: The human malaria parasite, Plasmodium falciparum, has extremely unusual rRNAs and hence there are likely to be unique characteristics to malarial ribosomes. There are three sets of rRNAs: cytoplasmic rRNAs, encoded in the nucleus and responsible for the majority of protein synthesis, and mitochondrial and plastid rRNAs, encoded by the mitochondrial and plastid genomes respective and responsible for protein synthesis in the cognate organelles. The plastid rRNAs appear conventional but different copies of the cytoplasmic rRNAs differ in sequence and are expressed stage-specifically. The mitochondrial rRNAs are highly fragmented and quite small but sequences for most of the functional regions have been identified. We propose to study several aspects of the structure, biogenesis, and function of the P. falciparum ribosomes. As yet, no sequences for the GTPase center, a region critical to protein synthesis, have been found for the mitochondrial ribosomes; identification of such sequences will bolster the hypothesis that the unique mitochondrial ribosomes are functional. Considerable data are available on P. falciparum rRNA structure and expression but nothing is known about its ribosomal protein biogenesis. Making ribosomes, which contain - about8O proteins, is energetically demanding so ribosomal protein synthesis tends to be coordinately regulated, with the regulatory mechanisms differing among organisms. Drug inhibition studies indicate that protein synthesis in all three compartments is important to parasite growth. However, they also suggest that different ribosome types are differentially sensitive and cytoplasmic protein synthesis may be susceptible to compounds, which normally affect only organelle ribosomes. Also, some drugs inhibit parasite growth differentially between life cycle stages and inhibition with some drugs is delayed. We will investigate potential mitochondrial GTPase center transcripts, assess regulatory mechanisms governing ribosomal protein synthesis, and evaluate differential effects of antibiotics on mitochondrial, plastid, and cytoplasmic ribosomes. Because the P. falciparum cytoplasmic and mitochondrial rRNAs are unique, structural and functional evaluation of the ribosomes containing them is expected to produce insights into basic cellular synthetic and regulatory mechanisms. In addition, these studies will examine critical functions of the malaria parasite and assess the targets of drugs being used to treat malaria. Our data may therefore produce information useful to development of new anti-malarial treatments.
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