Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum.
Reversible acetylation of core histones plays an important role in transcriptional regulation, cell cycle progression and developmental events. The acetylation state of histones is controlled by a dynamic equilibrium between activities of histone acetylase and deacetylase enzymes. Histone deacetylase (HDAC) was recently suggested to be the target of a fungus-derived antiprotozoal agent exhibiting structural similarity to known HDAC inhibitors. We have initiated a study of HDAC of human malaria parasite, Plasmodium falciparum, to evaluate its potential as the target for novel antimalarials and its role in parasite development. We have isolated HDAC1 gene from the P. falciparum genomic and cDNA libraries. The nucleotide sequence contains no intervening sequence and its open reading frame (ORF) codes for a protein of 449 amino acid residues. We have named the protein, PfHDAC1, as the sequence shows significant homology to yeast, human and other eukaryotic HDACs. Northern blot analysis of the total RNA from different asexual and sexual stages of the parasite reveals the presence of single mRNA transcript, which is predominantly expressed in mature asexual blood stages and in gametocytes. Antiserum raised against a carboxyl terminal peptide immunoprecipitated an in vitro translated P. falciparum HDAC gene product and recognized an approximately 50 kDa protein in the Triton X-100 insoluble fraction of parasites. Immunoelectron microscopy analysis showed majority of the protein localized in the nucleus of P. falciparum. To our knowledge, this is the first HDAC gene isolated from the malaria parasite.
Joshi
M B
MB
Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852-1448, USA.
Lin
D T
DT
Chiang
P H
PH
Goldman
N D
ND
Fujioka
H
H
Aikawa
M
M
Syin
C
C
D000595:Amino Acid Sequence; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D016054:DNA, Protozoan / Q000032:analysis; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics* / Q000254:growth & development; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
D016054:DNA, Protozoan; D006655:Histone Deacetylases