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 modification of the tyrosine hydroxylase assay is described in which ascorbate, rather than 2-mercaptoethanol or dihydropteridine reductase with NADPH, is used as the reductant. Enzyme activity is 3-4 times higher with ascorbate than with the other reducing agents. Low blanks are obtained with the ascorbate system provided that catalase is also included. The tissue distribution and kinetic activation of the enzyme have been studied with the ascorbate assay. The results obtained are consistent with the biological and regulatory properties of the enzyme which have been determined with the other reducing systems.
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PMID:Modification of the tyrosine hydroxylase assay. Increased enzyme activity in the presence of ascorbic acid. 3 15

Chronic (3 months) lead exposure increased the quinonoid dihydropteridine reductase activity and the tetrahydrobiopterin content but did not affect the GTP-cyclohydrolase activity and the dihydrobiopterin content. These results suggest that lead intoxication may enhance dopamine metabolism in neostriatum by increasing the content of tetrahydrobiopterin, the regulating cofactor of tyrosine hydroxylase activity.
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PMID:Effect of chronic lead exposure on biopterin metabolism in the rat neostriatum. 235 44

The substrates of dihydropteridine reductase (EC 1.6.99.7), quinonoid 7,8-dihydro(6 H)pterins, are unstable and decompose in various ways. In attempting to prepare a more stable substrate, 6,6,8-trimethyl-5,6,7,8-tetrahydro(3 H)pterin was synthesised and the quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin derived from it is extremely stable with a half-life in 0.1 M Tris/HCl (pH 7.6, 25 degrees C) of 33 h. Quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin is not a substrate for dihydropteridine reductase but it is reduced non-enzymically by NADH at a significant rate and it is a weak inhibitor of the enzyme: I50 200 microM, pH 7.6, 25 degrees C when using quinonoid 6-methyl-7,8-dihydro(6 H)pterin as substrate. 6,6,8-Trimethyl-5,6,7,8-tetrahydropterin is a cofactor for phenylalanine hydroxylase (EC 1.14.16.1) with an apparent Km of 0.33 mM, but no cofactor activity could be detected with tyrosine hydroxylase (EC 1.14.16.2). Its phenylalanine hydroxylase activity, together with the enhanced stability of quinonoid 6,6,8-trimethyl-7,8-dihydro(6 H)pterin, suggest that it may have potential for the treatment of variant forms of phenylketonuria.
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PMID:Reduced 6,6,8-trimethylpterins. Preparation, properties and enzymic reactivities with dihydropteridine reductase, phenylalanine hydroxylase and tyrosine hydroxylase. 285 23

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, at 10(-5) M inhibited hydroxylation of tyrosine to 3,4-dihydrophenylalanine (DOPA), the rate-limiting step of dopamine synthesis, in tissue slices of the striatum and nucleus accumbens of the rat. Nomifensine, an inhibitor of dopamine uptake, reversed the inhibition but sulpiride, a dopamine receptor antagonist, did not affect the inhibition. MPTP at 10(-5) M inhibited neither the purified tyrosine hydroxylase nor dihydropteridine reductase in vitro. The level of total biopterin did not change significantly, but the tetrahydrobiopterin level was decreased in the striatal slices incubated in the presence of MPTP. These results suggest that MPTP inhibits dopamine synthesis in situ at the tyrosine hydroxylase step probably through inhibition of dihydropteridine reductase.
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PMID:Inhibition of tyrosine hydroxylation in tissue slices of the rat striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 286 Sep 54

The effects of lead, a known neurotoxin on the metabolism of a vital tetrahydrobiopterin cofactor for the hydroxylation enzymes tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase, have been investigated. Reduced availability of this pteridine has the potential to reduce the level of the neurotransmitters noradrenaline, adrenaline and 5-hydroxytryptophan in the brain. Using the rat as a model, increases in tetrahydrobiopterin concentration and in the activity of dihydropteridine reductase, an enzyme involved in tetrahydrobiopterin metabolism, were observed after exposure to lead via the drinking water. Possible explanations for this increased level of tetrahydrobiopterin relate to alterations in the balance between synthesis and salvage of this co-factor.
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PMID:Neurotoxic action of lead: effect on tetrahydrobiopterin metabolism in the rat. 286 Oct 54

The effect of chronic uremia on activities of cerebral dihydropteridine reductase (DHPR) and tyrosine hydroxylase (TH) and content of norepinephrine and dopamine was investigated in the male Sprague-Dawley rats. The uremic animals were fed diets containing either 8% or 18% casein ad libitum, and sham-operated pair-fed and ad libitum fed animals were used as controls. There were no significant differences in TH activity between the groups fed the two levels of protein. Uremic rats had lower activity of TH than pair-fed controls, and pair-fed controls had lower activity than ad libitum-fed animals. DHPR activity and norepinephrine and dopamine content did not differ among the groups. Our study suggests that the chronic uremic condition or restricted feeding causes a decrease in brain TH activity which is not mediated by decreased DHPR activity. Further, this decreased enzyme activity does not result in depressed catecholamine content, indicating the presence of a highly regulated mechanism controlling catecholamine levels.
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PMID:Activities of cerebral dihydropteridine reductase and tyrosine hydroxylase in chronic uremia in rats. 287 42

Tetrahydrobiopterin (THB) analogues with 6-alkoxymethyl substituents, 3a-j, where the substituents were straight- and branched-chain alkyl ranging from methyl to octyl, have been synthesized by the Taylor method from pyrazine ortho amino nitriles by guanidine cyclization, hydrolysis in aqueous NaOH, and catalytic hydrogenation over Pt in trifluoroacetic acid (TFA). The best of these compounds, 3b, is an excellent cofactor for phenylalanine hydroxylase, tyrosine hydroxylase (V = 154% of THB), and tryptophan hydroxylase, does not destablize the binding of substrate (Kmtyr = 23 microM), and is recycled by dihydropteridine reductase (V = 419% of THB). The compounds are being evaluated as cofactor replacements in biopterin-deficiency diseases.
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PMID:Synthetic analogues of tetrahydrobiopterin with cofactor activity for aromatic amino acid hydroxylases. 287 18

Pargyline, an inhibitor of monoamine oxidase (MAO), prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced inhibition of dihydroxyphenylalanine (DOPA) production by tyrosine hydroxylase (TH) system in rat striatal tissue slices. The result suggests that the metabolism of MPTP in rat striatal tissue slices by MAO is necessary for the expression of the inhibitory effect. 1-Methyl-4-phenylpyridinium ion (MPP+), the metabolic product of MPTP by MAO, also inhibited DOPA formation in rat striatal tissue slices. The concentration of MPP+ producing significant inhibition was lower than that of MPTP, and the maximal inhibition produced by MPP+ was greater than that caused by MPTP. Since MPP+ at a concentration of 10(-4) M had no effect on the activity of pure TH in vitro, the inhibition of DOPA formation in tissue slices induced by MPP+ may not be due to direct inhibition of TH. Although hydroxylated derivatives of MPTP were reported to inhibit dihydropteridine reductase in vitro at lower concentrations than MPTP, 1-methyl-4-(p-hydroxyphenyl)-1,2,3,6-tetrahydropyridine showed only weak inhibition for tyrosine hydroxylation in striatal tissue slices.
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PMID:Inhibition of tyrosine hydroxylation in rat striatal tissue slices by 1-methyl-4-phenylpyridinium ion. 392 90

The low tissue concentrations of tetrahydrobiopterin, as well as the antagonism between the catecholamine feedback inhibition of tyrosine hydroxylase and the reduced cofactor concentrations, suggest that dihydropteridine reductase may play an important role in the regulation of catecholamine biosynthesis. The interaction of the different components involved in the hydroxylation of tyrosine was studied in vitro in a complex system composed of tyrosine hydroxylase, dihydropteridine reductase, and the different cofactors. This system has several important characteristics: (a) the rate of dihydroxyphenylalanine formation can be controlled by the concentration of dihydropteridine reductase; (b) low concentrations of catecholamines (2 x 10(-5) M) can produce a marked inhibition of tyrosine hydroxylase activity; and (c) the catecholamine feedback-inhibition of tyrosine hydroxylase can be antagonized by increasing concentrations of dihydropteridine reductase. The properties of the in vitro tyrosine hydroxylase-dihydropteridine reductase system suggest that dihydropteridine reductase may have an important role in vivo in the determination of the rates of dihydroxyphenylalanine formation and on the effectiveness of the catecholamine feedback-inhibition of tyrosine hydroxylase activity.
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PMID:Dihydropteridine reductase: implication on the regulation of catecholamine biosynthesis. 528 68

The activity of dihydropteridine reductase (DPR) in pheochromocytoma cells has been studied. The activity of this enzyme in crude extracts of pheochromocytoma cells is approximately 50 nmol/min/mg protein. This activity is very much greater than the activity of tyrosine 3-monooxygenase (TH) in these extracts and the rate of conversion of tyrosine to DOPA in intact pheochromocytoma cells. Incubation of the cells with 56 mM-K+ or with cholera toxin has previously been shown to increase the rate of catecholamine synthesis and to cause a stable activation of TH in the cells. These treatments do not produce a stable activation of DPR, as assayed in vitro. Methotrexate inhibits DPR activity in vitro with an I50 of approximately 20 microM, but has no effect on the rate of DOPA formation in intact pheochromocytoma cells. Therefore, DPR does not appear to be the rate-limiting enzyme in the pathway of catecholamine synthesis in pheochromocytoma cells. Moreover, the activities of DPR and of TH are not regulated coordinately in these cells.
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PMID:Studies on dihydropteridine reductase activity in pheochromocytoma cells. 611 3


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