The long-term goal of this proposal is to characterize the reversible protein phosphorylation pathways in reference to biochemical and genetic regulation in the Apicomplexan group of parasites. Protozan Apicomplexan parasites are exemplified by deadly pathogens such as Plasmodium that causes malaria, and Toxoplasma and Cryptosporidium that cause opportunistic infections in AIDS patients. Malaria, transmitted by mosquitoes, alone kills between 1.5 and 2.5 million people worldwide, mostly young children. The resurgence of drug-resistant parasites as well as pesticide-resistant mosquitoes and the global transmission of the disease have produced an urgent need to understand the fundamental regulatory pathways of the parasite. Although our knowledge in this area is still rudimentary, a large body of evidence accumulated over the last two decades has shown that in higher animals a reversible protein phosphorylation provides a major mechanism of biochemical and genetic regulation. In this proposal, therefore, a combination of biochemistry and molecular biology will be employed to study selected Plasmodium protein phosphatases, key enzymes that are responsible for the dephosphorylation of specific phosphoproteins. The properties and regulation of these enzymes and their interactions with specific physiological inhibitors and drugs will be studied in- depth. The anti-parasitic drugs such as okadaic acid, a potent marine toxin, and cyclosporin, an immunosuppressant, will be used as tools in the analysis of the structure and function of specific protein phosphatases of the parasite. These results should form the cornerstone in the detailed elucidation of the regulatory pathways and possible drug-target interactions in Plasmodium in particular, and Apicomplexans in general.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Tropical Medicine and Parasitology Study Section (TMP)
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Gottlieb, Michael
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University of South Alabama
Schools of Medicine
United States
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Urnowey, Sonya; Ansai, Toshihiro; Bitko, Vira et al. (2006) Temporal activation of anti- and pro-apoptotic factors in human gingival fibroblasts infected with the periodontal pathogen, Porphyromonas gingivalis: potential role of bacterial proteases in host signalling. BMC Microbiol 6:26
Kumar, Rajinder; Musiyenko, Alla; Barik, Sailen (2005) Plasmodium falciparum calcineurin and its association with heat shock protein 90: mechanisms for the antimalarial activity of cyclosporin A and synergism with geldanamycin. Mol Biochem Parasitol 141:29-37
Adams, Brian; Musiyenko, Alla; Kumar, Rajinder et al. (2005) A novel class of dual-family immunophilins. J Biol Chem 280:24308-14
Kumar, Rajinder; Adams, Brian; Musiyenko, Alla et al. (2005) The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity. Mol Biochem Parasitol 141:163-73
Barik, Sailen (2004) Development of gene-specific double-stranded RNA drugs. Ann Med 36:540-51
Kumar, Rajinder; Musiyenko, Alla; Oldenburg, Anja et al. (2004) Post-translational generation of constitutively active cores from larger phosphatases in the malaria parasite, Plasmodium falciparum: implications for proteomics. BMC Mol Biol 5:6
Barik, Sailen (2004) When proteome meets genome: the alpha helix and the beta strand of proteins are eschewed by mRNA splice junctions and may define the minimal indivisible modules of protein architecture. J Biosci 29:261-73
Kumar, Rajinder; Musiyenko, Alla; Cioffi, Eugene et al. (2004) A zinc-binding dual-specificity YVH1 phosphatase in the malaria parasite, Plasmodium falciparum, and its interaction with the nuclear protein, pescadillo. Mol Biochem Parasitol 133:297-310
Dobson, Sean; Kumar, Rajinder; Bracchi-Ricard, Valerie et al. (2003) Characterization of a unique aspartate-rich protein of the SET/TAF-family in the human malaria parasite, Plasmodium falciparum, which inhibits protein phosphatase 2A. Mol Biochem Parasitol 126:239-50
Kumar, Rajinder; Musiyenko, Alla; Barik, Sailen (2003) The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin. Malar J 2:30

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