Structure and catalytic regulation of Plasmodium falciparum IMP specific nucleotidase

• Published in: Nature communications Vol. 11; no. 1; pp. 3228 - 11
• Main Authors: Carrique, Loïc, Ballut, Lionel, Shukla, Arpit, Varma, Neelakshi, Ravi, Resmi, Violot, Sébastien, Srinivasan, Bharath, Ganeshappa, Umesh Tippagondanahalli, Kulkarni, Sonia, Balaram, Hemalatha, Aghajari, Nushin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/173; 631/45/603; 631/535/1266; 631/92/1643; 692/699/255/1629; 82/16; 82/80; 82/83; Adenosine triphosphate; Allosteric properties; Catalysis; Crystal structure; Dephosphorylation; Erythrocytes; Fused protein; Gametocytes; Humanities and Social Sciences; Immunofluorescence; Inosine monophosphate; Life Sciences; Localization; Malaria; Metabolites; multidisciplinary; Nucleotidase; Nucleotides; Parasites; Plasmodium falciparum; Science; Science (multidisciplinary); Substrates; Therapeutic targets; Vector-borne diseases
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17013-x

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 Pf ISN1 catalyzes the dephosphorylation of inosine monophosphate (IMP) and is allosterically activated by ATP. Crystal structures of tetrameric Pf ISN1 reveal complex rearrangements of domain organization tightly associated with catalysis. Immunofluorescence microscopy and expression of GFP-fused protein indicate cytosolic localization of Pf ISN1 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. Plasmodium falciparum IMP-specific 5′-nucleotidase 1 ( Pf ISN1) is of interest as a potential malaria drug target. Here, the authors report that IMP is a substrate, and ATP an allosteric activator, of Pf ISN1 and present Pf ISN1 crystal structures in the ligand-free state and bound to either IMP or ATP.