: 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040638-07
Application #
6877054
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Program Officer
Rogers, Martin J
Project Start
1998-01-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2005
Total Cost
$429,750
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Li, J; Maga, J A; Cermakian, N et al. (2001) Identification and characterization of a Plasmodium falciparum RNA polymerase gene with similarity to mitochondrial RNA polymerases. Mol Biochem Parasitol 113:261-9
Feagin, J E (2000) Mitochondrial genome diversity in parasites. Int J Parasitol 30:371-90
Rehkopf, D H; Gillespie, D E; Harrell, M I et al. (2000) Transcriptional mapping and RNA processing of the Plasmodium falciparum mitochondrial mRNAs. Mol Biochem Parasitol 105:91-103
Gillespie, D E; Salazar, N A; Rehkopf, D H et al. (1999) The fragmented mitochondrial ribosomal RNAs of Plasmodium falciparum have short A tails. Nucleic Acids Res 27:2416-22