Trypanosoma rangeli: Characterization of a Mg-dependent ecto ATP-diphosphohydrolase activity

Fonseca, Fabiana Valéria da; Souza, André Luíz Fonseca de; Mariano, Ana; Entringer, Peter F.; Gondim, Kátia C.; Meyer‐Fernandes, José Roberto

doi:10.1016/j.exppara.2005.09.005

Cited by 34 publications

(28 citation statements)

References 52 publications

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“…One explanation may be that in all three trypanosome species in which NTPDases have been studied, the enzymes hydrolyze ATP preferentially, resulting in liberation of ADP and transient platelet activation. Although preferential ATPase activity would provide ADP for activation of P2Y 1 and P2Y 12 receptors, ADP hydrolysis by these enzymes is nevertheless still relatively efficient (47,57,59). Again, more work is needed to clarify the contribution of NTPDases to platelet responses during infection.…”

Section: Interference With P2 Receptor Signaling By Parasitesmentioning

confidence: 99%

“…T. rangeli also exhibits Mg 2ϩ -dependent ecto-NTPDase activity that is highest against ATP, although ADP and other NTPs may also be hydrolyzed. NTPDase activity is stimulated by a number of carbohydrates, which has led to the suggestion that NTPDase activity may have a role in adhesion to the intermediate insect host, as carbohydrates on insect salivary glands play a part in adhesion by Trypanosoma species (59).…”

Section: Trypanosomatidsmentioning

confidence: 99%

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Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

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SUMMARYIn humans, purinergic signaling plays an important role in the modulation of immune responses through specific receptors that recognize nucleoside tri- and diphosphates as signaling molecules. Ecto-nucleoside triphosphate diphosphohydrolases (ecto-NTPDases) have important roles in the regulation of purinergic signaling by controlling levels of extracellular nucleotides. This process is key to pathophysiological protective responses such as hemostasis and inflammation. Ecto-NTPDases are found in all higher eukaryotes, and recently it has become apparent that a number of important parasitic pathogens of humans express surface-located NTPDases that have been linked to virulence. For those parasites that are purine auxotrophs, these enzymes may play an important role in purine scavenging, although they may also influence the host response to infection. Although ecto-NTPDases are rare in bacteria, expression of a secreted NTPDase in Legionella pneumophila was recently described. This ecto-enzyme enhances intracellular growth of the bacterium and potentially affects virulence. This discovery represents an important advance in the understanding of the contribution of other microbial NTPDases to host-pathogen interactions. Here we review other progress made to date in the characterization of ecto-NTPDases from microbial pathogens, how they differ from mammalian enzymes, and their association with organism viability and virulence. In addition, we postulate how ecto-NTPDases may contribute to the host-pathogen interaction by reviewing the effect of selected microbial pathogens on purinergic signaling. Finally, we raise the possibility of targeting ecto-NTPDases in the development of novel anti-infective agents based on potential structural and clear enzymatic differences from the mammalian ecto-NTPDases.

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Section: Interference With P2 Receptor Signaling By Parasitesmentioning

confidence: 99%

Section: Trypanosomatidsmentioning

confidence: 99%

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Sansom

Robson

Hartland

2008

Microbiol Mol Biol Rev

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“…For ATP hydrolysis a K cat /K m ratio of 1. 50 greater than 1 mM (34). Here we tested the ability of these particular polyoxometalates to inhibit rLpg1905 activity to determine whether a microbial ecto-NTPDase exhibited increased or decreased susceptibility to inhibition compared with mammalian NTPDases.…”

Section: Hydrolysis Of Atp and Adp By Lpg1905 Is Dependent Onmentioning

confidence: 99%

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

Sansom

Riedmaier

Newton

et al. 2008

Journal of Biological Chemistry

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Legionella pneumophila is the predominant cause of Legionnaires disease, a severe and potentially fatal form of pneumonia. Recently, we identified an ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) from L. pneumophila, termed Lpg1905, which enhances intracellular replication of L. pneumophila in eukaryotic cells. Lpg1905 is the first prokaryotic member of the CD39/NTPDase1 family of enzymes, which are characterized by the presence of five apyrase conserved regions and the ability to hydrolyze nucleoside tri-and diphosphates. Here we examined the substrate specificity of Lpg1905 and showed that apart from ATP and ADP, the enzyme catalyzed the hydrolysis of GTP and GDP but had limited activity against CTP, CDP, UTP, and UDP. Based on amino acid residues conserved in the apyrase conserved regions of eukaryotic NTPDases, we generated five site-directed mutants, Lpg1905E159A, R122A, N168A, Q193A, and W384A. Although the mutations E159A, R122A, Q193A, and W384A abrogated activity completely, N168A resulted in decreased activity caused by reduced affinity for nucleotides. When introduced into the lpg1905 mutant strain of L. pneumophila, only N168A partially restored the ability of L. pneumophila to replicate in THP-1 macrophages. Following intratracheal inoculation of A/J mice, none of the Lpg1905 mutants was able to restore virulence to an lpg1905 mutant during lung infection, thereby demonstrating the importance of NTPDase activity to L. pneumophila infection. Overall, the kinetic studies undertaken here demonstrated important differences to mammalian NTPDases and different sensitivities to NTPDase inhibitors that may reflect underlying structural variations.Legionella pneumophilia is the major causative agent of Legionnaires disease, a severe systemic disease characterized by acute pneumonia. During infection of the human lung, L. pneumophila is internalized by alveolar macrophages where the bacteria replicate within an intracellular vacuole that evades fusion with the endocytic pathway. Instead the L. pneumophila containing vacuole intercepts early secretory vesicles and following maturation exhibits properties of the endoplasmic reticulum (1-3). Establishment of the unique Legionella vacuole and the ability to replicate within eukaryotic cells requires the Dot/Icm type IV secretion system, which translocates bacterial effector proteins into the cytoplasm of the host cell (4 -7).The ability of L. pneumophila to replicate within mammalian cells appears to be a consequence of its association in the natural environment with free living protozoa. The three sequenced L. pneumophila genomes encode an unusually high number of proteins with similarity to eukaryotic proteins (8 -10), which may interfere with host cell processes by functional mimicry (11). We recently showed that Lpg1905 from L. pneumophila is a secreted member of the CD39/ NTPDase1 family of ecto-nucleoside triphosphate diphosphohydrolases (NTPDases; gene family ENTPD).5 NTPDases are extremely rare in bacteria, and Lpg1905 is the first prokaryotic...

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“…To test this possibility, the effects of potent ecto-ATPase blockers, such as suramin and DIDS [55,56] as well as ARL 67156 [57], could be examined. However, suramin was found to almost completely inhibit the luciferin-luciferase reaction (HT Liu and Y Okada, unpublished), and DIDS was reported to block the maxi-anion channel activity [58].…”

Section: +mentioning

confidence: 99%

Maxi-anion channel as a candidate pathway for osmosensitive ATP release from mouse astrocytes in primary culture

et al. 2008

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In the present study, we aimed to evaluate the pathways contributing to ATP release from mouse astrocytes during hypoosmotic stress. We first examined the expression of mRNAs for proteins constituting possible ATPreleasing pathways that have been suggested over the past several years. In RT-PCR analysis using both control and osmotically swollen astrocytes, amplification of cDNA fragments of expected size was seen for connexins (Cx32, Cx37, Cx43), pannexin 1 (Px1), the P2X7 receptor, MRP1 and MDR1, but not CFTR. Inhibitors of exocytotic vesicular release, gap junction hemi-channels, CFTR, MRP1, MDR1, the P2X7 receptor, and volume-sensitive outwardly rectifying chloride channels had no significant effects on the massive ATP release from astrocytes. In contrast, the hypotonicity-induced ATP release from astrocytes was most effectively inhibited by gadolinium (50 µM), an inhibitor of the maxi-anion channel, which has recently been shown to serve as a pathway for ATP release from several other cell types. Thus, we propose that the maxi-anion channel constitutes a major pathway for swelling-induced ATP release from cultured mouse astrocytes as well.

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Trypanosoma rangeli: Characterization of a Mg-dependent ecto ATP-diphosphohydrolase activity

Cited by 34 publications

References 52 publications

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

Enzymatic Properties of an Ecto-nucleoside Triphosphate Diphosphohydrolase from Legionella pneumophila

Maxi-anion channel as a candidate pathway for osmosensitive ATP release from mouse astrocytes in primary culture

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