An apicomplexan ankyrin-repeat histone deacetylase with relatives in photosynthetic eukaryotes.
Cryptosporidium parvum is a member of the Apicomplexa that lacks a plastid and associated nuclear-encoded genes, which has hampered its use in evolutionary comparisons with algae and eliminated a pool of potentially useful drug targets. Here we show that apicomplexan parasites possess an unusual family of class II histone deacetylase (HDAC) proteins with orthologues that are present in other chromalveolates and primitive algae. A striking feature of these HDAC proteins is the presence of ankyrin repeats in the amino-terminus that appear to be required for enzyme activity. In vitro and in vivo analyses of the C. parvum orthologue indicate that this subclass of chromatin-remodelling proteins is targeted by the anti-cancer drug suberoylanilide hydroxamic acid and that these proteins are most likely involved in the essential process of H4 histone deacetylation that coincides with DNA replication. We propose that members of this novel class of histone deacetylase can serve as promising new targets for treatments against debilitating diseases such as cryptosporidosis, toxoplasmosis and malaria.
Rider
S Dean
SD
Department of Pathobiology, Texas A&M University, College Station, TX 77843, USA. drider@cvm.tamu.edu
Zhu
Guan
G
D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics* / Q000502:physiology; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D016785:Cryptosporidium parvum / Q000235:genetics* / Q000254:growth & development; D004261:DNA Replication / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling / Q000379:methods; D016678:Genome; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D016366:Open Reading Frames; D010802:Phylogeny; D015800:Protozoan Proteins / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D000077337:Vorinostat; D006655:Histone Deacetylases