Plasmodium falciparum histone deacetylases
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P. falciparum (Pf) histone deacetylases (HDACs) have been proposed as new antimalarial drug targets. In higher eukaryotes, HDACs are involved in regulating gene expression and cellular development. The Pf genome encodes for at least five putative HDACs. One PfHDAC (PFI1260c; PfHDAC-1) shares greater than 50% sequence homology with class I HDACs from yeast, mice, and humans. Two Pf class II HDAC homologues (PF14_0690 (PfHDAC-2) & PF10_0078) have limited sequence similarity to mammalian HDACs, except in predicted deacetylase domains. One of two class III HDAC homologues (PfSir2) has been "knocked-out" in Pf and appears to play a role in regulating virulence gene expression (var genes). We have now begun to characterize the class I and II PfHDACs in order to understand the role of these enzymes in Plasmodium and to guide rational development of new antimalarial agents. We have found that PfHDAC-1 and 2 are transcribed in ring, trophozoite and schizont stage Pf parasites, as determined by Northern blot. Western blot using polyclonal antisera shows that PfHDAC-1 is expressed in all intraerythrocytic stages. Localization of PfHDAC-1 within the infected erythrocyte had been confirmed as being predominantly nuclear using transgenic Pf parasites over-expressing PfHDAC-1 fused to GFP or c-myc tags. Pf extracts display deacetylase activity and this activity can be inhibited by classic class I/II mammalian HDAC inhibitors such as trichostatin A (TSA). This work contributes to our understanding of the role of HDACs in Pf and to the development of antimalarial agents that act on this new class of drug target within the parasite.
International Journal for Parasitology