{"gene":"PF3D7_0515300","run_date":"2026-09-07T10:55:52","timeline":{"discoveries":[{"year":2010,"finding":"PI3K (PfPI3K) is exported to the host erythrocyte by the parasite in an active form. Within the parasite, it localizes to vesicular compartments near the membrane and in the food vacuole. It can generate various 3'-phosphorylated PIPs. Inhibition of PfPI3K by wortmannin or LY294002 resulted in entrapment of hemoglobin in vesicles in the parasite cytoplasm, preventing its transport to the food vacuole, attenuating hemoglobin digestion and parasite growth.","method":"Subcellular fractionation and export assay, PI3K inhibitor treatment (wortmannin, LY294002), fluorescence microscopy, in vitro parasite growth assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2/3 / Moderate — direct localization and inhibitor-based loss-of-function with specific phenotypic readout, single lab, multiple methods including export assay and imaging","pmids":["20093402"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"The PI3K gene could not be deleted in P. berghei, indicating it is essential in Plasmodium blood stages. In P. falciparum, in vitro growth was sensitive to a PI3K inhibitor. The class III PI3K encoded by the Plasmodium genome is of unusual size with large insertions and repetitive sequence motifs. PI3P production was parasite-dependent, sensitive to a PI3K inhibitor, and predominant in late parasite stages.","method":"Gene deletion attempt (knockout failure) in P. berghei, PI3K inhibitor treatment in P. falciparum, PI3P quantification in parasite-infected erythrocytes","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — failed gene deletion establishes essentiality, inhibitor effects on PI3P and growth confirmed, single lab but multiple methods","pmids":["20709789"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2015,"finding":"Artemisinins are potent inhibitors of PfPI3K. In artemisinin-resistant clinical strains, increased PfPI3K levels were associated with the C580Y mutation in PfKelch13. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 C580Y mutation, limiting proteolysis of PfPI3K and thereby increasing kinase levels and its lipid product PI3P. Elevated PI3P was identified as the key mediator of artemisinin resistance. PI3P levels were predictive of artemisinin resistance across clinical and laboratory parasite strains.","method":"Biochemical inhibition assays, polyubiquitination assay, co-immunoprecipitation (PfPI3K–PfKelch13 binding), PI3P quantification in clinical and engineered parasites, transgenic parasite expression, proteolysis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical inhibition, Co-IP, ubiquitination assay, PI3P quantification, transgenic parasites), replicated across clinical and laboratory strains, multiple labs implicitly via clinical isolates","pmids":["25874676"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"PfPI3K is a class III ('Vps34'-type) PI3K. When heterologously expressed in yeast and purified to homogeneity, it produces phosphatidylinositol 3'-phosphate from phosphatidylinositol. It is inhibited by artemisinin and related drugs, but only under conditions that cleave the endoperoxide bridge to generate reactive alkylating agents (i.e., irreversible inhibition by Fe2+-mediated covalent modification). Mutagenesis of key residues in the catalytic and N-lobe domains was used to investigate their importance.","method":"Heterologous expression in yeast, protein purification to homogeneity, quantitative PI3P production assay, drug inhibition assay, active-site mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified protein, mutagenesis, quantitative activity assay, single lab but multiple orthogonal methods","pmids":["28719180"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PI3P generated by PfPI3K stabilizes the digestive vacuole (DV) under heat stress. PI3K inhibitors destabilized the DV before parasite death, and this was reversible upon withdrawal of the inhibitor and heat stress. A chemoproteomic approach identified PfHsp70-1 as a PI3P-binding protein. Knockdown of PfHsp70-1 phenocopied PI3P-deficient parasites under heat shock, and PfHsp70-1 downregulation hypersensitized parasites to heat shock and PI3K inhibitors, establishing a mechanistic link between PI3P and PfHsp70-1 in DV stabilization during fever-like stress.","method":"Live cell microscopy with chemical and genetic PI3P reporters, PI3K inhibitor treatment, chemoproteomic pulldown to identify PI3P-binding proteins, Hsp70-1 knockdown, Hsp70 inhibitor treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (chemoproteomic pulldown, genetic knockdown, live imaging, pharmacological inhibition) in a single rigorous study, single lab","pmids":["32975513"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"MMV390048, a putative PfPI4KIIIβ inhibitor in advanced trials, was found to also potently inhibit PfPI3K (PfVps34) in vitro using purified enzyme, demonstrating dual PIK inhibitory activity.","method":"In vitro enzyme inhibition assay with purified PfPI3K and PfPI4KIIIβ proteins","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro assay with purified protein, single lab, single method","pmids":["32543181"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"PfK13-R539T ART-resistant parasites exhibited increased basal autophagy compared to wild-type. Suppression of PI3K activity rendered ART-resistant parasites unable to survive, establishing PI3K as a master autophagy regulator required for the pro-survival autophagic response in ART-resistant parasites.","method":"Autophagic flux assays, PI3K inhibitor treatment of PfK13-R539T and wild-type parasites, parasite survival assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — genetic background comparison combined with pharmacological PI3K inhibition and autophagic flux measurements, single lab","pmids":["37173329"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfPI3K is upregulated in P. falciparum-infected red blood cells during intraerythrocytic development. PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein E3 ligase, leading to increased ubiquitination and selective degradation of α-spectrin (but not β-spectrin) of the host erythrocyte. Inhibition of PfPI3K activity impaired P. falciparum development in vitro and P. berghei infectivity in mice.","method":"Western blot for PfPI3K expression, ubiquitination assays of erythrocytic α-spectrin, PI3K inhibitor treatment in vitro and in vivo (mouse model), co-immunoprecipitation/kinase activity assays","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple methods (expression profiling, ubiquitination assay, in vitro and in vivo inhibition), single lab","pmids":["38470053"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"finding":"PfPI3K interacts with PfVps15 (a pseudokinase/Vps15 orthologue) as shown by co-immunoprecipitation, but unlike in yeast and mammalian cells, they are potentially not part of a heterotetrameric complex. Knock-sideways removal of PfVps15 led to rapid parasite death, decreased PI3P levels, abrogation of host-cell cytosol delivery to the food vacuole, and defects in apicoplast biogenesis and mitochondrial fission, establishing that the PfVps15–PfPI3K interaction is required for PI3P synthesis and vesicular trafficking of host-cell cytosol.","method":"Co-immunoprecipitation (PfVps15–PfPI3K interaction), knock-sideways conditional mislocalisation, PI3P level quantification, live-cell fluorescence microscopy of vesicular trafficking, apicoplast and mitochondrion dynamics","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, conditional knock-sideways with defined phenotypic readouts (PI3P levels, trafficking, organelle dynamics), multiple orthogonal methods, single lab","pmids":["42611934"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"PI3K was characterised for the first time via expansion microscopy in P. falciparum. Inhibition of the PI3K-mediated pathway significantly reduced the number of Mtphagy-positive parasites (mitochondrial stress marker) and was associated with delayed recrudescence in DHA-treated parasites, implicating PI3K activity in the mitochondrial dynamics underlying artemisinin-induced growth arrest and recrudescence.","method":"Expansion microscopy (PI3K localisation), PI3K pathway inhibition combined with Mtphagy fluorescence assay, recrudescence assays after DHA treatment","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — expansion microscopy provides first direct localization; PI3K inhibitor phenotype in recrudescence is pharmacological, single lab","pmids":["42429611"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"Idelalisib, a PI3K inhibitor, effectively inhibited PfPI3K activity in P. falciparum, causing a decline in PI3P levels. This led to ROS accumulation, apoptosis-like parasite death, and accumulation of ubiquitinated proteins, downregulation of molecular chaperone gene expression, and increased eIF2α phosphorylation. Combination of idelalisib with dihydroartemisinin exerted synergistic antimalarial effects and reversed ART resistance.","method":"PfPI3K activity assay with idelalisib, PI3P level quantification, ROS measurement, ubiquitinated protein quantification, gene expression analysis of chaperones, eIF2α phosphorylation assay, in vitro drug combination assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple biochemical and cellular readouts of PI3K inhibition, single lab, no structural or mutagenesis validation","pmids":["41286015"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PfPI3K (PF3D7_0515300) is the sole class III (Vps34-type) PI3K in P. falciparum; it generates PI3P in the food vacuole membrane, apicoplast, and vesicular compartments, is exported to the host erythrocyte, and is essential for hemoglobin endocytosis and trafficking, digestive vacuole stability under heat stress (via PI3P–PfHsp70-1 interaction), α-spectrin ubiquitination in the host cell, and cytoprotective autophagy in ART-resistant parasites; its activity is regulated by PfKelch13-mediated polyubiquitination and proteolysis and by the interacting pseudokinase PfVps15, and it is irreversibly inhibited by activated artemisinin endoperoxides, making PI3P levels a key determinant of artemisinin resistance."},"narrative":{"mechanistic_narrative":"PF3D7_0515300 (PI3K) is a class III (Vps34-type) phosphatidylinositol 3-kinase and the enzyme responsible for generating phosphatidylinositol 3-phosphate (PI3P) in the intraerythrocytic stages of Plasmodium falciparum, where it is essential for parasite survival [PMID:20709789, PMID:28719180]. Purified enzyme converts phosphatidylinositol to PI3P [PMID:28719180], and within the parasite the kinase localizes to vesicular compartments near the membrane and to the food/digestive vacuole while also being exported in active form to the host erythrocyte [PMID:20093402]. Through its PI3P product, PI3K drives hemoglobin trafficking to the food vacuole and hemoglobin digestion [PMID:20093402], the endocytic delivery of host-cell cytosol [PMID:42611934], and stabilization of the digestive vacuole under fever-like heat stress via a PI3P–PfHsp70-1 interaction [PMID:32975513]. Its lipid kinase activity requires interaction with the pseudokinase PfVps15, loss of which collapses PI3P levels and disrupts host-cytosol trafficking, apicoplast biogenesis, and mitochondrial fission [PMID:42611934]. In the host erythrocyte, PI3K activates an erythrocytic E3 ubiquitin ligase to drive selective ubiquitination and degradation of α-spectrin [PMID:38470053]. PI3K is a central determinant of artemisinin resistance: artemisinin endoperoxides irreversibly inhibit the enzyme after Fe2+-mediated activation [PMID:28719180], and the PfKelch13 C580Y mutation reduces PI3K polyubiquitination and proteolysis, elevating PI3K and PI3P levels, with PI3P abundance predictive of resistance across strains [PMID:25874676]. Consistent with this, PI3K sustains pro-survival autophagy and mitochondrial-stress responses in artemisinin-resistant parasites, and its pharmacological inhibition reverses resistance [PMID:37173329, PMID:41286015].","teleology":[{"year":2010,"claim":"Establishing what PI3K does in the parasite required knowing where it acts and what pathway depends on it; localization and inhibitor studies showed it functions in vesicular hemoglobin trafficking and is exported to the host cell.","evidence":"Subcellular fractionation, export assay, wortmannin/LY294002 inhibition, and growth assays in P. falciparum","pmids":["20093402"],"confidence":"Medium","gaps":["Inhibitors used are not PI3K-specific, leaving direct enzyme attribution incomplete","Substrate specificity of the exported enzyme in the host cell not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"claim":"Whether PI3K is dispensable was unknown; a failed knockout in P. berghei and inhibitor sensitivity in P. falciparum established it as an essential blood-stage kinase producing PI3P in late stages.","evidence":"Gene deletion attempt in P. berghei, inhibitor treatment and PI3P quantification in P. falciparum","pmids":["20709789"],"confidence":"Medium","gaps":["Essentiality inferred from knockout failure rather than conditional depletion","Unusual gene size/insertions not functionally dissected"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2015,"claim":"The mechanistic basis of artemisinin resistance was unresolved; linking PfKelch13 to PI3K showed that reduced PI3K ubiquitination and proteolysis elevates PI3P, the key mediator of resistance.","evidence":"Biochemical inhibition, PfPI3K–PfKelch13 Co-IP, polyubiquitination and proteolysis assays, PI3P quantification across clinical and transgenic strains","pmids":["25874676"],"confidence":"High","gaps":["Downstream effectors of elevated PI3P in conferring resistance not fully defined","Direct enzymology of artemisinin inhibition not established in this study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Direct enzymatic identity and drug mechanism were unproven; reconstitution with purified enzyme confirmed it is a Vps34-type PI3K producing PI3P and inhibited by artemisinin only after endoperoxide cleavage to a covalent alkylator.","evidence":"Heterologous yeast expression, purification, quantitative PI3P assay, drug inhibition, and active-site mutagenesis","pmids":["28719180"],"confidence":"High","gaps":["No structural model of the enzyme","Roles of individual mutated catalytic/N-lobe residues in vivo not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"How PI3P protects the parasite was unclear; identifying PfHsp70-1 as a PI3P-binding protein linked PI3K activity to digestive vacuole stability under fever-like heat stress.","evidence":"Live-cell PI3P reporters, inhibitor treatment, chemoproteomic pulldown, and PfHsp70-1 knockdown in P. falciparum","pmids":["32975513"],"confidence":"High","gaps":["Structural basis of PI3P–PfHsp70-1 binding not defined","Whether other PI3P effectors contribute to DV stability unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Assessing target selectivity of antimalarial candidates required testing off-target kinases; the PfPI4KIIIβ candidate MMV390048 was found to also inhibit purified PI3K.","evidence":"In vitro enzyme inhibition assay with purified PfPI3K and PfPI4KIIIβ","pmids":["32543181"],"confidence":"Medium","gaps":["Cellular consequence of dual inhibition not tested","Single in vitro method"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"The survival advantage of resistant parasites was unexplained; PI3K was shown to be required for the elevated pro-survival autophagy in PfK13-mutant parasites.","evidence":"Autophagic flux assays and PI3K inhibition in PfK13-R539T versus wild-type parasites","pmids":["37173329"],"confidence":"Medium","gaps":["Molecular link between PI3P and autophagy machinery not defined","Pharmacological rather than genetic PI3K depletion"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"The exported kinase's host-cell function was undefined; PI3K was shown to activate an erythrocytic E3 ligase driving selective α-spectrin ubiquitination and degradation, supporting parasite development.","evidence":"Expression profiling, ubiquitination assays, kinase/Co-IP assays, and PI3K inhibition in vitro and in a P. berghei mouse model","pmids":["38470053"],"confidence":"Medium","gaps":["Identity of the erythrocytic E3 ligase substrate site not fully mapped","Direct kinase-substrate relationship of PI3K to the ligase not structurally resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2026,"claim":"The regulatory partner controlling PI3K activity in vivo was unknown; knock-sideways of PfVps15 showed the PfVps15–PI3K interaction is required for PI3P synthesis, host-cytosol trafficking, and organelle biogenesis.","evidence":"Reciprocal Co-IP, knock-sideways mislocalisation, PI3P quantification, and live imaging of trafficking and organelle dynamics in P. falciparum","pmids":["42611934"],"confidence":"High","gaps":["Whether PI3K forms a defined multi-subunit complex remains unresolved (unlike yeast/mammalian heterotetramers)","Mechanism by which PfVps15 activates PI3K not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"The role of PI3K in artemisinin recrudescence was unclear; expansion-microscopy localization plus inhibition linked PI3K activity to mitochondrial stress (Mtphagy) and delayed recrudescence after DHA.","evidence":"Expansion microscopy, PI3K pathway inhibition with Mtphagy assay, and recrudescence assays after DHA in P. falciparum","pmids":["42429611"],"confidence":"Medium","gaps":["Molecular connection between PI3P and mitochondrial dynamics not defined","Pharmacological inhibition of a 'pathway' rather than direct PI3K depletion"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Whether PI3K inhibition could be therapeutically exploited was open; idelalisib lowered PI3P and triggered ROS, apoptosis-like death, proteotoxic stress, and synergized with DHA to reverse resistance.","evidence":"PfPI3K activity assay, PI3P quantification, ROS/ubiquitin/eIF2α phosphorylation readouts, and idelalisib–DHA combination assays in P. falciparum","pmids":["41286015"],"confidence":"Medium","gaps":["Idelalisib selectivity for PI3K over other parasite kinases not established","No structural/mutagenesis validation of on-target engagement"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown how PI3P generated by PI3K is spatially and mechanistically coupled to its many downstream processes (hemoglobin trafficking, DV stability, autophagy, host α-spectrin degradation, organelle dynamics) and whether a defined PI3K complex organizes these outputs.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PI3K or its PfVps15 interface","Effector proteins reading PI3P at each compartment largely uncharacterized beyond PfHsp70-1","Direct regulation of resistance-associated autophagy at the molecular level unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PfPI3K–PfVps15 interaction (not established as a heterotetrameric complex in P. falciparum) [#8]"],"partners":["PFVPS15 (PSEUDOKINASE, VPS15 ORTHOLOGUE) — INTERACTION REQUIRED FOR PI3P SYNTHESIS AND HOST-CYTOSOL TRAFFICKING [#8]","PFKELCH13 — BINDS AND MEDIATES POLYUBIQUITINATION/PROTEOLYSIS OF PI3K [#2]","PFHSP70-1 — PI3P-BINDING EFFECTOR IN DIGESTIVE VACUOLE STABILIZATION [#4]","ERYTHROCYTIC UBIQUITIN-PROTEIN E3 LIGASE — PHOSPHORYLATED/ACTIVATED BY PI3K [#7]"],"other_free_text":["Essential in Plasmodium blood stages; PfPI3K knockout could not be obtained in P. berghei [#1]","Irreversibly inhibited by activated artemisinin endoperoxides after Fe2+-mediated bridge cleavage [#3, #2]","PI3P levels are predictive of artemisinin resistance across clinical and laboratory strains [#2]","Also inhibited in vitro by MMV390048 (a PfPI4KIIIβ candidate) and by idelalisib, the latter reversing ART resistance in combination with DHA [#5, #10]","First directly localized by expansion microscopy; activity linked to mitochondrial stress and recrudescence after DHA [#9]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25874676","id":"PMC_25874676","title":"A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/25874676","citation_count":423,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["phosphatidylinositol 3-kinase","PfPI3K"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29355852","id":"PMC_29355852","title":"Drug resistance in Plasmodium.","date":"2018","source":"Nature reviews. 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parasite in an active form. Within the parasite, it localizes to vesicular compartments near the membrane and in the food vacuole. It can generate various 3'-phosphorylated PIPs. Inhibition of PfPI3K by wortmannin or LY294002 resulted in entrapment of hemoglobin in vesicles in the parasite cytoplasm, preventing its transport to the food vacuole, attenuating hemoglobin digestion and parasite growth.\",\n      \"method\": \"Subcellular fractionation and export assay, PI3K inhibitor treatment (wortmannin, LY294002), fluorescence microscopy, in vitro parasite growth assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 / Moderate — direct localization and inhibitor-based loss-of-function with specific phenotypic readout, single lab, multiple methods including export assay and imaging\",\n      \"pmids\": [\"20093402\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The PI3K gene could not be deleted in P. berghei, indicating it is essential in Plasmodium blood stages. In P. falciparum, in vitro growth was sensitive to a PI3K inhibitor. The class III PI3K encoded by the Plasmodium genome is of unusual size with large insertions and repetitive sequence motifs. PI3P production was parasite-dependent, sensitive to a PI3K inhibitor, and predominant in late parasite stages.\",\n      \"method\": \"Gene deletion attempt (knockout failure) in P. berghei, PI3K inhibitor treatment in P. falciparum, PI3P quantification in parasite-infected erythrocytes\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — failed gene deletion establishes essentiality, inhibitor effects on PI3P and growth confirmed, single lab but multiple methods\",\n      \"pmids\": [\"20709789\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Artemisinins are potent inhibitors of PfPI3K. In artemisinin-resistant clinical strains, increased PfPI3K levels were associated with the C580Y mutation in PfKelch13. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 C580Y mutation, limiting proteolysis of PfPI3K and thereby increasing kinase levels and its lipid product PI3P. Elevated PI3P was identified as the key mediator of artemisinin resistance. PI3P levels were predictive of artemisinin resistance across clinical and laboratory parasite strains.\",\n      \"method\": \"Biochemical inhibition assays, polyubiquitination assay, co-immunoprecipitation (PfPI3K–PfKelch13 binding), PI3P quantification in clinical and engineered parasites, transgenic parasite expression, proteolysis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical inhibition, Co-IP, ubiquitination assay, PI3P quantification, transgenic parasites), replicated across clinical and laboratory strains, multiple labs implicitly via clinical isolates\",\n      \"pmids\": [\"25874676\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PfPI3K is a class III ('Vps34'-type) PI3K. When heterologously expressed in yeast and purified to homogeneity, it produces phosphatidylinositol 3'-phosphate from phosphatidylinositol. It is inhibited by artemisinin and related drugs, but only under conditions that cleave the endoperoxide bridge to generate reactive alkylating agents (i.e., irreversible inhibition by Fe2+-mediated covalent modification). Mutagenesis of key residues in the catalytic and N-lobe domains was used to investigate their importance.\",\n      \"method\": \"Heterologous expression in yeast, protein purification to homogeneity, quantitative PI3P production assay, drug inhibition assay, active-site mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified protein, mutagenesis, quantitative activity assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28719180\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PI3P generated by PfPI3K stabilizes the digestive vacuole (DV) under heat stress. PI3K inhibitors destabilized the DV before parasite death, and this was reversible upon withdrawal of the inhibitor and heat stress. A chemoproteomic approach identified PfHsp70-1 as a PI3P-binding protein. Knockdown of PfHsp70-1 phenocopied PI3P-deficient parasites under heat shock, and PfHsp70-1 downregulation hypersensitized parasites to heat shock and PI3K inhibitors, establishing a mechanistic link between PI3P and PfHsp70-1 in DV stabilization during fever-like stress.\",\n      \"method\": \"Live cell microscopy with chemical and genetic PI3P reporters, PI3K inhibitor treatment, chemoproteomic pulldown to identify PI3P-binding proteins, Hsp70-1 knockdown, Hsp70 inhibitor treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (chemoproteomic pulldown, genetic knockdown, live imaging, pharmacological inhibition) in a single rigorous study, single lab\",\n      \"pmids\": [\"32975513\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MMV390048, a putative PfPI4KIIIβ inhibitor in advanced trials, was found to also potently inhibit PfPI3K (PfVps34) in vitro using purified enzyme, demonstrating dual PIK inhibitory activity.\",\n      \"method\": \"In vitro enzyme inhibition assay with purified PfPI3K and PfPI4KIIIβ proteins\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assay with purified protein, single lab, single method\",\n      \"pmids\": [\"32543181\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PfK13-R539T ART-resistant parasites exhibited increased basal autophagy compared to wild-type. Suppression of PI3K activity rendered ART-resistant parasites unable to survive, establishing PI3K as a master autophagy regulator required for the pro-survival autophagic response in ART-resistant parasites.\",\n      \"method\": \"Autophagic flux assays, PI3K inhibitor treatment of PfK13-R539T and wild-type parasites, parasite survival assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — genetic background comparison combined with pharmacological PI3K inhibition and autophagic flux measurements, single lab\",\n      \"pmids\": [\"37173329\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfPI3K is upregulated in P. falciparum-infected red blood cells during intraerythrocytic development. PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein E3 ligase, leading to increased ubiquitination and selective degradation of α-spectrin (but not β-spectrin) of the host erythrocyte. Inhibition of PfPI3K activity impaired P. falciparum development in vitro and P. berghei infectivity in mice.\",\n      \"method\": \"Western blot for PfPI3K expression, ubiquitination assays of erythrocytic α-spectrin, PI3K inhibitor treatment in vitro and in vivo (mouse model), co-immunoprecipitation/kinase activity assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple methods (expression profiling, ubiquitination assay, in vitro and in vivo inhibition), single lab\",\n      \"pmids\": [\"38470053\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PfPI3K interacts with PfVps15 (a pseudokinase/Vps15 orthologue) as shown by co-immunoprecipitation, but unlike in yeast and mammalian cells, they are potentially not part of a heterotetrameric complex. Knock-sideways removal of PfVps15 led to rapid parasite death, decreased PI3P levels, abrogation of host-cell cytosol delivery to the food vacuole, and defects in apicoplast biogenesis and mitochondrial fission, establishing that the PfVps15–PfPI3K interaction is required for PI3P synthesis and vesicular trafficking of host-cell cytosol.\",\n      \"method\": \"Co-immunoprecipitation (PfVps15–PfPI3K interaction), knock-sideways conditional mislocalisation, PI3P level quantification, live-cell fluorescence microscopy of vesicular trafficking, apicoplast and mitochondrion dynamics\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, conditional knock-sideways with defined phenotypic readouts (PI3P levels, trafficking, organelle dynamics), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"42611934\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PI3K was characterised for the first time via expansion microscopy in P. falciparum. Inhibition of the PI3K-mediated pathway significantly reduced the number of Mtphagy-positive parasites (mitochondrial stress marker) and was associated with delayed recrudescence in DHA-treated parasites, implicating PI3K activity in the mitochondrial dynamics underlying artemisinin-induced growth arrest and recrudescence.\",\n      \"method\": \"Expansion microscopy (PI3K localisation), PI3K pathway inhibition combined with Mtphagy fluorescence assay, recrudescence assays after DHA treatment\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — expansion microscopy provides first direct localization; PI3K inhibitor phenotype in recrudescence is pharmacological, single lab\",\n      \"pmids\": [\"42429611\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Idelalisib, a PI3K inhibitor, effectively inhibited PfPI3K activity in P. falciparum, causing a decline in PI3P levels. This led to ROS accumulation, apoptosis-like parasite death, and accumulation of ubiquitinated proteins, downregulation of molecular chaperone gene expression, and increased eIF2α phosphorylation. Combination of idelalisib with dihydroartemisinin exerted synergistic antimalarial effects and reversed ART resistance.\",\n      \"method\": \"PfPI3K activity assay with idelalisib, PI3P level quantification, ROS measurement, ubiquitinated protein quantification, gene expression analysis of chaperones, eIF2α phosphorylation assay, in vitro drug combination assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple biochemical and cellular readouts of PI3K inhibition, single lab, no structural or mutagenesis validation\",\n      \"pmids\": [\"41286015\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfPI3K (PF3D7_0515300) is the sole class III (Vps34-type) PI3K in P. falciparum; it generates PI3P in the food vacuole membrane, apicoplast, and vesicular compartments, is exported to the host erythrocyte, and is essential for hemoglobin endocytosis and trafficking, digestive vacuole stability under heat stress (via PI3P–PfHsp70-1 interaction), α-spectrin ubiquitination in the host cell, and cytoprotective autophagy in ART-resistant parasites; its activity is regulated by PfKelch13-mediated polyubiquitination and proteolysis and by the interacting pseudokinase PfVps15, and it is irreversibly inhibited by activated artemisinin endoperoxides, making PI3P levels a key determinant of artemisinin resistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0515300 (PI3K) is a class III (Vps34-type) phosphatidylinositol 3-kinase and the enzyme responsible for generating phosphatidylinositol 3-phosphate (PI3P) in the intraerythrocytic stages of Plasmodium falciparum, where it is essential for parasite survival [#1, #3]. Purified enzyme converts phosphatidylinositol to PI3P [#3], and within the parasite the kinase localizes to vesicular compartments near the membrane and to the food/digestive vacuole while also being exported in active form to the host erythrocyte [#0]. Through its PI3P product, PI3K drives hemoglobin trafficking to the food vacuole and hemoglobin digestion [#0], the endocytic delivery of host-cell cytosol [#8], and stabilization of the digestive vacuole under fever-like heat stress via a PI3P–PfHsp70-1 interaction [#4]. Its lipid kinase activity requires interaction with the pseudokinase PfVps15, loss of which collapses PI3P levels and disrupts host-cytosol trafficking, apicoplast biogenesis, and mitochondrial fission [#8]. In the host erythrocyte, PI3K activates an erythrocytic E3 ubiquitin ligase to drive selective ubiquitination and degradation of α-spectrin [#7]. PI3K is a central determinant of artemisinin resistance: artemisinin endoperoxides irreversibly inhibit the enzyme after Fe2+-mediated activation [#3], and the PfKelch13 C580Y mutation reduces PI3K polyubiquitination and proteolysis, elevating PI3K and PI3P levels, with PI3P abundance predictive of resistance across strains [#2]. Consistent with this, PI3K sustains pro-survival autophagy and mitochondrial-stress responses in artemisinin-resistant parasites, and its pharmacological inhibition reverses resistance [#6, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing what PI3K does in the parasite required knowing where it acts and what pathway depends on it; localization and inhibitor studies showed it functions in vesicular hemoglobin trafficking and is exported to the host cell.\",\n      \"evidence\": \"Subcellular fractionation, export assay, wortmannin/LY294002 inhibition, and growth assays in P. falciparum\",\n      \"pmids\": [\"20093402\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Inhibitors used are not PI3K-specific, leaving direct enzyme attribution incomplete\", \"Substrate specificity of the exported enzyme in the host cell not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether PI3K is dispensable was unknown; a failed knockout in P. berghei and inhibitor sensitivity in P. falciparum established it as an essential blood-stage kinase producing PI3P in late stages.\",\n      \"evidence\": \"Gene deletion attempt in P. berghei, inhibitor treatment and PI3P quantification in P. falciparum\",\n      \"pmids\": [\"20709789\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Essentiality inferred from knockout failure rather than conditional depletion\", \"Unusual gene size/insertions not functionally dissected\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The mechanistic basis of artemisinin resistance was unresolved; linking PfKelch13 to PI3K showed that reduced PI3K ubiquitination and proteolysis elevates PI3P, the key mediator of resistance.\",\n      \"evidence\": \"Biochemical inhibition, PfPI3K–PfKelch13 Co-IP, polyubiquitination and proteolysis assays, PI3P quantification across clinical and transgenic strains\",\n      \"pmids\": [\"25874676\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream effectors of elevated PI3P in conferring resistance not fully defined\", \"Direct enzymology of artemisinin inhibition not established in this study\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Direct enzymatic identity and drug mechanism were unproven; reconstitution with purified enzyme confirmed it is a Vps34-type PI3K producing PI3P and inhibited by artemisinin only after endoperoxide cleavage to a covalent alkylator.\",\n      \"evidence\": \"Heterologous yeast expression, purification, quantitative PI3P assay, drug inhibition, and active-site mutagenesis\",\n      \"pmids\": [\"28719180\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of the enzyme\", \"Roles of individual mutated catalytic/N-lobe residues in vivo not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How PI3P protects the parasite was unclear; identifying PfHsp70-1 as a PI3P-binding protein linked PI3K activity to digestive vacuole stability under fever-like heat stress.\",\n      \"evidence\": \"Live-cell PI3P reporters, inhibitor treatment, chemoproteomic pulldown, and PfHsp70-1 knockdown in P. falciparum\",\n      \"pmids\": [\"32975513\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of PI3P–PfHsp70-1 binding not defined\", \"Whether other PI3P effectors contribute to DV stability unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Assessing target selectivity of antimalarial candidates required testing off-target kinases; the PfPI4KIIIβ candidate MMV390048 was found to also inhibit purified PI3K.\",\n      \"evidence\": \"In vitro enzyme inhibition assay with purified PfPI3K and PfPI4KIIIβ\",\n      \"pmids\": [\"32543181\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cellular consequence of dual inhibition not tested\", \"Single in vitro method\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The survival advantage of resistant parasites was unexplained; PI3K was shown to be required for the elevated pro-survival autophagy in PfK13-mutant parasites.\",\n      \"evidence\": \"Autophagic flux assays and PI3K inhibition in PfK13-R539T versus wild-type parasites\",\n      \"pmids\": [\"37173329\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular link between PI3P and autophagy machinery not defined\", \"Pharmacological rather than genetic PI3K depletion\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The exported kinase's host-cell function was undefined; PI3K was shown to activate an erythrocytic E3 ligase driving selective α-spectrin ubiquitination and degradation, supporting parasite development.\",\n      \"evidence\": \"Expression profiling, ubiquitination assays, kinase/Co-IP assays, and PI3K inhibition in vitro and in a P. berghei mouse model\",\n      \"pmids\": [\"38470053\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the erythrocytic E3 ligase substrate site not fully mapped\", \"Direct kinase-substrate relationship of PI3K to the ligase not structurally resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The regulatory partner controlling PI3K activity in vivo was unknown; knock-sideways of PfVps15 showed the PfVps15–PI3K interaction is required for PI3P synthesis, host-cytosol trafficking, and organelle biogenesis.\",\n      \"evidence\": \"Reciprocal Co-IP, knock-sideways mislocalisation, PI3P quantification, and live imaging of trafficking and organelle dynamics in P. falciparum\",\n      \"pmids\": [\"42611934\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether PI3K forms a defined multi-subunit complex remains unresolved (unlike yeast/mammalian heterotetramers)\", \"Mechanism by which PfVps15 activates PI3K not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The role of PI3K in artemisinin recrudescence was unclear; expansion-microscopy localization plus inhibition linked PI3K activity to mitochondrial stress (Mtphagy) and delayed recrudescence after DHA.\",\n      \"evidence\": \"Expansion microscopy, PI3K pathway inhibition with Mtphagy assay, and recrudescence assays after DHA in P. falciparum\",\n      \"pmids\": [\"42429611\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular connection between PI3P and mitochondrial dynamics not defined\", \"Pharmacological inhibition of a 'pathway' rather than direct PI3K depletion\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether PI3K inhibition could be therapeutically exploited was open; idelalisib lowered PI3P and triggered ROS, apoptosis-like death, proteotoxic stress, and synergized with DHA to reverse resistance.\",\n      \"evidence\": \"PfPI3K activity assay, PI3P quantification, ROS/ubiquitin/eIF2α phosphorylation readouts, and idelalisib–DHA combination assays in P. falciparum\",\n      \"pmids\": [\"41286015\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Idelalisib selectivity for PI3K over other parasite kinases not established\", \"No structural/mutagenesis validation of on-target engagement\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how PI3P generated by PI3K is spatially and mechanistically coupled to its many downstream processes (hemoglobin trafficking, DV stability, autophagy, host α-spectrin degradation, organelle dynamics) and whether a defined PI3K complex organizes these outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of PI3K or its PfVps15 interface\", \"Effector proteins reading PI3P at each compartment largely uncharacterized beyond PfHsp70-1\", \"Direct regulation of resistance-associated autophagy at the molecular level unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0035005\", \"supporting_discovery_ids\": [3, 1, 0]},\n      {\"term_id\": \"GO:0016303\", \"supporting_discovery_ids\": [3, 0]},\n      {\"term_id\": \"GO:0004672\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020020\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0030659\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006914\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0016197\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0016567\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"PfPI3K–PfVps15 interaction (not established as a heterotetrameric complex in P. falciparum) [#8]\"\n    ],\n    \"partners\": [\n      \"PfVps15 (pseudokinase, Vps15 orthologue) — interaction required for PI3P synthesis and host-cytosol trafficking [#8]\",\n      \"PfKelch13 — binds and mediates polyubiquitination/proteolysis of PI3K [#2]\",\n      \"PfHsp70-1 — PI3P-binding effector in digestive vacuole stabilization [#4]\",\n      \"Erythrocytic ubiquitin-protein E3 ligase — phosphorylated/activated by PI3K [#7]\"\n    ],\n    \"other_free_text\": [\n      \"Essential in Plasmodium blood stages; PfPI3K knockout could not be obtained in P. berghei [#1]\",\n      \"Irreversibly inhibited by activated artemisinin endoperoxides after Fe2+-mediated bridge cleavage [#3, #2]\",\n      \"PI3P levels are predictive of artemisinin resistance across clinical and laboratory strains [#2]\",\n      \"Also inhibited in vitro by MMV390048 (a PfPI4KIIIβ candidate) and by idelalisib, the latter reversing ART resistance in combination with DHA [#5, #10]\",\n      \"First directly localized by expansion microscopy; activity linked to mitochondrial stress and recrudescence after DHA [#9]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0515300","name":null,"product":"phosphatidylinositol 3-kinase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1114900","name":null,"product":"phosphatidylinositol 3-kinase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1017900","name":null,"product":"phosphatidylinositol 3-kinase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PI3K","evaluation":null}