Protein synthesis is a fundamental requirement for the development of an organism and a prime target for antibiotic action. There are five separate and essential protein synthesis systems that function at different points during the development of Plasmodium species making the control of protein synthesis fundamentally different in the parasite from its human host. The expression of distinct rRNAs suggests that changing the central catalytic component of the ribosome, the rRNA, is a trigger for development. We are presently investigating both transcriptional control of both Plasmodium messenger RNA and the distinct rRNA genes. Special interest has been directed to putative functional differences between the rRNAs and control regions of messenger RNAs. We would expect to see coordinate control of different ribosomes and stage specific protein. To date, we have found that core differences among the rRNA genes concentrate in the site for stimulation of GTP hydrolysis in a manner that may be predicted to modulate its catalytic activity. Hydrolysis of GTP is a key regulatory step in other systems and, therefore, we predict that alteration of the site may trigger the development of the parasite. The control regions of messenger RNAs that are expressed differentially in different stages of the life cycle, like the circumsporozoite protein message, have revealed consistent differences that appear to correlate with changes in ribosomes. The effect of these changes are currently being investigated in vivo by gene replacement and selective drug targeting of genes, and in vitro by transcription of synthetic genes with T7 RNA polymerase. In a related study, we are examining structure-function relationships of the circumsporozoite protein. It is a central vaccine target and yet no one knows much about either structure or function. In the process of looking at expression and control regions of the protein we have made both wild type and mutated versions of the protein and are investigating the parasite invasion process.
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