Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dip-pen nanolithography (DPN) is a widely used technique to create nanoscopic patterns of many different materials. F(0)F(1) -ATPase is a nanoscale rotary molecular motor, and could be used as a biosensor or an ideal motor device in a micro-/nanosystem. In this paper, the DPN technique was used to create nanoarrays of F(0)F(1) -ATPase within chromatophore on a gold surface. The feature size of our F(0)F(1) -ATPase patterns was an average of 130 nm, and mathematically, there were no more than ten F(0)F(1) -ATPases in each dot. The biological activity of patterned F(0)F(1) -ATPase was demonstrated by its adenosine triphosphate synthesis, which was indicated by the fluorescence change of labeled F1300. The patterned F(0)F(1) -ATPase nanoarrays were further constructed as biosensors to detect H9 influenza A virus. The results showed that the biosensor arrays had a remarkable S/N ratio and excellent specificity. This type of biosensor arrays can be further used in high-throughput, high-sensitive detection in future. Meanwhile, the precise patterning of F(0)F(1) -ATPase with desired size, position, and biological activity would accelerate its application in many fields.
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PMID:Preparation of F0F1 -ATPase nanoarray by dip-pen nanolithography and its application as biosensors. 1877 99

Shortly after the release of singlet oxygen ((1)O(2)) in chloroplasts drastic changes in nuclear gene expression occur in the conditional flu mutant of Arabidopsis that reveal a rapid transfer of signals from the plastid to the nucleus. Factors involved in this retrograde signaling were identified by mutagenizing a transgenic flu line expressing a (1)O(2)-responsive reporter gene. The reporter gene consisted of the luciferase open reading frame and the promoter of an AAA-ATPase gene (At3g28580) that was selectively activated by (1)O(2) but not by superoxide or hydrogen peroxide. A total of eight second-site mutants were identified that either constitutively activate the reporter gene and the endogenous AAA-ATPase irrespectively of whether (1)O(2) was generated or not (constitutive activators of AAA-ATPase, caa) or abrogated the (1)O(2)-dependent up-regulation of these genes as seen in the transgenic parental flu line (non-activators of AAA-ATPase, naa). The characterization of the mutants strongly suggests that (1)O(2)-signaling does not operate as an isolated linear pathway but rather forms an integral part of a signaling network that is modified by other signaling routes and impacts not only stress responses of plants but also their development.
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PMID:Arabidopsis mutants reveal multiple singlet oxygen signaling pathways involved in stress response and development. 1944 51

Shortly after the release of singlet oxygen ((1)O(2)) in chloroplasts, changes in nuclear gene expression occur in the conditional flu mutant of Arabidopsis that reveal a rapid transfer of signals from the plastid to the nucleus. Extensive genetic screens aimed at identifying constituents involved in (1)O(2)-mediated plastid-to-nucleus signaling have failed to identify extraplastidic signaling components. This finding suggests that (1)O(2)-mediated signals are not translocated to the nucleus via a single linear pathway, but rather through a signaling network that is difficult to block by single mutations. The complexity of this signaling network has been tackled by mutagenizing a transgenic flu line expressing the luciferase reporter gene under the control of the promoter of a (1)O(2)-responsive AAA-ATPase gene (At3g28580) and isolating second site mutants that constitutively express the reporter gene at a high level. One of the mutants was shown by map-based cloning and sequencing to contain a single amino acid change in the PLEIOTROPIC RESPONSE LOCUS 1 (PRL1) protein. PRL1 suppresses the expression of AAA-ATPase and other (1)O(2)-responsive genes. PRL1 seems to play a major role in modulating responses of plants to environmental changes by interconnecting (1)O(2)-mediated retrograde signaling with other signaling pathways.
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PMID:Modulation of O-mediated retrograde signaling by the PLEIOTROPIC RESPONSE LOCUS 1 (PRL1) protein, a central integrator of stress and energy signaling. 1950 Feb 98

Influenza is a disease for deeply affecting millions of people every year. Recently, there has been considerable concern regarding the highly pathogenic H5N1 avian influenza virus, and its human pandemic potential. With developments in viral biology, there are more novel antiviral strategies targeting these viruses. In this review, we will discuss several proven and potential anti-influenza targets, including viral factors (such as hemagglutinin (HA), M2 ion channel protein, RNA-dependent RNA polymerase (RdRp), nucleoprotein (NP), non-structural protein (NS) and neuraminidase (NA)) and host factors (such as v-ATPase, protease, inosine monophosphate dehydrogenase (IMPDH) and intracellular signalling cascades), and their relevant inhibitors.
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PMID:Potential targets and their relevant inhibitors in anti-influenza fields. 1974 44

Human influenza viruses attach to sialic acid with an alpha2,6linkage (SAalpha2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A(1), a macrolide antibiotic and a specific inhibitor of vacuolar H(+)-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clinically used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1beta and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAalpha2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the number and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-kappaB (NF-kappaB) proteins, including p50 and p65, in the nuclear extracts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAalpha2,6Gal partly through the inhibition of NF-kappaB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.
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PMID:Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. 2004 May 78

The vacuolar (H(+))-ATPases are ATP-dependent proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane of eukaryotic cells. Intracellular V-ATPases play an important role in normal physiological processes such as receptor-mediated endocytosis, intracellular membrane trafficking, pro-hormone processing, protein degradation, and the coupled uptake of small molecules, such as neurotransmitters. They also function in the entry of various pathogenic agents, including many envelope viruses, like influenza virus, and toxins, like anthrax toxin. Plasma membrane V-ATPases function in renal pH homeostasis, bone resorption and sperm maturation, and various disease processes, including renal tubular acidosis, osteopetrosis, and tumor metastasis. V-ATPases are composed of a peripheral V(1) domain containing eight different subunits that is responsible for ATP hydrolysis and an integral V(0) domain containing six different subunits that translocates protons. In mammalian cells, most of the V-ATPase subunits exist in multiple isoforms which are often expressed in a tissue specific manner. Isoforms of one of the V(0) subunits (subunit a) have been shown to possess information that targets the V-ATPase to distinct cellular destinations. Mutations in isoforms of subunit a lead to the human diseases osteopetrosis and renal tubular acidosis. A number of mechanisms are employed to regulate V-ATPase activity in vivo, including reversible dissociation of the V(1) and V(0) domains, control of the tightness of coupling of proton transport and ATP hydrolysis, and selective targeting of V-ATPases to distinct cellular membranes. Isoforms of subunit a are involved in regulation both via the control of coupling and via selective targeting. This review will begin with a brief introduction to the function, structure, and mechanism of the V-ATPases followed by a discussion of the role of V-ATPase subunit isoforms and the mechanisms involved in regulation of V-ATPase activity.
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PMID:Regulation and isoform function of the V-ATPases. 2045 Jan 91

The process of budding of many enveloped viruses utilizes the cellular ESCRT (endosomal sorting complex required for transport) machinery, that is normally involved in the formation of luminal vesicles of endosomal multivesiculate bodies (MVB). A late step in the MVB pathway involves the recruitment of VPS4, an AAA+ ATPase, to the ESCRT complexes. Our earlier work had shown that the formation of influenza virus-like particles was not inhibited by dominant negative VPS4A. However, it was not known if there was a role of VPS4 and the ESCRT pathway in influenza virus particle budding and this needed to be investigated. It was found that neither siRNA knockdown of VPS4A and VPS4B expression nor the use of cell lines that inducibly express VPS4A or VPS4B dominant negative mutants, inhibited influenza virus budding. In contrast, and in keeping with more recent data, vesicular stomatitis virus budding was diminished by VPS4 dysfunction.
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PMID:Influenza virus budding does not require a functional AAA+ ATPase, VPS4. 2062 Nov 36

Infantile malignant osteopetrosis (IMO) (OMIM 259700) is a lethal autosomal recessive disease. The underlying gene in most IMO patients is TCIRG1. This codes for the TCIRG1 protein involved in the cellular proton pump, which is highly expressed on surfaces of osteoclasts. We have characterized a family comprising two affected siblings born to healthy parents. The sister and her younger brother both presented classical X-ray images of IMO at 17 h and 16 weeks, respectively, after birth, and both died after the appearance of fever and flu-like symptoms months later. Radiographs revealed normal bone density in both parents. Mutation detection of the TCIRG1 gene was performed in the boy and the parents. The novel mutation c.242delC (p.Pro81ArgfsX85) and the known mutation c.1114C>T (p.Gln372X) were both identified in the boy. Both mutations are predicted to introduce premature stop codons, with deletion of 666 amino acids from the C terminus of the TCIRG1 protein of one allele and 459 from the other. Both mutations involve loss of part or the whole of the ATPase V0-complex domain of the protein. The father carries the c.242delC (p.Pro81ArgfsX85) mutation and the mother the c.1114C>T (p.Gln372X). Our findings provide new data for pre- and post-natal genetic diagnosis and identification of heterozygous carriers of the disease.
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PMID:Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients. 2104 19

The vacuolar (H+)-ATPases (V-ATPases) facilitate the release of influenza A virus (IAV) genome into the cytoplasm by acidifying the endosomal interior. The regulation of V-ATPases by signalling pathways has been demonstrated in various model systems. However, little is known about signalling-regulated V-ATPase activation during IAV infection. Here we show that V-ATPase activity is elevated during infection of cell monolayers with IAV, as measured by intracellular pH change, via a mechanism mediated by extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K). Inhibition of IAV-induced early activation of these kinases reduced V-ATPase activity and the acidification of intracellular compartments in infected cells. IAV-activated ERK and PI3K appear to interact directly, and they colocalize with the E subunit of V-ATPase V1 domain. Further, siRNAs targeting the E2 subunit isoform significantly reduced virus titres. Interestingly, suppression of PI3K early activation, but not that of ERK or V-ATPase, negatively affected virus internalization, suggesting the involvement of the pathway in earlier, V-ATPase-independent infection-promoting events. Cell treatment with a V-ATPase-specific inhibitor impaired the nuclear localization of incoming viral ribonucleoproteins, inhibiting replication/transcription of viral RNAs. These findings highlight the importance of IAV-induced ERK and PI3K early activation as signalling mediators in V-ATPase-stimulated endosomal acidification required for fusion.
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PMID:Influenza A virus-induced early activation of ERK and PI3K mediates V-ATPase-dependent intracellular pH change required for fusion. 2112 42

Influenza viruses impose a constant threat to vertebrates susceptible to this family of viruses. We have developed a new tool to study virus-host interactions that play key roles in viral replication and to help identify novel anti-influenza drug targets. Via the UAS/Gal4 system we ectopically expressed the influenza virus M2 gene in Drosophila melanogaster and generated dose-sensitive phenotypes in the eye and wing. We have confirmed that the M2 proton channel is properly targeted to cell membranes in Drosophila tissues and functions as a proton channel by altering intracellular pH. As part of the efficacy for potential anti-influenza drug screens, we have also demonstrated that the anti-influenza drug amantadine, which targets the M2 proton channel, suppressed the UAS-M2 mutant phenotype when fed to larvae. In a candidate gene screen we identified mutations in components of the vacuolar V1V0 ATPase that modify the UAS-M2 phenotype. Importantly, in this study we demonstrate that Drosophila genetic interactions translate directly to physiological requirements of the influenza A virus for these components in mammalian cells. Overexpressing specific V1 subunits altered the replication capacity of influenza virus in cell culture and suggests that drugs targeting the enzyme complex via these subunits may be useful in anti-influenza drug therapies. Moreover, this study adds credence to the idea of using the M2 "flu fly" to identify new and previously unconsidered cellular genes as potential drug targets and to provide insight into basic mechanisms of influenza virus biology.
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PMID:A Drosophila model for genetic analysis of influenza viral/host interactions. 2177 72


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