Abstract
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.
Highlights
INTRODUCTIONThere are four important subfamilies of ecto-nucleotidases with different substrate specificities (nucleotide hydrolysis): (i) the ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), (ii) the ecto-5’nucleotidases (5’-NT), (iii) the ecto-nucleotidase pyrophosphatase/phosphodiesterases (NPPs), and (iv) alkaline phosphatases (Aps) (Barros et al, 2000; Meyer-Fernandes et al, 2000; de Souza Leite et al, 2007; Paletta-Silva and Meyer-Fernandes, 2012; Zimmermann et al, 2012)
The pre-treatment with curcumin in rats infected with T. evansi decreased parasitemia and mortality (Wolkmer et al, 2013; Wolkmer et al, 2019), maintained the NTPDase activity reduced and enhanced ADA activity on the surface of lymphocytes. These results suggest that curcumin treatment can improve immunomodulatory response mediated by ecto-nucleotidases, favoring the response against the parasite (Wolkmer et al, 2019)
Since E-NTPDases have been implicated in important events for different parasite species, such enzymes have been considered as ideal drug targets for many therapeutic applications, including parasitic diseases
Summary
There are four important subfamilies of ecto-nucleotidases with different substrate specificities (nucleotide hydrolysis): (i) the ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), (ii) the ecto-5’nucleotidases (5’-NT), (iii) the ecto-nucleotidase pyrophosphatase/phosphodiesterases (NPPs), and (iv) alkaline phosphatases (Aps) (Barros et al, 2000; Meyer-Fernandes et al, 2000; de Souza Leite et al, 2007; Paletta-Silva and Meyer-Fernandes, 2012; Zimmermann et al, 2012). Since E-NTPDases have been implicated in different processes of parasite physiology, such as differentiation, nutrition, invasion, survival in the host cell, and modulation of the host immune response to establish infection, these enzymes have been seen as promising targets for drug development (Paes-Vieira et al, 2018) In this sense, many works have shown the effects of several compounds on parasite E-NTPDases (Knowles, 2011; Pimentel et al, 2016; de Carvalho et al, 2019; da Silva et al, 2021). Because of the interaction between adenosine and P1 receptors, activated macrophages reduce IL-12 and TNF-a cytokines levels, leading to the decrement of nitric oxide (NO) production and the establishment of parasites in the host cell. These studies show that purinergic signaling carries out a pivotal function in the immune and inflammatory responses in the course of parasite infections
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