Affinage · Plasmodium

HDAC1

PF3D7_0925700 · histone deacetylase 1

Annotated
2026-09-08
29 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 Medium

    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

    PMID:10215020

    Open questions at the time
    • Did not demonstrate enzymatic activity
    • No identification of chromatin substrates or partners
  2. 2009 High

    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

    PMID:19317450

    Open questions at the time
    • Physiological substrates not defined in vitro
    • No structural basis for catalysis
  3. 2009 Medium

    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

    PMID:19338767

    Open questions at the time
    • Modest (44%) knockdown limits interpretation
    • No transcriptomic or chromatin-level mechanism
  4. 2014 High

    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

    PMID:24904967 PMID:26199860 PMID:33541085 PMID:34491031 PMID:35175762 PMID:40850017

    Open questions at the time
    • Selectivity over sibling PfHDACs not fully resolved
    • In-parasite target engagement mostly inferred from hyperacetylation rather than direct binding
  5. 2020 High

    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

    PMID:33311461

    Open questions at the time
    • Direct chromatin targets not mapped
    • Distinction between direct and secondary transcriptional effects unresolved
  6. 2023 Medium

    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

    PMID:36744922

    Open questions at the time
    • Binding site on PfHDAC1 not mapped
    • Not independently replicated
    • Direct versus indirect effect on activity not fully separated
  7. 2024 High

    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

    PMID:38709067

    Open questions at the time
    • Kinase(s) phosphorylating PfHDAC1 not identified
    • Mechanism of DHA-induced destabilization unresolved
    • Direct chromatin-remodeling complex composition not defined
  8. 2024 Low

    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

    PMID:39445823

    Open questions at the time
    • No reciprocal pull-down or functional validation of the PfHDAC1-PfSET10 interaction
    • Complex stoichiometry and biological consequence unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No characterized stable protein complex beyond a single proximity interactor
  • Regulatory kinase unidentified
  • No structural model of the enzyme or its ligand-binding pocket

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PFSET10 (PROXIMITY INTERACTOR, UNVALIDATED) [#10]

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Molecular cloning, Northern blot, immunoprecipitation, immunoelectron microscopy Molecular and biochemical parasitology Medium 10215020
2009 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. Recombinant protein expression, purification, biochemical deacetylase activity assay Journal of medicinal chemistry High 19317450
2009 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. dsRNA-mediated knockdown, [3H]-hypoxanthine incorporation growth assay, microscopic examination, RT-PCR Biochemical and biophysical research communications Medium 19338767
2015 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. Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot International journal for parasitology. Drugs and drug resistance High 26199860
2014 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. Recombinant PfHDAC1 enzymatic inhibition assay, P. falciparum nuclear extract deacetylase assay, histone hyperacetylation Western blot European journal of medicinal chemistry High 24904967
2020 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. Conditional knockdown, transcriptomic profiling (RNA-seq), enzymatic inhibition assay Cell discovery High 33311461
2021 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. PfHDAC gene knockdown, enzymatic inhibition assay, Western blot for histone acetylation Journal of medicinal chemistry Medium 33541085
2022 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. Induced PfHDAC1/2 knockdown, PfHDAC1 enzyme inhibition assay, molecular docking Journal of medicinal chemistry Medium 35175762
2023 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. Interaction assay (S1P-PfHDAC1 binding), HDAC activity assay, histone acetylation Western blot, pharmacological SphK-1 inhibition, transcriptional profiling Microbiology spectrum Medium 36744922
2024 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. ChIP-seq, conditional overexpression, HDAC inhibitor treatment, invasion assays, transcriptomic profiling, in vitro deacetylase activity assay, phosphorylation analysis mBio High 38709067
2024 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. TurboID proximity labeling coupled with mass spectrometry (interactome screen) mSphere Low 39445823
2021 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. Recombinant PfHDAC1 enzymatic inhibition assay, histone H4 hyperacetylation Western blot, in silico modeling, reversibility/wash-out assays ACS infectious diseases Medium 34491031
2025 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. Solvent-induced protein stability (SIPS) Western blot assay, histone H4 hyperacetylation assay International journal for parasitology. Drugs and drug resistance Medium 40850017

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Potent antimalarial activity of histone deacetylase inhibitor analogues. Antimicrobial agents and chemotherapy 103 18212103
2008 A series of potent and selective, triazolylphenyl-based histone deacetylases inhibitors with activity against pancreatic cancer cells and Plasmodium falciparum. Journal of medicinal chemistry 100 18494463
2015 Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites. International journal for parasitology. Drugs and drug resistance 80 26199860
2009 Identification and characterization of small molecule inhibitors of a class I histone deacetylase from Plasmodium falciparum. Journal of medicinal chemistry 69 19317450
1999 Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum. Molecular and biochemical parasitology 66 10215020
2017 Adaptation of Plasmodium falciparum to its transmission environment. Nature ecology & evolution 59 29255304
2014 Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages. European journal of medicinal chemistry 57 24904967
2008 Structural insights into the Plasmodium falciparum histone deacetylase 1 (PfHDAC-1): A novel target for the development of antimalarial therapy. Bioorganic & medicinal chemistry 46 18362073
2015 Targeting Lysine Deacetylases (KDACs) in Parasites. PLoS neglected tropical diseases 43 26402733
2020 A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1. Cell discovery 42 33311461
2015 Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors. Journal of molecular graphics & modelling 39 26595183
2016 Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs. ACS medicinal chemistry letters 33 27190592
2010 Antimalarial histone deacetylase inhibitors containing cinnamate or NSAID components. Bioorganic & medicinal chemistry letters 33 20951583
2021 Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat. Journal of medicinal chemistry 30 33541085
2022 Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety. Journal of medicinal chemistry 26 35175762
2019 Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor. European journal of medicinal chemistry 19 31627059
2021 Cyclic Tetrapeptide HDAC Inhibitors with Improved Plasmodium falciparum Selectivity and Killing Profile. ACS infectious diseases 18 34491031
2017 Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6. ACS omega 18 30023639
2017 Design and Synthesis of Novel Anti-Plasmodial Histone Deacetylase Inhibitors Containing an Alkoxyamide Connecting Unit. Archiv der Pharmazie 14 28317157
2009 Inhibition of Plasmodium falciparum proliferation in vitro by double-stranded RNA directed against malaria histone deacetylase. Biochemical and biophysical research communications 14 19338767
2015 Valproic acid as a potential inhibitor of Plasmodium falciparum histone deacetylase 1 (PfHDAC1): an in silico approach. International journal of molecular sciences 12 25679451
2018 In silico identification of inhibitors against Plasmodium falciparum histone deacetylase 1 (PfHDAC-1). Journal of molecular modeling 8 30109440
2024 PfHDAC1 is an essential regulator of P. falciparum asexual proliferation and host cell invasion genes with a dynamic genomic occupancy responsive to artemisinin stress. mBio 7 38709067
2023 Host-Erythrocytic Sphingosine-1-Phosphate Regulates Plasmodium Histone Deacetylase Activity and Exhibits Epigenetic Control over Cell Death and Differentiation. Microbiology spectrum 7 36744922
2021 Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice. International journal for parasitology. Drugs and drug resistance 7 34560571
2024 The Plasmodium falciparum histone methyltransferase SET10 participates in a chromatin modulation network crucial for intraerythrocytic development. mSphere 6 39445823
2024 Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors. European journal of medicinal chemistry 4 39549507
2025 Antiplasmodial activity of pentyloxyamide-based histone deacetylase inhibitors against Plasmodium falciparum parasites. International journal for parasitology. Drugs and drug resistance 2 40850017
2026 Discovery of γ-Tetrahydrocarboline Derivatives as Plasmodium falciparum Histone Deacetylase Inhibitors for Treatment of Malaria. Journal of medicinal chemistry 0 41485139