme diversity and this may be important in the control of melanogenesis in this tumor model.
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PMID:Tyrosinase isozyme heterogeneity in differentiating B16/C3 melanoma. 309 4

To determine if alterations of electrolyte balance or sympathetic nervous system activity are present in Dahl salt-sensitive rats (DS) before the onset of hypertension, we compared electrolyte balances, extracellular fluid volume (inulin space), plasma volume (radiolabeled albumin), and norepinephrine turnover in peripheral tissues (heart and interscapular brown fat) in prehypertensive DS and Dahl salt-resistant rats (DR). Animals were maintained for 5 to 7 days on either a "normal" or high NaCl diet. Tissue norepinephrine turnover was evaluated by measuring the rate at which norepinephrine content decreased following tyrosine hydroxylase inhibition with alpha-methyl-p-tyrosine. Blood pressure was higher (p less than 0.05) in DS (135 +/- 2 [SE] mm Hg) than in DR (129 +/- 2 mm Hg) and was not affected by the diets. Extracellular fluid volume and net Na+ and Cl- balances did not differ between DS and DR. However, plasma volume was greater in DS than in DR (p less than 0.05). In both fat and heart, norepinephrine turnover was decreased by dietary NaCl loading in DR (p less than 0.01), but not in DS. Thus, the tendency of the DS to become hypertensive with high NaCl intake may be related to the combined effects of an increased plasma volume and the failure of high dietary NaCl to inhibit peripheral sympathetic nervous system activity.
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PMID:Failure of salt loading to inhibit tissue norepinephrine turnover in prehypertensive Dahl salt-sensitive rats. 320 61

A tyrosinase has been purified from the skin of the frog Xenopus laevis. Dihydroxyphenylalanine oxidase and tyrosine hydroxylase activities co-purify throughout the procedure. The enzyme is isolated in an inactive form, but both enzymatic activities are activated by a variety of anionic detergents. Of these, sodium dodecyl sulfate (NaDodSO4) is the most effective. The enzyme activation occurs at NaDodSO4 concentrations well below the critical micelle concentration and it remains active at concentrations as high as 30 mM (1%). Neither activity is stimulated by cationic or nonionic detergents, or a variety of other agents, including trypsin. The purified tyrosinase is a glycoprotein having a polypeptide Mr = 175,000 by NaDodSO4-polyacrylamide gel electrophoresis. This monomeric species is enzymatically active in the presence of NaDodSO4. Detergent-activated tyrosinase has a KM for dihydroxyphenylalanine of 6 X 10(-4) M and a KM for tyrosine of 4 X 10(-4) M. Both activities are inhibited by copper chelators but not by an iron chelator. Further characterization of the detergent activation of this enzyme is presented in a companion paper (Wittenberg, C., and Triplett, E. L. (1985) J. Biol. Chem. 260, 12542-12546).
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PMID:A detergent-activated tyrosinase from Xenopus laevis. I. Purification and partial characterization. 393 Apr 97

Mouse neuroblastoma cells in culture have been used as a model for the study of the mechanism by which activities of tyrosine hydroxylase (EC 1.14.3.a) are regulated in sympathetic tissue. The activity of tyrosine hydroxylase in cultured cells drops to barely detectable activities after 1 week and remains low for months in culture in the uncloned cell line of neuroblastoma. Activity in an adrenergic clone isolated from the uncloned line has about 20% of the activity of the fresh grated tumor cell. N(6), O(2')-dibutyryl adenosine 3':5'-cyclic monophosphate causes a concentration and time-dependent increase in enzyme activity in both the cloned and uncloned cell lines. Enzyme activity is elevated by other stable analogs of adenosine 3':5'-cyclic monophosphate, notably the N(6)-monobutyryl, 8-aminomethyl, and 8-methylthio derivatives of the cyclic nucleotide; by the inhibitor of cyclic nucleotide phosphodiesterase, papaverine; and by sodium butyrate. Changes in cell morphology and tyrosine hydroxylase activity are shown not to be necessarily related.
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PMID:Regulation of tyrosine hydroxylase activity in cultured mouse neuroblastoma cells: elevation induced by analogs of adenosine 3':5'-cyclic monophosphate. 440 8

The influence of 2-(2-oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1, 1-dioxide (supidimide), a representative of a new class of sedative drugs, on the noradrenergic, dopaminergic, serotoninergic and gamma-aminobutyric acid (GABA)ergic neuronal systems of rodent brains was investigated. In each case the brain transmitter levels after administration of supidimide were determined. Utilisation of noradrenaline (norepinephrine, NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) was also investigated ex vivo. The study was complemented with in vitro investigations of biosynthesis, synaptosomal uptake, degradation, and receptor binding of the transmitters. Based on a preliminary study of the distribution of [35S]-supidimide in rat brain, in vitro effects observed at greater than 10(-4) mol/l were considered irrelevant. Similarly, in vivo effects requiring dosages higher than 300 mg/kg i.p. were not regarded adequate to explain the sedative and antiaggressive efficacy of supidimide. With the above restrictions, the following parameters can be rated as not influenced by supidimide: levels of tryptophan in rat brain and serum (free and total); 5-HT biosynthesis in vivo (rat brain; 5-HT accumulation after monoamine oxidase (MAO) blockade); activity of MAO-A and MAO-B (rat brain mitochondria); uptake of 5-HT, NE and DA (rat synaptosomes); 5-HT receptor binding ( [3H]-LSD binding assay in rat cortical membranes); tyrosine hydroxylase activity (rat adrenal glands); catechol-O-methyl transferase (COMT) (rat liver); NE binding to central alpha 1- and alpha 2-receptors (rat brain; radioligand assay with [3H]-dihydroergocryptine, [3H]-prazosin and [3H]-WB 4101 (2',6'-dimethoxy-(G-3H]-phenoxy]-ethylaminomethylbenzo-1,4-dioxane ); DA levels (whole rat brain and striata); dihydroxyphenylacetic acid (DOPAC) levels (whole rat brain without cerebellum and striata); elevated DOPAC levels after pretreatment with haloperidol; DA-dependent adenylate cyclase in vitro (rat striatum); D2 receptor binding ( [3H]-spiperone binding assay, rat striatum); GABA levels (mouse brain); GABA transaminase activity (mouse brain stem); sodium-independent [3H]-GABA receptor binding (rat brain) and benzodiazepine binding (rat cortical membranes, [3H]-diazepam binding assay). Two effects on the GABAergic system were induced by supidimide. Starting at 300 mg/kg i.p., supidimide slowed down the GABA accumulation in brains of aminooxyacetate-treated mice. At 10(-4) mol/l supidimide caused a significant inhibition of GABA uptake (rat synaptosomes).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of supidimide on brain neurotransmitter systems of rats and mice. 608 11

1. Isolated superior cervical ganglia of the rat were incubated for 2--30 min (37 degrees C) in Krebs' solution or tissue culture medium (BGJb) containing 22Na and then washed for 30 min in ice-cold 22Na-free Krebs' solution (to clear extracellular space). The radioactivity remaining in the ganglia was taken as a measure of 22Na influx into the intracellular compartment of the ganglion. 2. Addition of cholinomimetics (100 microM nicotine or 100 microM carbachol) to the incubation led to an increase in 22Na influx. This increase reached maximal values after 10 min of incubation; it was more pronounced after incubation in Krebs' solution than in BGJb medium. 3. While chlorisondamine (3 microM) or dopamine (100 microM) greatly reduced the carbachol-induced 22Na influx, tetrodotoxin (2 microM) did not have any effect. 4. In ganglia obtained from animals treated with 6-hydroxydopamine in the early postnatal phase (resulting in an extensive destruction of peripheral sympathetic neurons) neither carbachol (100 microM) nor nicotine (100 microM) produced an increase in 22Na influx demonstrating that the intraneuronal compartment is responsible for this enhanced influx. 5. The effects of dopamine, chlorisondamine and tetrodotoxin on the carbachol-induced 22Na uptake into superior cervical ganglia are similar to their effects on carbachol-mediated induction of tyrosine hydroxylase in superior cervical ganglia kept in tissue culture (Thoenen and Otten 1977b). It is concluded that the induction of tyrosine hydroxylase via nicotinic receptors is closely linked to the enhanced sodium influx into the adrenergic neurons mediated by the same receptors.
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PMID:The role of sodium influx mediated by nicotinic receptors as an initial event in trans-synaptic induction of tyrosine hydroxylase in adrenergic neurons. 610 66


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