Abstract
Plasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite. Purine nucleotide levels are regulated by anabolic processes and by nucleotidases that hydrolyse these metabolites into nucleosides. Certain apicomplexan parasites, including Pf, have an IMP-specific-nucleotidase 1 (ISN1). Here we show, by comprehensive substrate screening, that PfISN1 catalyzes the dephosphorylation of inosine monophosphate (IMP) and is allosterically activated by ATP. Crystal structures of tetrameric PfISN1 reveal complex rearrangements of domain organization tightly associated with catalysis. Immunofluorescence microscopy and expression of GFP-fused protein indicate cytosolic localization of PfISN1 and expression in asexual and gametocyte stages of the parasite. With earlier evidence on isn1 upregulation in female gametocytes, the structures reported in this study may contribute to initiate the design for possible transmission-blocking agents.
Highlights
Plasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite
Gametocyte formation brought about by LysoPC depletion is associated with activation of expression of more than 300 genes, including genes involved in phosphocholine (PC) biosynthesis, DNA replication and macromolecule modification
Live-cell imaging of P. falciparum and P. berghei parasites episomally expressing P. falciparum ISN1 (PfISN1) fused to GFP confirmed the cytoplasmic localization (Fig. 1b, c)
Summary
Plasmodium falciparum (Pf) relies solely on the salvage pathway for its purine nucleotide requirements, making this pathway indispensable to the parasite. Certain apicomplexan parasites, including Pf, have an IMP-specific-nucleotidase 1 (ISN1). Maintaining the optimal nucleotide balance required for normal cell proliferation is controlled by 5′-nucleotidases amongst other processes[4]. These enzymes catalyze the dephosphorylation of ribo- and deoxyribonucleoside monophosphates to their corresponding nucleosides, and exhibit, in certain cases phosphotransferase activity[5]. We show the cytosolic localization in asexual and sexual stages of the parasite These structural and functional studies reveal the molecular reaction mechanism employed in this family of 5′-nucleotidases and their regulation via inter-domain interactions
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