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.

恶性疟原虫（Pf）仅依赖于补救途径来满足其嘌呤核苷酸的需求，因此该途径对寄生虫是必不可少的。嘌呤核苷酸水平受合成代谢过程和将这些代谢物水解成核苷的核苷酸酶调节。某些apicomplexan寄生虫，包括Pf，具有IMP特异性核苷酸酶1（ISN1）。在这里，我们通过全面的底物筛选显示，Pf ISN1催化肌苷单磷酸酯（IMP）的去磷酸化并被ATP变构激活。四聚体Pf的晶体结构ISN1揭示了与催化作用紧密相关的域组织的复杂重排。免疫荧光显微镜检查和GFP融合蛋白的表达表明Pf ISN1的胞浆定位以及在该寄生虫的无性和配子细胞阶段表达。有了有关雌配子细胞中is1上调的早期证据，本研究报道的结构可能有助于启动可能的传输阻断剂的设计。