{"gene":"PF3D7_0925700","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":1999,"finding":"PfHDAC1 (PF3D7_0925700) was cloned from P. falciparum genomic and cDNA libraries; its open reading frame encodes a 449 amino acid protein. Immunoelectron microscopy localized the protein predominantly to the nucleus of P. falciparum, and antiserum against a C-terminal peptide immunoprecipitated an ~50 kDa protein from the Triton X-100 insoluble fraction of parasites.","method":"Molecular cloning, Northern blot, immunoprecipitation, immunoelectron microscopy","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunoelectron microscopy with supporting biochemical fractionation; single lab, two orthogonal methods","pmids":["10215020"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Recombinant PfHDAC1 (PF3D7_0925700) was expressed, purified, and shown to have deacetylase enzymatic activity in a biochemical assay, confirming it is a functional class I HDAC enzyme.","method":"Recombinant protein expression, purification, biochemical deacetylase activity assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with purified recombinant protein; single lab but direct demonstration of catalytic activity","pmids":["19317450"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Knockdown of PfHDAC1 (PF3D7_0925700) mRNA by dsRNA treatment (44% reduction in transcript) blocked maturation of trophozoites to schizonts and inhibited P. falciparum K1 strain growth by ~47%, demonstrating that PfHDAC1 is required for normal intraerythrocytic development.","method":"dsRNA-mediated knockdown, [3H]-hypoxanthine incorporation growth assay, microscopic examination, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined stage-specific phenotype, single lab, single method for knockdown","pmids":["19338767"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"K1"}]},{"year":2015,"finding":"Recombinant PfHDAC1 (PF3D7_0925700) deacetylase activity was inhibited in vitro by anti-cancer HDAC inhibitors including SAHA, romidepsin, belinostat, and panobinostat, and these compounds also induced histone hyperacetylation in P. falciparum nuclear extracts, confirming on-target activity of these inhibitors against PfHDAC1.","method":"Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot","journal":"International journal for parasitology. Drugs and drug resistance","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with purified recombinant protein plus cellular hyperacetylation; two orthogonal methods, single lab","pmids":["26199860"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Recombinant PfHDAC1 (PF3D7_0925700) deacetylase activity was inhibited by alkoxyamide-containing HDAC inhibitors, and representative compounds also inhibited P. falciparum nuclear extract deacetylase activity and caused histone hyperacetylation in parasites, demonstrating PfHDAC1 as a target of these antiplasmodial compounds.","method":"Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot","journal":"European journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein plus nuclear extract assay plus cellular hyperacetylation; multiple orthogonal methods, single lab","pmids":["24904967"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"PfHDAC1 (PF3D7_0925700) knockdown in P. falciparum led to downregulation of essential parasite genes, and the transcriptomic changes were highly consistent with those induced by the compound JX21108 (a quisinostat derivative), establishing PfHDAC1 as an epigenetic regulator essential for parasite growth and invasion gene expression.","method":"Conditional knockdown, transcriptomic profiling (RNA-seq), enzymatic inhibition assay","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with transcriptomic readout plus enzymatic inhibition assay; multiple orthogonal methods in a single study","pmids":["33311461"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"PfHDAC1 (PF3D7_0925700) knockdown combined with Western blot and enzymatic inhibition experiments confirmed PfHDAC1 as the molecular target of a novel spirocyclic hydroxamic acid antimalarial compound, and the compound caused histone hyperacetylation consistent with PfHDAC1 inhibition.","method":"PfHDAC gene knockdown, enzymatic inhibition assay, Western blot for histone acetylation","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown plus enzymatic assay plus Western blot; multiple orthogonal methods, single lab","pmids":["33541085"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"PfHDAC1/2 (PF3D7_0925700-containing) knockdown assays combined with PfHDAC1 enzyme inhibition assays confirmed that PfHDAC1 is the antimalarial target of the quisinostat derivative JX35, which showed triple-stage antiplasmodial activity.","method":"Induced PfHDAC1/2 knockdown, PfHDAC1 enzyme inhibition assay, molecular docking","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown and enzymatic assay confirm target engagement; single lab, two orthogonal methods","pmids":["35175762"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Host erythrocyte-derived sphingosine-1-phosphate (S1P) was shown to interact with PfHDAC1 (PF3D7_0925700) and modulate its histone deacetylase activity, establishing a 'lipid sequestration' mechanism by which host sphingolipid signaling epigenetically regulates parasite gene transcription (including gametocytogenesis, virulence, and proliferation genes). Pharmacological inhibition of SphK-1 (with PF-543) dysregulated PfHDAC1 activity and increased global histone acetylation.","method":"Interaction assay (S1P-PfHDAC1 binding), HDAC activity assay, histone acetylation Western blot, pharmacological SphK-1 inhibition, transcriptional profiling","journal":"Microbiology spectrum","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical interaction and enzymatic activity assays plus cellular readouts; single lab, multiple methods but not yet independently replicated","pmids":["36744922"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"ChIP-seq mapping of PfHDAC1 (PF3D7_0925700) across the intraerythrocytic cycle revealed dynamic chromatin occupancy over developmentally relevant genes. Overexpression of PfHDAC1 increased parasite load over multiple asexual cycles, enhanced expression of invasion-related genes (merozoite surface proteins, rhoptry proteins), and increased merozoite invasion efficiency. Class-specific inhibitor treatment demonstrated that PfHDAC1 activity is required for timely intraerythrocytic development. PfHDAC1 overexpression also decreased parasite sensitivity to dihydroartemisinin. Dihydroartemisinin exposure was found to reduce PfHDAC1 abundance and chromatin occupancy, redistribute it to artemisinin-response genes, and interrupt both its in vitro catalytic deacetylase activity and its post-translational phosphorylation.","method":"ChIP-seq, conditional overexpression, HDAC inhibitor treatment, invasion assays, transcriptomic profiling, in vitro deacetylase activity assay, phosphorylation analysis","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, genetic overexpression, enzymatic assay, PTM analysis, transcriptomics, invasion assay) in a single study with rigorous controls","pmids":["38709067"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PfHDAC1 (PF3D7_0925700) was identified as an interactor of the histone methyltransferase PfSET10 by TurboID proximity ligation coupled with mass spectrometry, placing PfHDAC1 within a broader chromatin modulation network in P. falciparum blood stages.","method":"TurboID proximity labeling coupled with mass spectrometry (interactome screen)","journal":"mSphere","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling MS identifies PfHDAC1 as a PfSET10 interactor but no reciprocal pull-down or functional validation of the PfHDAC1–PfSET10 interaction was performed","pmids":["39445823"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"Cyclic tetrapeptide HDAC inhibitors inhibited recombinant PfHDAC1 (PF3D7_0925700) catalytic activity in vitro and caused hyperacetylation of histone H4 in P. falciparum parasites, confirming PfHDAC1 as their antiplasmodial target. Notably, epoxide-containing analogues showed reversible (plasmodistatic) effects, while a diacetyloxy analogue (CTP-NPDG 19) showed rapid irreversible parasite killing.","method":"Recombinant PfHDAC1 enzymatic inhibition assay, histone H4 hyperacetylation Western blot, in silico modeling, reversibility/wash-out assays","journal":"ACS infectious diseases","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein plus cellular hyperacetylation readout; single lab, two orthogonal methods","pmids":["34491031"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"A pentyloxyamide-based HDAC inhibitor (4o) was shown to stabilize PfHDAC1 (PF3D7_0925700) protein in P. falciparum lysates using a solvent-induced protein stability (SIPS) Western blot assay with anti-PfHDAC1 antibody, providing direct evidence of target engagement in parasite protein lysates.","method":"Solvent-induced protein stability (SIPS) Western blot assay, histone H4 hyperacetylation assay","journal":"International journal for parasitology. Drugs and drug resistance","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — thermal/solvent stability shift assay directly demonstrates compound-PfHDAC1 interaction in lysate; single lab, novel but single method for target engagement","pmids":["40850017"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0925700 (PfHDAC1) is a nuclear, class I histone deacetylase in P. falciparum whose catalytic deacetylase activity (demonstrated with purified recombinant protein) is essential for timely intraerythrocytic development, invasion gene expression, and merozoite invasion efficiency; it occupies chromatin dynamically across the asexual cycle, is post-translationally phosphorylated (required for genomic function), is modulated by host sphingosine-1-phosphate binding, and its overexpression confers decreased sensitivity to dihydroartemisinin while artemisinin stress reciprocally reduces PfHDAC1 abundance, chromatin occupancy, and catalytic activity."},"narrative":{"mechanistic_narrative":"PF3D7_0925700 (PfHDAC1) is a nuclear class I histone deacetylase in Plasmodium falciparum that acts as an essential epigenetic regulator of the intraerythrocytic developmental cycle [PMID:10215020, PMID:33311461]. First cloned as a 449-residue protein and localized predominantly to the parasite nucleus [PMID:10215020], recombinant PfHDAC1 was directly shown to possess deacetylase catalytic activity, establishing it as a functional enzyme [PMID:19317450]. Its activity is required for parasite viability: transcript knockdown blocks trophozoite-to-schizont maturation and suppresses growth [PMID:19338767], while conditional knockdown downregulates essential genes with a transcriptomic signature matching pharmacological HDAC inhibition [PMID:33311461]. ChIP-seq shows PfHDAC1 occupies developmentally relevant chromatin dynamically across the asexual cycle, and its overexpression enhances invasion-gene expression (merozoite surface and rhoptry proteins) and merozoite invasion efficiency, confirming a role in timely development and invasion [PMID:38709067]. PfHDAC1 is post-translationally phosphorylated, a modification tied to its genomic function, and its activity is modulated by host erythrocyte-derived sphingosine-1-phosphate, which binds the enzyme to couple host sphingolipid signaling to parasite gene transcription [PMID:36744922, PMID:38709067]. PfHDAC1 overexpression decreases sensitivity to dihydroartemisinin, and conversely dihydroartemisinin reduces its abundance, chromatin occupancy, catalytic activity, and phosphorylation [PMID:38709067]. It is a validated antimalarial drug target engaged by multiple HDAC inhibitor chemotypes that induce histone hyperacetylation in parasites [PMID:26199860, PMID:24904967, PMID:34491031]. Beyond its identification as a proximity interactor of the histone methyltransferase PfSET10 [PMID:39445823], PfHDAC1's associated chromatin complexes remain uncharacterized in the available corpus.","teleology":[{"year":1999,"claim":"Establishing the gene product's identity and subcellular home was the first prerequisite for assigning any epigenetic function; cloning and imaging placed PfHDAC1 in the nucleus.","evidence":"Molecular cloning of a 449-aa ORF with immunoelectron microscopy and immunoprecipitation from P. falciparum","pmids":["10215020"],"confidence":"Medium","gaps":["Did not demonstrate enzymatic activity","No identification of chromatin substrates or partners"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Whether the annotated protein was a genuine deacetylase enzyme was resolved by showing purified recombinant PfHDAC1 catalyzes deacetylation in vitro.","evidence":"Recombinant expression, purification, and biochemical deacetylase assay","pmids":["19317450"],"confidence":"High","gaps":["Physiological substrates not defined in vitro","No structural basis for catalysis"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"The functional importance of PfHDAC1 was first tested by loss-of-function, showing it is required for stage progression and growth.","evidence":"dsRNA knockdown with growth and microscopy readouts in P. falciparum K1","pmids":["19338767"],"confidence":"Medium","gaps":["Modest (44%) knockdown limits interpretation","No transcriptomic or chromatin-level mechanism"],"attribution":[{"species":"Plasmodium falciparum","strain":"K1"}]},{"year":2014,"claim":"To exploit PfHDAC1 pharmacologically, its druggability was established by demonstrating diverse HDAC inhibitor chemotypes engage the recombinant enzyme and hyperacetylate parasite histones.","evidence":"Recombinant enzyme inhibition, nuclear extract deacetylase assays, and histone hyperacetylation Western blots with alkoxyamide, anti-cancer, cyclic tetrapeptide, spirocyclic and pentyloxyamide inhibitors","pmids":["24904967","26199860","33541085","35175762","34491031","40850017"],"confidence":"High","gaps":["Selectivity over sibling PfHDACs not fully resolved","In-parasite target engagement mostly inferred from hyperacetylation rather than direct binding"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Linking enzyme activity to a defined transcriptional program, conditional knockdown showed PfHDAC1 governs essential and invasion-gene expression with a signature matching chemical inhibition.","evidence":"Conditional knockdown, RNA-seq, and enzymatic inhibition comparison to JX21108","pmids":["33311461"],"confidence":"High","gaps":["Direct chromatin targets not mapped","Distinction between direct and secondary transcriptional effects unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"How host signaling reaches parasite chromatin was addressed by showing host-derived S1P binds PfHDAC1 and modulates its activity, coupling sphingolipid signaling to parasite gene control.","evidence":"S1P-PfHDAC1 binding assay, HDAC activity assay, SphK-1 pharmacological inhibition and transcriptional profiling","pmids":["36744922"],"confidence":"Medium","gaps":["Binding site on PfHDAC1 not mapped","Not independently replicated","Direct versus indirect effect on activity not fully separated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"A comprehensive study defined PfHDAC1's genomic occupancy, regulation, and drug-response role, connecting chromatin binding to invasion, development, phosphorylation, and dihydroartemisinin sensitivity.","evidence":"ChIP-seq, conditional overexpression, invasion assays, transcriptomics, in vitro deacetylase and phosphorylation analysis under DHA stress","pmids":["38709067"],"confidence":"High","gaps":["Kinase(s) phosphorylating PfHDAC1 not identified","Mechanism of DHA-induced destabilization unresolved","Direct chromatin-remodeling complex composition not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Placing PfHDAC1 in a wider chromatin network, proximity labeling identified it as an interactor of the histone methyltransferase PfSET10.","evidence":"TurboID proximity labeling coupled with mass spectrometry","pmids":["39445823"],"confidence":"Low","gaps":["No reciprocal pull-down or functional validation of the PfHDAC1-PfSET10 interaction","Complex stoichiometry and biological consequence unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The composition of the native PfHDAC1 chromatin complex, the kinase controlling its functionally required phosphorylation, and the structural basis for its S1P and inhibitor binding remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No characterized stable protein complex beyond a single proximity interactor","Regulatory kinase unidentified","No structural model of the enzyme or its ligand-binding pocket"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFSET10 (PROXIMITY INTERACTOR, UNVALIDATED) [#10]"],"other_free_text":["Catalytic activity essential for trophozoite-to-schizont maturation and asexual growth [#2, #5]","Dynamic chromatin occupancy across the intraerythrocytic cycle; overexpression enhances invasion-gene expression and merozoite invasion efficiency [#9]","Post-translationally phosphorylated, with phosphorylation required for genomic function [#9]","Activity modulated by host erythrocyte-derived sphingosine-1-phosphate binding [#8]","Overexpression decreases dihydroartemisinin sensitivity; DHA reduces PfHDAC1 abundance, chromatin occupancy, activity and phosphorylation [#9]","Validated antimalarial target engaged by multiple HDAC inhibitor chemotypes, confirmed in-lysate by solvent-induced protein stability assay [#3, #4, #11, #12]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"18212103","id":"PMC_18212103","title":"Potent antimalarial activity of histone deacetylase inhibitor analogues.","date":"2008","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/18212103","citation_count":103,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["HDAC1","PfHDAC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18494463","id":"PMC_18494463","title":"A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum.","date":"2008","source":"Journal of medicinal 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Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/40850017","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfHDAC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41485139","id":"PMC_41485139","title":"Discovery of γ-Tetrahydrocarboline Derivatives as Plasmodium falciparum Histone Deacetylase Inhibitors for Treatment of Malaria.","date":"2026","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41485139","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["histone deacetylase 1","PfHDAC1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17227,"output_tokens":3886,"usd":0.054985,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9916,"output_tokens":3620,"usd":0.07004,"stage2_stop_reason":"end_turn"},"total_usd":0.125025,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"PfHDAC1 (PF3D7_0925700) was cloned from P. falciparum genomic and cDNA libraries; its open reading frame encodes a 449 amino acid protein. Immunoelectron microscopy localized the protein predominantly to the nucleus of P. falciparum, and antiserum against a C-terminal peptide immunoprecipitated an ~50 kDa protein from the Triton X-100 insoluble fraction of parasites.\",\n      \"method\": \"Molecular cloning, Northern blot, immunoprecipitation, immunoelectron microscopy\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunoelectron microscopy with supporting biochemical fractionation; single lab, two orthogonal methods\",\n      \"pmids\": [\"10215020\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recombinant PfHDAC1 (PF3D7_0925700) was expressed, purified, and shown to have deacetylase enzymatic activity in a biochemical assay, confirming it is a functional class I HDAC enzyme.\",\n      \"method\": \"Recombinant protein expression, purification, biochemical deacetylase activity assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with purified recombinant protein; single lab but direct demonstration of catalytic activity\",\n      \"pmids\": [\"19317450\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Knockdown of PfHDAC1 (PF3D7_0925700) mRNA by dsRNA treatment (44% reduction in transcript) blocked maturation of trophozoites to schizonts and inhibited P. falciparum K1 strain growth by ~47%, demonstrating that PfHDAC1 is required for normal intraerythrocytic development.\",\n      \"method\": \"dsRNA-mediated knockdown, [3H]-hypoxanthine incorporation growth assay, microscopic examination, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined stage-specific phenotype, single lab, single method for knockdown\",\n      \"pmids\": [\"19338767\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"K1\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Recombinant PfHDAC1 (PF3D7_0925700) deacetylase activity was inhibited in vitro by anti-cancer HDAC inhibitors including SAHA, romidepsin, belinostat, and panobinostat, and these compounds also induced histone hyperacetylation in P. falciparum nuclear extracts, confirming on-target activity of these inhibitors against PfHDAC1.\",\n      \"method\": \"Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot\",\n      \"journal\": \"International journal for parasitology. Drugs and drug resistance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with purified recombinant protein plus cellular hyperacetylation; two orthogonal methods, single lab\",\n      \"pmids\": [\"26199860\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant PfHDAC1 (PF3D7_0925700) deacetylase activity was inhibited by alkoxyamide-containing HDAC inhibitors, and representative compounds also inhibited P. falciparum nuclear extract deacetylase activity and caused histone hyperacetylation in parasites, demonstrating PfHDAC1 as a target of these antiplasmodial compounds.\",\n      \"method\": \"Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein plus nuclear extract assay plus cellular hyperacetylation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24904967\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PfHDAC1 (PF3D7_0925700) knockdown in P. falciparum led to downregulation of essential parasite genes, and the transcriptomic changes were highly consistent with those induced by the compound JX21108 (a quisinostat derivative), establishing PfHDAC1 as an epigenetic regulator essential for parasite growth and invasion gene expression.\",\n      \"method\": \"Conditional knockdown, transcriptomic profiling (RNA-seq), enzymatic inhibition assay\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with transcriptomic readout plus enzymatic inhibition assay; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"33311461\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PfHDAC1 (PF3D7_0925700) knockdown combined with Western blot and enzymatic inhibition experiments confirmed PfHDAC1 as the molecular target of a novel spirocyclic hydroxamic acid antimalarial compound, and the compound caused histone hyperacetylation consistent with PfHDAC1 inhibition.\",\n      \"method\": \"PfHDAC gene knockdown, enzymatic inhibition assay, Western blot for histone acetylation\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown plus enzymatic assay plus Western blot; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33541085\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PfHDAC1/2 (PF3D7_0925700-containing) knockdown assays combined with PfHDAC1 enzyme inhibition assays confirmed that PfHDAC1 is the antimalarial target of the quisinostat derivative JX35, which showed triple-stage antiplasmodial activity.\",\n      \"method\": \"Induced PfHDAC1/2 knockdown, PfHDAC1 enzyme inhibition assay, molecular docking\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown and enzymatic assay confirm target engagement; single lab, two orthogonal methods\",\n      \"pmids\": [\"35175762\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Host erythrocyte-derived sphingosine-1-phosphate (S1P) was shown to interact with PfHDAC1 (PF3D7_0925700) and modulate its histone deacetylase activity, establishing a 'lipid sequestration' mechanism by which host sphingolipid signaling epigenetically regulates parasite gene transcription (including gametocytogenesis, virulence, and proliferation genes). Pharmacological inhibition of SphK-1 (with PF-543) dysregulated PfHDAC1 activity and increased global histone acetylation.\",\n      \"method\": \"Interaction assay (S1P-PfHDAC1 binding), HDAC activity assay, histone acetylation Western blot, pharmacological SphK-1 inhibition, transcriptional profiling\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical interaction and enzymatic activity assays plus cellular readouts; single lab, multiple methods but not yet independently replicated\",\n      \"pmids\": [\"36744922\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ChIP-seq mapping of PfHDAC1 (PF3D7_0925700) across the intraerythrocytic cycle revealed dynamic chromatin occupancy over developmentally relevant genes. Overexpression of PfHDAC1 increased parasite load over multiple asexual cycles, enhanced expression of invasion-related genes (merozoite surface proteins, rhoptry proteins), and increased merozoite invasion efficiency. Class-specific inhibitor treatment demonstrated that PfHDAC1 activity is required for timely intraerythrocytic development. PfHDAC1 overexpression also decreased parasite sensitivity to dihydroartemisinin. Dihydroartemisinin exposure was found to reduce PfHDAC1 abundance and chromatin occupancy, redistribute it to artemisinin-response genes, and interrupt both its in vitro catalytic deacetylase activity and its post-translational phosphorylation.\",\n      \"method\": \"ChIP-seq, conditional overexpression, HDAC inhibitor treatment, invasion assays, transcriptomic profiling, in vitro deacetylase activity assay, phosphorylation analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP-seq, genetic overexpression, enzymatic assay, PTM analysis, transcriptomics, invasion assay) in a single study with rigorous controls\",\n      \"pmids\": [\"38709067\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PfHDAC1 (PF3D7_0925700) was identified as an interactor of the histone methyltransferase PfSET10 by TurboID proximity ligation coupled with mass spectrometry, placing PfHDAC1 within a broader chromatin modulation network in P. falciparum blood stages.\",\n      \"method\": \"TurboID proximity labeling coupled with mass spectrometry (interactome screen)\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling MS identifies PfHDAC1 as a PfSET10 interactor but no reciprocal pull-down or functional validation of the PfHDAC1–PfSET10 interaction was performed\",\n      \"pmids\": [\"39445823\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cyclic tetrapeptide HDAC inhibitors inhibited recombinant PfHDAC1 (PF3D7_0925700) catalytic activity in vitro and caused hyperacetylation of histone H4 in P. falciparum parasites, confirming PfHDAC1 as their antiplasmodial target. Notably, epoxide-containing analogues showed reversible (plasmodistatic) effects, while a diacetyloxy analogue (CTP-NPDG 19) showed rapid irreversible parasite killing.\",\n      \"method\": \"Recombinant PfHDAC1 enzymatic inhibition assay, histone H4 hyperacetylation Western blot, in silico modeling, reversibility/wash-out assays\",\n      \"journal\": \"ACS infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with recombinant protein plus cellular hyperacetylation readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"34491031\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A pentyloxyamide-based HDAC inhibitor (4o) was shown to stabilize PfHDAC1 (PF3D7_0925700) protein in P. falciparum lysates using a solvent-induced protein stability (SIPS) Western blot assay with anti-PfHDAC1 antibody, providing direct evidence of target engagement in parasite protein lysates.\",\n      \"method\": \"Solvent-induced protein stability (SIPS) Western blot assay, histone H4 hyperacetylation assay\",\n      \"journal\": \"International journal for parasitology. Drugs and drug resistance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — thermal/solvent stability shift assay directly demonstrates compound-PfHDAC1 interaction in lysate; single lab, novel but single method for target engagement\",\n      \"pmids\": [\"40850017\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0925700 (PfHDAC1) is a nuclear, class I histone deacetylase in P. falciparum whose catalytic deacetylase activity (demonstrated with purified recombinant protein) is essential for timely intraerythrocytic development, invasion gene expression, and merozoite invasion efficiency; it occupies chromatin dynamically across the asexual cycle, is post-translationally phosphorylated (required for genomic function), is modulated by host sphingosine-1-phosphate binding, and its overexpression confers decreased sensitivity to dihydroartemisinin while artemisinin stress reciprocally reduces PfHDAC1 abundance, chromatin occupancy, and catalytic activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0925700 (PfHDAC1) is a nuclear class I histone deacetylase in Plasmodium falciparum that acts as an essential epigenetic regulator of the intraerythrocytic developmental cycle [#0, #5]. First cloned as a 449-residue protein and localized predominantly to the parasite nucleus [#0], recombinant PfHDAC1 was directly shown to possess deacetylase catalytic activity, establishing it as a functional enzyme [#1]. Its activity is required for parasite viability: transcript knockdown blocks trophozoite-to-schizont maturation and suppresses growth [#2], while conditional knockdown downregulates essential genes with a transcriptomic signature matching pharmacological HDAC inhibition [#5]. ChIP-seq shows PfHDAC1 occupies developmentally relevant chromatin dynamically across the asexual cycle, and its overexpression enhances invasion-gene expression (merozoite surface and rhoptry proteins) and merozoite invasion efficiency, confirming a role in timely development and invasion [#9]. PfHDAC1 is post-translationally phosphorylated, a modification tied to its genomic function, and its activity is modulated by host erythrocyte-derived sphingosine-1-phosphate, which binds the enzyme to couple host sphingolipid signaling to parasite gene transcription [#8, #9]. PfHDAC1 overexpression decreases sensitivity to dihydroartemisinin, and conversely dihydroartemisinin reduces its abundance, chromatin occupancy, catalytic activity, and phosphorylation [#9]. It is a validated antimalarial drug target engaged by multiple HDAC inhibitor chemotypes that induce histone hyperacetylation in parasites [#3, #4, #11]. Beyond its identification as a proximity interactor of the histone methyltransferase PfSET10 [#10], PfHDAC1's associated chromatin complexes remain uncharacterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing the gene product's identity and subcellular home was the first prerequisite for assigning any epigenetic function; cloning and imaging placed PfHDAC1 in the nucleus.\",\n      \"evidence\": \"Molecular cloning of a 449-aa ORF with immunoelectron microscopy and immunoprecipitation from P. falciparum\",\n      \"pmids\": [\"10215020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not demonstrate enzymatic activity\", \"No identification of chromatin substrates or partners\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether the annotated protein was a genuine deacetylase enzyme was resolved by showing purified recombinant PfHDAC1 catalyzes deacetylation in vitro.\",\n      \"evidence\": \"Recombinant expression, purification, and biochemical deacetylase assay\",\n      \"pmids\": [\"19317450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not defined in vitro\", \"No structural basis for catalysis\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The functional importance of PfHDAC1 was first tested by loss-of-function, showing it is required for stage progression and growth.\",\n      \"evidence\": \"dsRNA knockdown with growth and microscopy readouts in P. falciparum K1\",\n      \"pmids\": [\"19338767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modest (44%) knockdown limits interpretation\", \"No transcriptomic or chromatin-level mechanism\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"K1\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"To exploit PfHDAC1 pharmacologically, its druggability was established by demonstrating diverse HDAC inhibitor chemotypes engage the recombinant enzyme and hyperacetylate parasite histones.\",\n      \"evidence\": \"Recombinant enzyme inhibition, nuclear extract deacetylase assays, and histone hyperacetylation Western blots with alkoxyamide, anti-cancer, cyclic tetrapeptide, spirocyclic and pentyloxyamide inhibitors\",\n      \"pmids\": [\"24904967\", \"26199860\", \"33541085\", \"35175762\", \"34491031\", \"40850017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over sibling PfHDACs not fully resolved\", \"In-parasite target engagement mostly inferred from hyperacetylation rather than direct binding\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linking enzyme activity to a defined transcriptional program, conditional knockdown showed PfHDAC1 governs essential and invasion-gene expression with a signature matching chemical inhibition.\",\n      \"evidence\": \"Conditional knockdown, RNA-seq, and enzymatic inhibition comparison to JX21108\",\n      \"pmids\": [\"33311461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets not mapped\", \"Distinction between direct and secondary transcriptional effects unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How host signaling reaches parasite chromatin was addressed by showing host-derived S1P binds PfHDAC1 and modulates its activity, coupling sphingolipid signaling to parasite gene control.\",\n      \"evidence\": \"S1P-PfHDAC1 binding assay, HDAC activity assay, SphK-1 pharmacological inhibition and transcriptional profiling\",\n      \"pmids\": [\"36744922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site on PfHDAC1 not mapped\", \"Not independently replicated\", \"Direct versus indirect effect on activity not fully separated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A comprehensive study defined PfHDAC1's genomic occupancy, regulation, and drug-response role, connecting chromatin binding to invasion, development, phosphorylation, and dihydroartemisinin sensitivity.\",\n      \"evidence\": \"ChIP-seq, conditional overexpression, invasion assays, transcriptomics, in vitro deacetylase and phosphorylation analysis under DHA stress\",\n      \"pmids\": [\"38709067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) phosphorylating PfHDAC1 not identified\", \"Mechanism of DHA-induced destabilization unresolved\", \"Direct chromatin-remodeling complex composition not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placing PfHDAC1 in a wider chromatin network, proximity labeling identified it as an interactor of the histone methyltransferase PfSET10.\",\n      \"evidence\": \"TurboID proximity labeling coupled with mass spectrometry\",\n      \"pmids\": [\"39445823\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reciprocal pull-down or functional validation of the PfHDAC1-PfSET10 interaction\", \"Complex stoichiometry and biological consequence unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The composition of the native PfHDAC1 chromatin complex, the kinase controlling its functionally required phosphorylation, and the structural basis for its S1P and inhibitor binding remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No characterized stable protein complex beyond a single proximity interactor\", \"Regulatory kinase unidentified\", \"No structural model of the enzyme or its ligand-binding pocket\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004407\", \"supporting_discovery_ids\": [1, 3, 4, 11]},\n      {\"term_id\": \"GO:0033558\", \"supporting_discovery_ids\": [1, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0000785\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006338\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0016575\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0006355\", \"supporting_discovery_ids\": [5, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfSET10 (proximity interactor, unvalidated) [#10]\"\n    ],\n    \"other_free_text\": [\n      \"Catalytic activity essential for trophozoite-to-schizont maturation and asexual growth [#2, #5]\",\n      \"Dynamic chromatin occupancy across the intraerythrocytic cycle; overexpression enhances invasion-gene expression and merozoite invasion efficiency [#9]\",\n      \"Post-translationally phosphorylated, with phosphorylation required for genomic function [#9]\",\n      \"Activity modulated by host erythrocyte-derived sphingosine-1-phosphate binding [#8]\",\n      \"Overexpression decreases dihydroartemisinin sensitivity; DHA reduces PfHDAC1 abundance, chromatin occupancy, activity and phosphorylation [#9]\",\n      \"Validated antimalarial target engaged by multiple HDAC inhibitor chemotypes, confirmed in-lysate by solvent-induced protein stability assay [#3, #4, #11, #12]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0925700","name":null,"product":"histone deacetylase 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0826500","name":null,"product":"histone deacetylase 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0723600","name":null,"product":"histone deacetylase 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"HDAC1","evaluation":null}