NTPDase activities: possible roles on <i>Leishmania spp</i> infectivity and virulence

Paes-Vieira, Lisvane; Gomes-Vieira, André Luiz; Meyer‐Fernandes, José Roberto

doi:10.1002/cbin.10944

Cited by 16 publications

(15 citation statements)

References 70 publications

(155 reference statements)

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“…On the one hand, Leishmania or host derived ATPe might activate parasite killing by activation of P2X7 receptors of macrophages [101]. Alternatively, ATPe may be degraded by Leishmania NTPDases, as part of a mechanism for purine salvage ([135]; see Section 5).…”

Section: Transport Of Atpmentioning

confidence: 99%

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ATPe Dynamics in Protozoan Parasites. Adapt or Perish

Lauri

Bazzi

Álvarez

et al. 2018

Genes

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In most animals, transient increases of extracellular ATP (ATPe) are used for physiological signaling or as a danger signal in pathological conditions. ATPe dynamics are controlled by ATP release from viable cells and cell lysis, ATPe degradation and interconversion by ecto-nucleotidases, and interaction of ATPe and byproducts with cell surface purinergic receptors and purine salvage mechanisms. Infection by protozoan parasites may alter at least one of the mechanisms controlling ATPe concentration. Protozoan parasites display their own set of proteins directly altering ATPe dynamics, or control the activity of host proteins. Parasite dependent activation of ATPe conduits of the host may promote infection and systemic responses that are beneficial or detrimental to the parasite. For instance, activation of organic solute permeability at the host membrane can support the elevated metabolism of the parasite. On the other hand ecto-nucleotidases of protozoan parasites, by promoting ATPe degradation and purine/pyrimidine salvage, may be involved in parasite growth, infectivity, and virulence. In this review, we will describe the complex dynamics of ATPe regulation in the context of protozoan parasite–host interactions. Particular focus will be given to features of parasite membrane proteins strongly controlling ATPe dynamics. This includes evolutionary, genetic and cellular mechanisms, as well as structural-functional relationships.

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Section: Transport Of Atpmentioning

confidence: 99%

“…In several Leishmania species ATP can be hydrolysed to adenosine at the cell surface, indicating the presence of NTPDase and 5′-ecto-nucleotidase activity [135]. Nucleotidase activity is higher in virulent strains than avirulent strains and is increased more than 10-fold in the obligate intracellular amastigote stage [155,156].…”

Section: Ecto-nucleotidasesmentioning

confidence: 99%

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

Lauri

Bazzi

Álvarez

et al. 2018

Genes

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“…In parasites, nucleotidases/E-NTPDases seem to be involved in crucial processes, such as virulence, infectivity, purine salvage pathways, and parasite adhesion on the host cell ( Sansom, 2012 ; Figueiredo et al., 2016 ; Paes-Vieira et al., 2018 ; Silva-Gomes et al., 2020 ). During parasite infection, the host cell releases ATP as a danger signal, leading to the augmentation of the extracellular ATP level ( Trautmann, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities

Paes-Vieira

Gomes-Vieira

Meyer‐Fernandes

2021

Front. Cell. Infect. Microbiol.

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Belonging to the GDA1/CD39 protein superfamily, nucleoside triphosphate diphosphohydrolases (NTPDases) catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP) and inorganic phosphate (Pi). Several NTPDase isoforms have been described in different cells, from pathogenic organisms to animals and plants. Biochemical characterization of nucleotidases/NTPDases has revealed the existence of isoforms with different specificities regarding divalent cations (such as calcium and magnesium) and substrates. In mammals, NTPDases have been implicated in the regulation of thrombosis and inflammation. In parasites, such as Trichomonas vaginalis, Trypanosoma spp., Leishmania spp., Schistosoma spp. and Toxoplasma gondii, NTPDases were found on the surface of the cell, and important processes like growth, infectivity, and virulence seem to depend on their activity. For instance, experimental evidence has indicated that parasite NTPDases can regulate the levels of ATP and Adenosine (Ado) of the host cell, leading to the modulation of the host immune response. In this work, we provide a comprehensive review showing the involvement of the nucleotidases/NTPDases in parasites infectivity and virulence, and how inhibition of NTPDases contributes to parasite clearance and the development of new antiparasitic drugs.

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“…The NTPDase family comprises of eight members or isozymes (NTPDase1-8), these isozymes differ in their catalytic properties and show varying substrate preference (Allard et al, 2017;Zhong et al, 2017). NTPDase1, -2, -3, and -8 are membrane bound isoforms that play an important role in purinergic signaling (Castilhos et al, 2018;Bertoni et al, 2020) whereas NTPDase4, -5, -6, and -7 are expressed within intracellular organelles (Zhong et al, 2017;Paes-Vieira et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases

et al. 2020

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Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC50 values in lower micromolar range, these include compounds 8b (IC50 = 0.29 ± 0.02 µM), 8e (IC50 = 0.15 ± 0.009 µM), 8f (IC50 = 0.24 ± 0.01 µM) and 8l (IC50 = 0.30 ± 0.03 µM). Similarly, compound 8k (IC50 = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC50 = 0.19 ± 0.02 µM) and 8m (IC50 = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.

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NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Cited by 16 publications

References 70 publications

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities

Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases

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