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)

We have previously reported that intracerebroventricular administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4), a cofactor for tyrosine hydroxylase, enhances biosynthesis of 3,4-dihydroxyphenylethylamine (dopamine) in the rat brain. In the present study, we have more precisely examined the effects of 6R-BH4 on dopamine release in vivo from the rat striatum using brain microdialysis. The amount of dopamine collected in striatal dialysates was determined using HPLC with electrochemical detection after purification with an alumina batch method. When the striatum was dialyzed with Ringer solution containing various concentrations of 6R-BH4 (0.25, 0.5, and 1.0 mM), dopamine levels in striatal dialysates increased in a concentration-dependent manner. Biopterin had little effect on dopamine levels in dialysates. The 6R-BH4-induced increase in dopamine levels in dialysates was abolished after pretreatment with tetrodotoxin (50 microM) added to the perfusion fluid, but after pretreatment with nomifensine (100 mg/kg, intraperitoneal injection), an inhibitor of dopamine uptake mechanism, a larger increase was observed. After inhibition of tyrosine hydroxylase by pretreatment with alpha-methyl-p-tyrosine (250 mg/kg, intraperitoneal injection), most of the increase persisted. These results suggest that 6R-BH4 has a dopamine-releasing action, which is not dependent on biosynthesis of dopamine.
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PMID:Enhancement of dopamine release in vivo from the rat striatum by dialytic perfusion of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin. 196 62

Total biopterin concentrations in the post-mortem human brain (caudate nucleus) and in the urine of controls and parkinsonian patients were measured by a newly developed radioimmunoassay. There was good correlation between the total biopterin level and tyrosine hydroxylase activity in the human brain. Biopterin concentrations in the caudate nucleus were greatly reduced in parkinsonian patients. In contrast, the reduction of urinary biopterin in parkinsonian patients was slight and not statistically significant, as compared with normal controls.
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PMID:Biopterin in human brain and urine from controls and parkinsonian patients: application of a new radioimmunoassay. 611 78

Hereditary progressive dystonia with marked diurnal fluctuation (HPD or dopa-responsive dystonia) is a clinical entity characterized by childhood-onset dystonia followed by parkinsonism, which shows dramatic response to levodopa. However, the same combination of the symptoms is also characteristic of some patients with juvenile parkinsonism (JP: manifesting below the age of 40), and sometimes the correct differentiation between these HPD and JP patients, in the early course of the disorder, may be difficult. In this study, therefore, we analyzed cerebrospinal fluid (CSF) biopterin (BP) and neopterin (NP) concentrations in 2 patients with HPD, 58 with idiopathic parkinsonism (IP: this group includes 25 cases with JP), 9 with dopa-nonresponsive dystonia (DNRD) and 18 controls, to search for biochemical differences among these disorders. Biopterin is the natural cofactor for tyrosine hydroxylase and NP consists of degradation products of dihydroneopterin triphosphate, which is the first intermediate in the BP biosynthesis from guanosine triphosphate (GTP). As a result, the mean BP level in the IP patients (8.5 +/- 0.3 pmol/ml; mean +/- SE) was significantly lower than those in both the controls (13.2 +/- 0.5, p < 0.001) and the DNRD patients (14.2 +/- 1.2, p < 0.001). The BP levels in the HPD patients (7.1, 5.9) were lower than the mean BP level in the IP patients. With regard to NP content, there were no significant differences in the mean NP levels among the controls (25.2 +/- 2.0 pmol/ml; mean +/- SE) and the patients with IP and DNRD (22.6 +/- 1.0, 25.2 +/- 2.2).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Significance of CSF biopterin and neopterin in hereditary progressive dystonia with marked diurnal fluctuation (HPD)--a clue to pathogenesis]. 766 28

One of the possibly mutated genes in DOPA-responsive dystonia (DRD, Segawa's disease) is the gene encoding GTP cyclohydrolase I, which is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. Based on our findings on 6-pyruvoyltetrahydropterin synthase (PTS) gene-disrupted (Pts(-/-)) mice, we suggested that the amount of tyrosine hydroxylase (TH) protein in dopaminergic nerve terminals is regulated by the intracellular concentration of BH4. In this present work, we rescued Pts(-/-) mice by transgenic introduction of human PTS cDNA under the control of the dopamine beta-hydroxylase promoter to examine regional differences in the sensitivity of dopaminergic neurons to BH4-insufficiency. The DPS-rescued (Pts(-/-), DPS) mice showed severe hyperphenylalaninemia. Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. Biopterin and dopamine contents, and TH activity in the striatum were poorly restored compared with those in the midbrain. TH-immunoreactivity in the lateral region of the striatum was far weaker than that in the medial region or in the nucleus accumbens. We concluded that dopaminergic nerve terminals projecting to the lateral region of the striatum are the most sensitive to BH4-insufficiency. Biochemical and pathological changes in DPS-rescued mice were similar to those in human malignant hyperphenylalaninemia and DRD.
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PMID:Genetically rescued tetrahydrobiopterin-depleted mice survive with hyperphenylalaninemia and region-specific monoaminergic abnormalities. 1613 92

The present work proposes an extra neural site of catecholamine production along the nephron. LLC-PK(1), MDCK, and mIMCD-3 (proximal and distal tubules and inner medullary collecting duct, respectively) presented the following amine concentrations in the cell homogenates: Norepinephrine = 275+/-34, 56+/-16 and 255+/-21; Epinephrine = 161+/-20, 83+/-17 and 53+/-7; and Dopamine = 63+/-15, 39+/-6 and 36+/-7 pg/mg cell protein (Means +/- SEM), respectively. The culture medium showed Norepinephrine = 168+/-25, 22+/-3 and 135+/-8; Epinephrine = 32+/-6, 152+/-17 and 39+/-5; and Dopamine = 27+/-9, 241+/-34 and 26+/-5 pg/mg cell protein, respectively. The synthesis enzymes as tyrosine hydroxylase, dopa decarboxylase and dopamine beta-hydroxylase were detected by Western blotting. Biopterin, the enzymatic cofactor of tyrosine hydroxylase, was quantified in the intracellular and medium of mIMCD-3 cells (17+/-4 and 24+/-3 nmol/mg cell protein, respectively) and in the medium of MDCK cells (19+/-4 nmol/mg cell protein). The data confirmed that the proximal tubule is an important source of dopa decarboxilase and Dopamine and epithelial cell along the nephron express the biochemical pathway for catecholamine production.
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PMID:Catecholamine production along the nephron. 1798 74

Biopterin, the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, was decreased in caudate nucleus, hypothalamus and cerebellum of the rolling mouse. Though there were not significant differences of tyrosine hydroxylase and tryptophan hydroxylase activities between the rolling and normal control mouse in the hypothalamus, the rolling showed significant increase of biopterin concentration and tyrosine hydroxylase activity after administration of thyrotropin releasing hormone (TRH). These results suggest that ataxic gait of the rolling mouse may be partly due to some abnormalities of catecholaminergic neurons, especially noradrenergic neurons, and that TRH may improve the abnormalities of catecholaminergic neurons. The changes of biopterin concentration by TRH administration indicate that biopterin may be a regulatory factor in catecholamine biosynthesis.
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PMID:Tyrosine hydroxylase and tryptophan hydroxylase activities and its cofactor biopterin level in brain regions of the rolling mouse: The influence of thyrotropin releasing hormone. 2048 3