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)

Wilson's disease and Menkes disease are inherited genetic disorders of copper metabolism. Each disease results from the absence or dysfunction of homologous copper-transporting ATPases present in the trans-Golgi network of cells. The Wilson ATPase transports copper into the hepatocyte secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Thus, patients with Wilson's disease of the autosomal recessive trait present with signs and symptoms arising from impaired biliary copper excretion. The Menkes ATPase transports copper across the placenta, gastrointestinal tract, and blood-brain barrier, and the clinical features of this X-linked disease arise from copper deficiency. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same fashion within the cell. The different clinical features of each disease are the results of the tissue specific expression of these ATPases. In Wilson's disease, impaired biliary copper excretion leads to accumulation of this metal in the liver. When the capacity for hepatic storage is exceeded, cell death ensues, with copper release into the plasma resulting in hemolysis and deposition of copper in extrahepatic tissues. Affected patients usually present in the first or second decade of life with chronic hepatitis and cirrhosis or acute liver failure. Copper accumulation in the cornea results in Kayser-Fleischer rings. Neuropsychiatric symptoms are more common in adults and include dystonia, tremor, personality changes, and cognitive impairment as a results of copper accumulation in the basal ganglia and other brain regions. The diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper, and elevated hepatic copper concentration. A large number of different mutations occur in the genes of patients with Wilson disease. Copper chelation drugs and zinc are effective in most cases. New treatment guidelines now advise physicians to start patients on zinc.
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PMID:[Genetic disorders of copper transport--diagnosis and new treatment for the patients of Wilson's disease]. 1577 21

SWI2/SNF2 ATPases remodel chromatin or other DNA:protein complexes by a poorly understood mechanism that involves ATP-dependent DNA translocation and generation of superhelical torsion. Crystal structures of a dsDNA-translocating SWI2/SNF2 ATPase core from Sulfolobus solfataricus reveal two helical SWI2/SNF2 specific subdomains, fused to a DExx box helicase-related ATPase core. Fully base paired duplex DNA binds along a central cleft via both minor groove strands, indicating that SWI2/SNF2 ATPases travel along the dsDNA minor groove without strand separation. A structural switch, linking DNA binding and the active site DExx motif, may account for the stimulation of ATPase activity by dsDNA. Our results suggest that torque in remodeling processes is generated by an ATP-driven screw motion of DNA along the active site cleft. The structures also redefine SWI2/SNF2 functional motifs and uncover unexpected structural correlation of mutations in Cockayne and X-linked mental retardation syndromes.
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PMID:X-ray structures of the Sulfolobus solfataricus SWI2/SNF2 ATPase core and its complex with DNA. 1588 19

Mutations in the human methyl-CpG-binding protein gene MECP2 cause the neurological disorder Rett syndrome and some cases of X-linked mental retardation (XLMR). We report that MeCP2 interacts with ATRX, a SWI2/SNF2 DNA helicase/ATPase that is mutated in ATRX syndrome (alpha-thalassemia/mental retardation, X-linked). MeCP2 can recruit the helicase domain of ATRX to heterochromatic foci in living mouse cells in a DNA methylation-dependent manner. Also, ATRX localization is disrupted in neurons of Mecp2-null mice. Point mutations within the methylated DNA-binding domain of MeCP2 that cause Rett syndrome or X-linked mental retardation inhibit its interaction with ATRX in vitro and its localization in vivo without affecting methyl-CpG binding. We propose that disruption of the MeCP2-ATRX interaction leads to pathological changes that contribute to mental retardation.
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PMID:Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. 1729 36

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a peptide with broad anti-inflammatory effects. The present research was designed to determine production and effects of alpha-MSH in acute bleomycin-induced lung injury in rats. Intratracheal bleomycin instillation induced alpha-MSH expression in lung infiltrating cells and a marked peptide increase in the circulation. In experiments on the therapeutic potential of alpha-MSH on lung injury, we determined influences of the synthetic alpha-MSH analogue [Nle4-dPhe7]-alpha-MSH (NDP-alpha-MSH) on pulmonary edema, circulating nitric oxide, and gene expression profile in lungs 8 and 24 h after bleomycin instillation. Three main gene categories, known to be involved in the development of acute lung injury, were explored: stress response, inflammation, and fluid homeostasis. Peptide treatment was associated with a significant reduction in interstitial edema, with a virtually normal wet/dry weight ratio. Several stress-related genes, which were either upregulated or reduced by bleomycin, were only marginally altered during NDP-alpha-MSH treatment. NDP-alpha-MSH prevented bleomycin-related transcriptional alterations in genes involved in lung fluid homeostasis, including upregulation of Na/K-transporting ATPase and epithelial sodium channels and downregulation of cystic fibrosis transmembrane conductance regulator. Bleomycin-induced expression of proinflammatory and profibrotic factors (interleukin 6, tumor necrosis factor-alpha, transforming growth factor-beta1, and inducible nitric oxide synthase) and chemokines (chemokine [C-C motif] ligand 2 and chemokine [C-C motif] ligand 5) was likewise significantly reduced by NDP-alpha-MSH. In conclusion, treatment with the alpha-MSH analogue NDP-alpha-MSH greatly improved the clinical and molecular picture of bleomycin-induced lung injury. Treatment with alpha-MSH-related agents can exert beneficial effects in acute lung injury.
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PMID:Production and effects of alpha-melanocyte-stimulating hormone during acute lung injury. 1730 15

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. Direct MeCP2 targets underlying RTT pathogenesis remain largely unknown. Here, we report that FXYD1, which encodes a transmembrane modulator of Na(+), K(+) -ATPase activity, is elevated in frontal cortex (FC) neurons of RTT patients and Mecp2-null mice. Increasing neuronal FXDY1 expression is sufficient to reduce dendritic arborization and spine formation, hallmarks of RTT neuropathology. Mecp2-null mouse cortical neurons have diminished Na(+),K(+)-ATPase activity, suggesting that aberrant FXYD1 expression contributes to abnormal neuronal activity in RTT. MeCP2 represses Fxyd1 transcription through direct interactions with sequences in the Fxyd1 promoter that are methylated in FC neurons. FXYD1 is therefore a MeCP2 target gene whose de-repression may directly contribute to RTT neuronal pathogenesis.
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PMID:FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice. 1730 81

In Drosophila, dosage compensation-the equalization of most X-linked gene products between XY males and XX females-is mediated by the MSL complex that preferentially associates with numerous sites on the X chromosome in somatic cells of males, but not of females. The complex consists of a noncoding RNA and a core of five protein subunits that includes a histone acetyltransferase (MOF) and an ATP-dependent DEXH box RNA/DNA helicase (MLE). Both of these enzymatic activities are necessary for the spreading of the complex to its sites of action along the X chromosome. MLE is related to the ATPases present in complexes that remodel chromatin by altering the positioning or the architectural relationship between nucleosomes and DNA. In contrast to MLE, none of these enzymatic subunits has been shown to possess double-stranded nucleic acid-unwinding activity. We investigated the function of MLE in the process of dosage compensation by generating mutations that separate ATPase activity from duplex unwinding. We show that the ATPase activity is sufficient for MLE's role in transcriptional enhancement, while the helicase activity is necessary for the spreading of the complex along the X chromosome.
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PMID:The MLE subunit of the Drosophila MSL complex uses its ATPase activity for dosage compensation and its helicase activity for targeting. 1803 54

Prevention of graft dysfunction is a major objective in transplantation medicine. Previous research on experimental heart transplantation indicated that treatment with the immunomodulatory peptide alpha-melanocyte stimulating hormone (alpha-MSH) improves histopathology, prolongs allograft survival, and reduces expression of the main tissue injury mediators. Because calcium-handling is critical in heart graft function, we determined the effects of transplantation injury and influences of alpha-MSH treatment on representative calcium regulatory proteins in rat heart allografts. Hearts from Brown Norway rats were transplanted heterotopically into MHC incompatible Lewis rats. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), protein kinase C epsilon (PKC epsilon), sarcoplasmic/endoplasmic reticulum calcium-ATPase 2 (SERCA2a), arrestin-beta1 (Arrb1), cholinergic receptor M2 (Chrm2), and inositol 1,4,5-triphosphate receptor 1 (InsP(3)R1) were examined in: (1) non-transplanted donor hearts; (2) allografts from saline-treated rats; and (3) allografts from rats treated with the synthetic alpha-MSH analog Nle4-DPhe7-alpha-MSH (NDP-alpha-MSH) (100 microg i.p. every 12h). Transplantation injury was associated with severe reduction in calcium regulatory protein transcription and expression level. NDP-alpha-MSH administration partly reversed inhibition of protein transcription and almost completely prevented protein loss. Finally, because certain effects of cyclic 3'-5'-adenosine monophosphate (cAMP) signaling on calcium handling in cardiac myocytes depend on activation of exchange protein directly activated by cAMP 1 (Epac1), we determined Epac1 mRNA and protein expression in heart allografts. Transplantation injury markedly reduced Epac1. NDP-alpha-MSH treatment significantly preserved both Epac1 protein and mRNA in the allografts. Administration of alpha-MSH or related melanocortins could reduce transplantation-induced dysfunction through protection of heart calcium regulatory proteins.
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PMID:Treatment with alpha-melanocyte stimulating hormone preserves calcium regulatory proteins in rat heart allografts. 1817 58

A spontaneous mutation in Bruton's tyrosine kinase (Btk) induces a defect in B-cell development that results in the immunodeficiency diseases X-linked agammaglobulinemia in humans and X-linked immunodeficiency (Xid) in mice. Here we show an unexpected role of Btk in osteoclast formation. When bone marrow cells derived from Xid mice were stimulated with receptor activator of NF-kappaB ligand, an osteoclast differentiation factor, they did not completely differentiate into mature multinucleated osteoclasts. Moreover, we found that the defects appeared to occur at the stage in which mononuclear preosteoclasts fuse to generate multinucleated cells. Supporting this notion, macrophages from Xid mice also failed to form multinucleated foreign body giant cells. The fusion defect of the Xid mutant osteoclasts was caused by decreased expression of nuclear factor of activated T cells c1 (NFATc1), a master regulator of osteoclast differentiation, as well as reduced expression of various osteoclast fusion-related molecules, such as the d2 isoform of vacuolar H(+)-ATPase V0 domain and the dendritic cell-specific transmembrane protein. This deficiency was completely rescued by the introduction of a constitutively active form of NFATc1 into bone marrow-derived macrophages. Our data provide strong evidence that Btk plays a critical role in osteoclast multinucleation by modulating the activity of NFATc1.
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PMID:The tec family tyrosine kinase Btk Regulates RANKL-induced osteoclast maturation. 1828 Dec 76

Copper-transporting ATPase 1 and 2 (ATP7A and ATP7B) are two highly homologous P-type copper ATPase exporters. Mutations in ATP7A can lead to Menkes disease which is an X-linked disorder of copper deficiency. Mutations in ATP7B can cause Wilson disease which is an autosomal recessive disorder of copper toxicity. In this study, we attempt to build a quantitative relationship between mutated ATPase and Menkes/Wilson disease. First, we use the amino-acid distribution probability as a measure to quantify the difference in ATPase before and after mutation. Second, we use the cross-impact analysis to define the quantitative relationship between mutant ATPase protein and Menkes/Wilson disease, and compute various probabilities. Finally, we use the Bayesian equation to determine the probability that Menkes/Wilson disease is diagnosed under a mutation. The results show (i) the vast majority of mutations lead to the amino-acid distribution probability increase in mutant ATP7As and decrease in ATP7Bs, and (ii) the probability that a mutation causes Menkes/Wilson disease is about nine tenth. Thus we provide a way to use the descriptively probabilistic method to couple the mutation with its clinical outcome after quantifying mutations in proteins.
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PMID:Quantitative relationship between mutated amino-acid sequence of human copper-transporting ATPases and their related diseases. 1868 37

Polyuria, hypernatremia, and hypovolemia are the major clinical signs of inherited nephrogenic diabetes insipidus (NDI). Hypernatremia is commonly considered a secondary sign caused by the net loss of water due to insufficient insertion of aquaporin-2 water channels into the apical membrane of the collecting duct cells. In the present study, we employed transcriptome-wide expression analysis to study gene expression in V2 vasopressin receptor (Avpr2)-deficient mice, an animal model for X-linked NDI. Gene expression changes in NDI mice indicate increased proximal tubular sodium reabsorption. Expression of several key genes including Na+-K+-ATPase and carbonic anhydrases was increased at the mRNA levels and accompanied by enhanced enzyme activities. In addition, altered expression was also observed for components of the eicosanoid and thyroid hormone pathways, including cyclooxygenases and deiodinases, in both kidney and hypothalamus. These effects are likely to contribute to the clinical NDI phenotype. Finally, our data highlight the involvement of the renin-angiotensin-aldosterone system in NDI pathophysiology and provide clues to explain the effectiveness of diuretics and indomethacin in the treatment of NDI.
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PMID:V2 vasopressin receptor deficiency causes changes in expression and function of renal and hypothalamic components involved in electrolyte and water homeostasis. 1871 41


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