Mechanism of growth inhibition of intraerythrocytic stages of Plasmodium falciparum by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)

Bulusu, Vinay and Thakur, Suman S and Venkatachala, Roopa and Balaram, Hemalatha (2011) Mechanism of growth inhibition of intraerythrocytic stages of Plasmodium falciparum by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). In: Molecular and Biochemical Parasitology, 177 (1). pp. 1-11.

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Abstract

Purine nucleotide synthesis in Plasmodium falciparum takes place solely by the purine salvage pathway in which preformed purine base(s) are salvaged from the host and acted upon by a battery of enzymes to generate AMP and GMP. Inhibitors of this pathway have a potent effect on the in vitro growth of P. falciparum and are hence, implicated as promising leads for the development of new generation anti-malarials. Here, we describe the mechanism of inhibition of the intraerythrocytic growth of P. falciparum by the purine nucleoside precursor, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Our results show that AICAR toxicity is mediated through the erythrocyte in which AICAR is phosphorylated to its nucleotide, ZMP. Further, purine metabolite labeling of the parasitized erythrocytes by H-3]-hypoxanthine, in the presence of AICAR, showed a significant decrease in radioactive counts in adenylate fractions but not in guanylate fractions. The most dramatic effect on parasite growth was observed when erythrocytes pretreated with AICAR were used in culture. Pretreatment of erythrocytes with AICAR led to significant intracellular accumulation of ZMP and these erythrocytes were incapable of supporting parasite growth. These results implicate that in addition to the purine salvage pathway in P. falciparum, AICAR alters the metabolic status of the erythrocytes, which inhibits parasite growth. As AICAR and ZMP are metabolites in the human serum and erythrocytes, our studies reported here throw light on their possible role in disease susceptibility, and also suggests the possibility of AICAR being a potential prophylactic or chemotherapeutic anti-malarial compound. (C) 2011 Elsevier B.V. All rights reserved.

Item Type:	Journal Article
Publication:	Molecular and Biochemical Parasitology
Publisher:	Elsevier Science
Additional Information:	Copyright of this article belongs to Elsevier Science B.V.
Keywords:	Plasmodium falciparum; AICAR;ZMP; Adenylosuccinate lyase; Purine salvage pathway;Anti-malarial
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	06 May 2011 05:36
Last Modified:	06 May 2011 05:36
URI:	http://eprints.iisc.ac.in/id/eprint/37375

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