Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured the CSF levels of 21, and the plasma levels of 26, amino acids in 31 patients with Parkinson's disease (PD) and in 45 matched controls. We used an ion-exchange chromatography method. When compared to controls, PD patients had lower CSF levels of taurine, alanine, valine, leucine, isoleucine, ethanolamine, citrulline, ornithine, lysine, histidine, arginine, and alpha-aminobutyric acid. PD patients not treated with levodopa or with dopamine agonists had higher CSF tyrosine and phenylalanine levels than those not treated with these drugs and also than controls. PD patients had higher plasma levels of phosphoserine, threonine, methionine, tyrosine, sarcosine and alpha-aminoadipic acid, and lower plasma levels of valine, leucine, and tryptophan, than controls. The CSF/plasma ratio of many of these amino acids was significantly lower in PD patients than those of controls, suggesting that PD patients might have a dysfunction in the transport of neutral and basic amino acids across the blood-brain barrier.
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PMID:Decreased cerebrospinal fluid levels of neutral and basic amino acids in patients with Parkinson's disease. 926 38

Since binding sites for morphine, nicotine and strychnine exist in the brain, it is possible that they may have some role in neuronal function. The presence/variation in the levels of these alkaloids in the brain of rats fed tryptophan and tyrosine, and in the serum of patients with some neurodegenerative and psychiatric disorders were studied. Brain of rats loaded with tyrosine (500 mg/kg b wt X 14 days) showed increased amounts of morphine, while that from animals loaded with tryptophan (in the same dose) showed presence of strychnine and increased amounts of nicotine. Strychnine is being reported in mammalian brain for the first time. Serum of patients with epilepsy, Parkinson's disease (PD) and manic depressive psychosis (MDP) was also examined for the presence of these alkaloids. Serum of control subjects did not show the presence of any of these alkaloids, while that of all 3 patients groups contained strychnine. Morphine was present only in the serum of patients of MDP. Nicotine was present in trace amounts in the serum of all these patients. Presence of these alkaloids in the serum of patients of neurodegenerative and psychiatric disorders is being reported for the first time, to the best of our knowledge.
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PMID:Endogenous alkaloids in the brain of rats loaded with tyrosine/tryptophan & in the serum of patients of neurodegenerative & psychiatric disorders. 967 Jun 21

The neurotransmitter serotonin has been implicated in numerous physiological functions and pathophysiological disorders. The hydroxylation of the aromatic amino acid tryptophan is rate-limiting in the synthesis of serotonin. Tryptophan hydroxylase (TPH), as the rate-limiting enzyme, determines the concentrations of serotonin in vivo. Relative serotonin concentrations are clearly important in neural transmission, but serotonin has also been reported to function as a local antioxidant. Identification of the mechanisms regulating TPH activity has been hindered by its low levels in tissues and the instability of the enzyme. Several TPH expression systems have been developed to circumvent these problems. In addition, eukaryotic expressions systems are currently being developed and represent a new avenue of research for identifying TPH regulatory mechanisms. Recombinant DNA technology has enabled the synthesis of TPH deletions, chimeras, and point mutations that have served as tools for identifying structural and functional domains within TPH. Notably, the experiments have proven long-held hypotheses that TPH is organized into N-terminal regulatory and C-terminal catalytic domains, that serine-58 is a site for PKA-mediated phosphorylation, and that a C-terminal leucine zipper is involved in formation of the tetrameric holoenzyme. Several new findings have also emerged regarding regulation of TPH activity by posttranslational phosphorylation, kinetic inhibition, and covalent modification. Inhibition of TPH by L-DOPA may have implications for depression in Parkinson's disease (PD) patients. In addition, TPH inactivation by nitric oxide may be involved in amphetamine-induced toxicity. These regulatory concepts, in conjunction with new systems for studying TPH activity, are the focus of this article.
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PMID:Advances in the molecular characterization of tryptophan hydroxylase. 977 Jun 40

Parkinson's disease (PD) is characterized by decreased striatal dopamine, but serotonin (5-HT) is also reduced. Because 5-HT decreases following a single levodopa injection, levodopa has been suggested to contribute to PD's serotonergic deficits. However, in a recent study, rat striatal serotonin levels were reported to increase following 15-day levodopa administration. To address this issue, we administered levodopa (50 mg/kg) to rabbits for 5 days, then measured serotonin, its precursors tryptophan and 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindole-acetic acid (5-HIAA) in striatum and CSF. Striatal serotonin and tryptophan were unchanged, while 5-HTP and 5-HIAA increased 4- and 7-fold, respectively. CSF 5-HTP and 5-HIAA were also significantly increased. In levodopa-treated animals, 5-HTP concentrations were moderately correlated (r = 0.679) between striatum and CSF, while weak correlations were present between striatal and CSF concentrations of both serotonin and 5-HIAA. These results suggest that repeated levodopa treatment increases striatal serotonin turnover without changing serotonin content. However, levodopa-induced alterations in striatal serotonin metabolism may not be accurately reflected by measurement of serotonin and 5-HIAA in CSF.
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PMID:Influence of repeated levodopa administration on rabbit striatal serotonin metabolism, and comparison between striatal and CSF alterations. 982 Nov 56

Tetrahydrobiopterin (BH(4)) cofactor is essential for various processes, and is present in probably every cell or tissue of higher organisms. BH(4) is required for various enzyme activities, and for less defined functions at the cellular level. The pathway for the de novo biosynthesis of BH(4) from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase. Cofactor regeneration requires pterin-4a-carbinolamine dehydratase and dihydropteridine reductase. Based on gene cloning, recombinant expression, mutagenesis studies, structural analysis of crystals and NMR studies, reaction mechanisms for the biosynthetic and recycling enzymes were proposed. With regard to the regulation of cofactor biosynthesis, the major controlling point is GTP cyclohydrolase I, the expression of which may be under the control of cytokine induction. In the liver at least, activity is inhibited by BH(4), but stimulated by phenylalanine through the GTP cyclohydrolase I feedback regulatory protein. The enzymes that depend on BH(4) are the phenylalanine, tyrosine and tryptophan hydroxylases, the latter two being the rate-limiting enzymes for catecholamine and 5-hydroxytryptamine (serotonin) biosynthesis, all NO synthase isoforms and the glyceryl-ether mono-oxygenase. On a cellular level, BH(4) has been found to be a growth or proliferation factor for Crithidia fasciculata, haemopoietic cells and various mammalian cell lines. In the nervous system, BH(4) is a self-protecting factor for NO, or a general neuroprotecting factor via the NO synthase pathway, and has neurotransmitter-releasing function. With regard to human disease, BH(4) deficiency due to autosomal recessive mutations in all enzymes (except sepiapterin reductase) have been described as a cause of hyperphenylalaninaemia. Furthermore, several neurological diseases, including Dopa-responsive dystonia, but also Alzheimer's disease, Parkinson's disease, autism and depression, have been suggested to be a consequence of restricted cofactor availability.
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PMID:Tetrahydrobiopterin biosynthesis, regeneration and functions. 1072 95

Previous work from this laboratory had demonstrated the presence of endogenous morphine, strychnine and nicotine in the mammalian brain and human serum samples. Morphine is synthesised from tyrosine and strychnine and nicotine from tryptophan. This study examines the role of strychnine, nicotine and morphine in neuropsychiatric disorders. The blood levels of tyrosine, tryptophan, strychnine, nicotine and morphine were studied as also RBC membrane Na(+)-K+ ATPase activity. It was found that serum tyrosine levels were reduced and tryptophan levels elevated in all neuropsychiatric disorders studied with a reduction in RBC Na(+)-K+ ATPase activity. Nicotine was present in significant amounts in serum of patients with schizophrenia, CNS glioma and syndrome X with multiple lacunar state. Morphine was present in significant amounts only in the serum of patients with multiple sclerosis and MDP. Strychnine was present in significant amounts in the serum of patients with epilepsy, Parkinson's disease and MDP. The presence of nicotine and strychnine in significant amounts could be related to elevated tryptophan levels suggesting the synthesis of these alkaloids from tryptophan. Morphine was not detected in most of the disorders owing to low tyrosine levels noted in them. Na(+)-K+ ATPase inhibition noticed in most of the disorders could be related to decreased hyperpolarising morphinergic transmission and increased depolarising nicotinergic and strychinergic transmission. The role of morphine, strychnine and nicotine in the pathogenesis of these disorders in the setting of membrane Na(+)-K+ ATPase inhibition is discussed.
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PMID:Endogenous strychnine, nicotine, and morphine--description of hypo and hyper-strychninergic, nicotinergic and morphinergic state in relation to neuropsychiatric diseases. 1111 26

Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. TPH belongs to the family of the aromatic amino acid hydroxylases, including phenylalanine hydroxylase (PAH) and tyrosine hydroxylase (TH), which all have a strict requirement for dioxygen, non-heme iron (II) and tetrahydrobiopterin (BH4). During the last three years there has been a formidable increase in the amount of structural information about PAH and TH, which has provided new insights into the active site structure, the binding of substrates, inhibitors and pterins, as well as on the effect of disease-causing mutations in these hydroxylases. Although structural information about TPH is not yet available, the high sequence homology between the three mammalian hydroxylases, notably at the catalytic domains, and the similarity of the reactions that they catalyze, indicate that they share a similar 3D-structure and a common catalytic mechanism. Thus, we have prepared a model of the structure of TPH based on the crystal structures of TH and PAH. This structural model provides a frame for understanding the specific interactions of TPH with L-tryptophan and substrate analogues, BH4 and cofactor analogues, L-DOPA and catecholamines. The interactions of these ligands with the enzyme are discussed focusing on the physiological and pharmacological regulation of serotonin biosynthesis, notably by tryptophan supplementation therapy and substitution therapy with tetrahydrobiopterin analogues (positive effects), as well as the effect of catecholamines on TPH activity in L-DOPA treated Parkinson's disease patients (enzyme inhibition).
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PMID:A structural approach into human tryptophan hydroxylase and its implications for the regulation of serotonin biosynthesis. 1147 42

The isoprenoid pathway produces three key metabolites-digoxin (membrane sodium-potassium ATPase inhibitor and regulator of intracellular calcium-magnesium ratios), dolichol (regulator of N-glycosylation of proteins) and ubiquinone (free radical scavenger). The pathway was assessed in a rare and specific type of familial basal ganglia calcification described. The family had a coexistence of basal ganglia calcification (six out of 10 cases), schizophrenia, Parkinson's disease, Alzheimer's disease, rheumatoid arthritis, systemic tumours and syndrome X and were all right hemispheric dominant. The isoprenoid pathway was also studied for comparison in right hemispheric dominant, bihemispheric dominant and left hemispheric dominant individuals. The isoprenoid pathway was upregulated with increased digoxin synthesis in familial basal ganglia calcification. Membrane sodium-potassium ATPase inhibition can lead on to increase in intracellular calcium and calcification of the basal ganglia. There was increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was also an increase in dolichol and glycoconjugate levels with reduced lysosomal stability in these patients. The ubiquinone levels were low and free radical levels increased. The cholesterol-phospholipid ratio was increased and glycoconjugate level of the RBC membrane reduced in these group of patients. No significance difference was noted in family members with and without basal ganglia calcification. This findings were correlated with the pathogenesis of syndrome X, immune mediated diseases, degenerations, tumours and psychiatric disorders noted in the familial basal ganglia calcification described. The biochemical patterns obtained in familial basal ganglia calcification correlated with those in right hemispheric dominance.
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PMID:Hypothalamic digoxin related membrane Na+-K+ ATPase inhibition and familial basal ganglia calcification. 1181 7

Tetrahydrobiopterin (H4-biopterin) is an essential cofactor of a set of enzymes that are of central metabolic importance, i.e. the hydroxylases of the three aromatic amino acids phenylalanine, tyrosine, and tryptophan, of ether lipid oxidase, and of the three nitric oxide synthase (NOS) isoenzymes. As a consequence, H4-biopterin plays a key role in a vast number of biological processes and pathological states associated with neurotransmitter formation, vasorelaxation, and immune response. In mammals, its biosynthesis is controlled by hormones, cytokines and certain immune stimuli. This review aims to summarize recent developments concerning regulation of H4-biopterin biosynthetic and regulatory enzymes and pharmacological effects of H4-biopterin in various conditions, e.g. endothelial dysfunction or apoptosis of neuronal cells. Also, approaches towards gene therapy of diseases like the different forms of phenylketonuria or of Parkinson's disease are reviewed. Additional emphasis is given to H4-biopterin biosynthesis and function in non-mammalian species such as fruit fly, zebra fish, fungi, slime molds, the bacterium Nocardia as well as to the parasitic protozoan genus of Leishmania that is not capable of pteridine biosynthesis but has evolved a sophisticated salvage network for scavenging various pteridine compounds, notably folate and biopterin.
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PMID:Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. 1200 48

Large amounts of neopterin are produced by interferon-(IFN)-gamma-stimulated human monocytes/macrophages, and increased neopterin concentrations indicate cellular immune activation. In parallel, IFN-gamma induces indoleamine 2,3-dioxygenase which degrades 1-tryptophan to kynurenine. Increased tryptophan degradation rates are indicated by an increased kynurenine/tryptophan ratio (kyn/trp-ratio), reflecting immune system activation, too. In 22 patients with Parkinson's disease (PD) and in 11 age-matched controls, serum and cerebrospinal fluid (CSF) neopterin concentrations were measured by ELISA. Tryptophan and kynurenine concentrations were determined by HPLC. Neopterin concentrations and kyn/trp-ratios were increased both in serum and CSF of patients as compared to controls. Serum tryptophan was lower in patients. Patients with the highest disease activity presented with highest degree of immune activation. Significant correlations existed between neopterin concentrations and kyn/trp-ratios in serum and CSF. Increased formation of neopterin and enhanced degradation of tryptophan suggest activated cell-mediated immune response in a subgroup of patients with advanced Parkinson's disease.
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PMID:Increased neopterin production and tryptophan degradation in advanced Parkinson's disease. 1207 58


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