Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Arora, Kashika; Kumar, Ambak

doi:10.1007/s12639-018-1061-4

Cited by 5 publications

(4 citation statements)

References 88 publications

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“…As in the case of Toxoplasma infection, effects of adenosine on Leishmania parasitism were also reported [105]. Patients with visceral leishmaniasis present higher concentrations of adenosine in serum than healthy people [106].…”

Section: Purinergic Signalingmentioning

confidence: 99%

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: Purinergic Signalingmentioning

confidence: 99%

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

Lauri

Bazzi

Álvarez

et al. 2018

Genes

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“…Leishmania demonstrates its parasitism by extracting essential components from the host cells for their metabolic requirements, maintenance, and survival [ 23 ]; since the parasite lacks a de novo purine biosynthesis, it needs the host’s preformed purine nucleosides and bases to be salvaged to create new nucleoside monophosphates. Likewise, nucleosides can either be salvaged directly or first cleaved to release nucleobases, while cleavage can be performed by nucleoside hydrolases or by phosphorylases [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting with Structural Analogs of Natural Products the Purine Salvage Pathway in Leishmania (Leishmania) infantum by Computer-Aided Drug-Design Approaches

Barazorda-Ccahuana,

Cárcamo-Rodriguez,

Centeno-Lopez

et al. 2024

TropicalMed

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Visceral Leishmaniasis (VL) has a high death rate, with 500,000 new cases and 50,000 deaths occurring annually. Despite the development of novel strategies and technologies, there is no adequate treatment for the disease. Therefore, the purpose of this study is to find structural analogs of natural products as potential novel drugs to treat VL. We selected structural analogs from natural products that have shown antileishmanial activities, and that may impede the purine salvage pathway using computer-aided drug-design (CADD) approaches. For these, we started with the vastly studied target in the pathway, the adenine phosphoribosyl transferase (APRT) protein, which alone is non-essential for the survival of the parasite. Keeping this in mind, we search for a substance that can bind to multiple targets throughout the pathway. Computational techniques were used to study the purine salvage pathway from Leishmania infantum, and molecular dynamic simulations were used to gather information on the interactions between ligands and proteins. Because of its low homology to human proteins and its essential role in the purine salvage pathway proteins network interaction, the findings further highlight the significance of adenylosuccinate lyase protein (ADL) as a therapeutic target. An analog of the alkaloid Skimmianine, N,N-diethyl-4-methoxy-1-benzofuran-6-carboxamide, demonstrated a good binding affinity to APRT and ADL targets, no expected toxicity, and potential for oral route administration. This study indicates that the compound may have antileishmanial activity, which was granted in vitro and in vivo experiments to settle this finding in the future.

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“…According to these studies, parasite E-NTPDases (CD39 gene family) hydrolyze extracellular ATP to ADP and AMP, which is, in sequence, hydrolyzed by the parasite ecto-5’-nucleotidases (CD73 gene family). The hydrolysis of AMP by parasite ecto-5’-nucleotidases increases the levels of adenosine, leading to the reduction of the host inflammatory response ( Fredholm et al., 2007 ; Sansom et al., 2008 ; Arora and Rai, 2019 ).…”

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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Dependence of Leishmania parasite on host derived ATP: an overview of extracellular nucleotide metabolism in parasite

Cited by 5 publications

References 88 publications

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

ATPe Dynamics in Protozoan Parasites. Adapt or Perish

Targeting with Structural Analogs of Natural Products the Purine Salvage Pathway in Leishmania (Leishmania) infantum by Computer-Aided Drug-Design Approaches

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

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