Garcinol Inhibits GCN5-Mediated Lysine Acetyltransferase Activity and Prevents Replication of the Parasite Toxoplasma gondii

Antimicrob Agents Chemother. 2016 Mar 25;60(4):2164-70. doi: 10.1128/AAC.03059-15. Print 2016 Apr.


Lysine acetylation is a critical posttranslational modification that influences protein activity, stability, and binding properties. The acetylation of histone proteins in particular is a well-characterized feature of gene expression regulation. In the protozoan parasiteToxoplasma gondii, a number of lysine acetyltransferases (KATs) contribute to gene expression and are essential for parasite viability. The natural product garcinol was recently reported to inhibit enzymatic activities of GCN5 and p300 family KATs in other species. Here we show that garcinol inhibits TgGCN5b, the only nuclear GCN5 family KAT known to be required forToxoplasmatachyzoite replication. Treatment of tachyzoites with garcinol led to a reduction of global lysine acetylation, particularly on histone H3 and TgGCN5b itself. We also performed transcriptome sequencing (RNA-seq), which revealed increasing aberrant gene expression coincident with increasing concentrations of garcinol. The majority of the genes that were most significantly affected by garcinol were also associated with TgGCN5b in a previously reported chromatin immunoprecipitation assay with microarray technology (ChIP-chip) analysis. The dysregulated gene expression induced by garcinol significantly inhibitsToxoplasmatachyzoite replication, and the concentrations used exhibit no overt toxicity on human host cells. Garcinol also inhibitsPlasmodium falciparumasexual replication with a 50% inhibitory concentration (IC50) similar to that forToxoplasma Together, these data support that pharmacological inhibition of TgGCN5b leads to a catastrophic failure in gene expression control that prevents parasite replication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antiprotozoal Agents / pharmacology*
  • Erythrocytes / drug effects
  • Erythrocytes / parasitology
  • Fibroblasts / drug effects
  • Fibroblasts / parasitology
  • Gene Expression Profiling
  • Histone Acetyltransferases / antagonists & inhibitors*
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Histones / antagonists & inhibitors*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Life Cycle Stages / drug effects
  • Life Cycle Stages / genetics
  • Lysine / metabolism
  • Microarray Analysis
  • Molecular Sequence Annotation
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / metabolism
  • Protein Processing, Post-Translational*
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Sequence Analysis, RNA
  • Terpenes / pharmacology*
  • Toxoplasma / drug effects*
  • Toxoplasma / genetics
  • Toxoplasma / metabolism
  • Transcriptome


  • Antiprotozoal Agents
  • Histones
  • Protozoan Proteins
  • Terpenes
  • GCN5 protein, Toxoplasma gondii
  • Histone Acetyltransferases
  • Lysine
  • garcinol