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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glycoproteins, defective membrane formation and structure and reduced lysosomal stability leading to disordered contact inhibition and tumour antigen presentation contributing to oncogenesis. Digoxin induced alteration in intracellular calcium/magnesium ratios and low ubiquinone levels can lead to a mitochondrial dysfunction resulting in increased free radical generation and reduced scavenging & caspase-3 activation producing a P21 defect contributing to oncogenesis.
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PMID:Hypothalamic digoxin mediated model for oncogenesis. 1187 54

The Long-Evans Cinnamon (LEC) rat is a mutant animal model for Wilson's disease. It is known that an abnormal accumulation of Cu and Fe in the liver and low concentrations of both ceruloplasmin and Cu in the serum occur in these rats. The accumulation of Cu is explained by the defective expression of the Cu-transporting P-type ATPase gene, homologous to the gene for Wilson's disease (ATP7B). The aim of this work was to clarify the action mechanism of Zn, and to verify the role that this metal plays in LEC rats in short-term treatment experiments (1 and 2 weeks) on concentrations of Cu, Zn, Fe, metallothionein (MT), 8-hydroxy-2'-deoxyguanosine (oh(8)dG) and on the activity of antioxidant enzymes. It is well known that Zn induces MT and has the ability to prevent redox-active metals, Cu and Fe, binding to and causing oxidative damage at active sites of Zn metalloenzymes and nonspecific binding sites on proteins. Zn administration reduces Cu and Fe transport from mucosal to serosal intestinal sides through competitive mechanisms. Our findings show that treatment with zinc acetate increases tissue Zn and MT contents and decreases Cu and Fe concentrations in the liver and kidneys, even if hepatic Zn and MT concentrations decrease with treatment period. Induction of MT synthesis by Zn contributes to the reduction in free radicals produced by Cu and Fe. We also observed that the superoxide dismutase (SOD)activity in liver decreases with treatment duration in association with the Cu and Fe liver decrease. However, the SOD activity in kidney increases in untreated rats at 2 weeks relative to those untreated for 1 week.
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PMID:Metallothionein and antioxidant enzymes in Long-Evans Cinnamon rats treated with zinc. 1224 8

The unicellular green alga Chlamydomonas reinhardtii is a valuable model for studying metal metabolism in a photosynthetic background. A search of the Chlamydomonas expressed sequence tag database led to the identification of several components that form a copper-dependent iron assimilation pathway related to the high-affinity iron uptake pathway defined originally for Saccharomyces cerevisiae. They include a multicopper ferroxidase (encoded by Fox1), an iron permease (encoded by Ftr1), a copper chaperone (encoded byAtx1), and a copper-transporting ATPase. A cDNA, Fer1, encoding ferritin for iron storage also was identified. Expression analysis demonstrated that Fox1 and Ftrl were coordinately induced by iron deficiency, as were Atx1 and Fer1, although to lesser extents. In addition, Fox1 abundance was regulated at the posttranscriptional level by copper availability. Each component exhibited sequence relationship with its yeast, mammalian, or plant counterparts to various degrees; Atx1 of C. reinhardtii is also functionally related with respect to copper chaperone and antioxidant activities. Fox1 is most highly related to the mammalian homologues hephaestin and ceruloplasmin; its occurrence and pattern of expression in Chlamydomonas indicate, for the first time, a role for copper in iron assimilation in a photosynthetic species. Nevertheless, growth of C. reinhardtii under copper- and iron-limiting conditions showed that, unlike the situation in yeast and mammals, where copper deficiency results in a secondary iron deficiency, copper-deficient Chlamydomonas cells do not exhibit symptoms of iron deficiency. We propose the existence of a copper-independent iron assimilation pathway in this organism.
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PMID:Copper-dependent iron assimilation pathway in the model photosynthetic eukaryote Chlamydomonas reinhardtii. 1245 93

This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Alzheimer's disease (AD). The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find the role of cerebral dominance in the genesis of Alzheimer's disease. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while serum tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated in Alzheimer's disease. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid increased. The activity of all free radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in Alzheimer's disease, while the concentration of lipid peroxidation products and NO increased. The hypomagnesemia-related NMDA excitotoxicity, ubiquinone deficiency related mitochondrial dysfunction, and altered glycoconjugates/lysosomal stability could contribute to the pathogenesis of Alzheimer's disease. The biochemical patterns, including hyperdigoxinemia observed in Alzheimer's disease, correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for Alzheimer's disease.
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PMID:Hypothalamic digoxin, hemispheric chemical dominance, and Alzheimer's disease. 1280 39

The isoprenoid pathway produces four key metabolites important in cellular function--digoxin (endogenous membrane Na(+)-K+ ATPase inhibitor), dolichol (important in N-glycosylation of proteins), ubiquinone (free-radical scavenger), and cholesterol (component of cellular membranes). This study assessed the changes in the isoprenoid pathway and the consequences of its dysfunction in Parkinson's disease (PD). There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol levels, and a reduction in serum magnesium, RBC membrane Na(+)-K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, strychnine, nicotine, and quinolinic acid were elevated, while tyrosine, morphine, dopamine, and noradrenaline were decreased. The total serum glycosaminoglycans (GAG) and glycosaminoglycan fractions (except chondroitin sulphates and hyaluronic acid), the activity of GAG degrading enzymes, carbohydrate residues of serum glycoproteins, the activity of glycohydrolase-beta galactosidase, and serum glycolipids were elevated. HDL cholesterol was reduced and free fatty acids increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and cholesterol were reduced, while phospholipid was increased. The activity of all serum free-radical scavenging enzymes, concentration of glutathione, alpha tocopherol, iron binding capacity, and ceruloplasmin decreased significantly in PD, while the concentration of serum lipid peroxidation products and nitric oxide increased. A dysfunctional isoprenoid pathway and related cascade are important in the pathogenesis of Parkinson's disease. A hypothalamic digoxin mediated model for Parkinson's disease is also postulated.
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PMID:Hypothalamic digoxin-mediated model for Parkinson's disease. 1285 80

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in multiple myeloma. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+ - K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, nicotine, strychnine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins, cholesterol and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of lipid peroxidation products and NO increased. Hyperdigoxinemia related altered intracellular Ca++ mediated oncogene activation, dolichol induced altered glycoconjugate metabolism and ubiquinone deficiency related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical findings reported could be the cause or the consequence of multiple myeloma.
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PMID:Isoprenoid pathway related cascade in multiple myeloma. 1285 16

Wilson's disease is an autosomal recessive disorder of copper metabolism. The Wilson disease protein is a copper-transporting P-type ATPase, ATP7B, the malfunction of which results in the toxic accumulation of copper in the liver and brain, causing the hepatic and/or neurological symptoms accompanying this disease. Patients present, generally between the ages of 10 and 40 years, with liver disease, neurological disease of a movement disorder type, or behavioral abnormalities, and often with a combination of these. Because Wilson's disease is effectively treated, it is extremely important for physicians to learn to recognize and diagnose the disease. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 200 unique mutations have been identified and most individuals are compound heterozygotes. The treatment of Wilson's disease must be life long. Copper chelation with penicillamine is an effective therapy in most patients. Another chelating agent which has been used successfully as the initial therapy is trientine. The search for new anticopper drugs for Wilson's disease is culminating in two excellent new drugs: zinc for maintenance therapy and ammonium tetrathiomolybdate (which is to date still an experimental drug) for initial therapy. Liver transplantation is indicated for the fulminant form and in those patients with severe disease not responding to optimal medical management. This paper reviews the pathogenesis, pathology, clinical presentation and diagnosis of the Wilson's disease as well as the most recent views on the molecular genetics and the treatment of this disease.
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PMID:[Wilson's disease]. 1458 69

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol, and ubiquinone in multiple myeloma. The isoprenoid pathway and digoxin status were also studied for comparison in individuals of differing hemispheric dominance to find out the rote of cerebral dominance in the genesis of multiple myeloma and neoplasms. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism--in multiple myeloma, as well as in individuals of differing hemispheric dominance. There was elevation in plasma HMG CoA reductase activity, serum digoxin, and dolichol, and a reduction in RBC membrane Na(+)-K+ ATPase activity, serum ubiquinone, and magnesium levels. Serum tryptophan, serotonin, nicotine, strychnine, and quinolinic acid were elevated, while tyrosine, dopamine, noradrenaline, and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins, and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose, and fucose residues of glycoproteins, cholesterol, and phospholipids were reduced. The activity of all free-radical scavenging enzymes, concentration of glutathione, iron binding capacity, and ceruloplasmin decreased significantly, while the concentration of lipid peroxidation products and nitric oxide increased. Hyperdigoxinemia-related altered intracellular Ca++/Mg++ ratios mediated oncogene activation, dolichol-induced altered glycoconjugate metabolism, and ubiquinone deficiency-related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical patterns obtained in multiple myeloma are similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with multiple myeloma were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Multiple myeloma occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.
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PMID:Hypothalamic digoxin, hemispheric chemical dominance, and oncogenesis: evidence from multiple myeloma. 1460 44

The Wilson protein (ATP7B) is a copper-transporting CPx-type ATPase defective in the copper toxicity disorder Wilson disease. In hepatocytes, ATP7B delivers copper to apo-ceruloplasmin and mediates the excretion of excess copper into bile. These distinct functions require the protein to localize at two different subcellular compartments. At the trans-Golgi network, ATP7B transports copper for incorporation into apo-ceruloplasmin. When intracellular copper levels are increased, ATP7B traffics to post-Golgi vesicles in close proximity to the canalicular membrane to facilitate biliary copper excretion. In the present study, we investigated the role of the six N-terminal MBSs (metal-binding sites) in the trafficking process. Using site-directed mutagenesis, we mutated or deleted various combinations of the MBSs and assessed the effect of these changes on the localization and trafficking of ATP7B. Results show that the MBSs required for trafficking are the same as those previously found essential for the copper transport function. Either MBS 5 or MBS 6 alone was sufficient to support the redistribution of ATP7B to vesicular compartments. The first three N-terminal motifs were not required for copper-dependent intracellular trafficking and could not functionally replace sites 4-6 when placed in the same sequence position. Furthermore, the N-terminal region encompassing MBSs 1-5 (amino acids 64-540) was not essential for trafficking, with only one MBS close to the membrane channel, necessary and sufficient to support trafficking. Our findings were similar to those obtained for the closely related ATP7A protein, suggesting similar mechanisms for trafficking between copper-transporting CPx-type ATPases.
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PMID:Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. 1499 71

Copper is an essential cofactor for approximately a dozen cuproenzymes in which copper is bound to specific amino acid residues in an active site. However, free cuprous ions react readily with hydrogen peroxide to yield the deleterious hydroxyl radical. Therefore, copper homeostasis is regulated very tightly, and unbound copper is extremely low in concentration. Copper imported by the plasma membrane transport protein Ctr1 rapidly binds to intracellular copper chaperone proteins. Atox1 delivers copper to the secretory pathway and docks with either copper-transporting ATPase ATP7B in the liver or ATP7A in other cells. ATP7B directs copper to plasma ceruloplasmin or to biliary excretion in concert with a newly discovered chaperone, Murr1, the protein missing in canine copper toxicosis. ATP7A directs copper within the transgolgi network to the proteins dopamine beta-monooxgenase, peptidylglycine alpha-amidating monooxygenase, lysyl oxidase, and tyrosinase, depending on the cell type. CCS is the copper chaperone for Cu,Zn-superoxide dismutase; it delivers copper in the cytoplasm and intermitochondrial space. Cox17 delivers copper to mitochondria to cytochrome c oxidase via the chaperones Cox11, Sco1, and Sco2. Other copper chaperones may exist and might include metallothionein and amyloid precursor protein (APP). Genetic and nutritional studies have illustrated the essential nature of these copper-binding proteins; alterations in their levels are associated with severe pathology.
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PMID:Intracellular copper transport in mammals. 1511 35


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