Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum

Reversible acetylation of core histones plays an important role in transcri ptional regulation, cell cycle progression and developmental events. The ac etylation state of histones is controlled by a dynamic equilibrium between activities of histone acetylase and deacetylase enzymes. Histone deacetylas e (HDAC) was recently suggested to be the target of a fungus-derived antipr otozoal agent exhibiting structural similarity to known HDAC inhibitors. We have initiated a study of HDAC of human malaria parasite, Plasmodium falci parum, to evaluate its potential as the target for novel antimalarials and its role in parasite development. We have isolated HDAC1 gene from the P. f alciparum genomic and cDNA libraries. The nucleotide sequence contains no i ntervening sequence and its open reading frame (ORF) codes for a protein of 449 amino acid residues. We have named the protein, PfHDAC1, as the sequen ce shows significant homology to yeast, human and other eukaryotic HDACs. N orthern blot analysis of the total RNA from different asexual and sexual st ages of the parasite reveals the presence of single mRNA transcript, which is predominantly expressed in mature asexual blood stages and in gametocyte s. Antiserum raised against a carboxyl terminal peptide immunoprecipitated an in vitro translated P. falciparum HDAC gene product and recognized a app roximate to 50 kDa protein in the Triton X-100 insoluble fraction of parasi tes. Immunoelectron microscopy analysis showed majority of the protein loca lized in the nucleus of P. falciparum. To our knowledge, this is the first HDAC gene isolated from the malaria parasite. (C) 1999 Elsevier Science B.V . All rights reserved.