Protein Synthesis And Developmental Transitions In Plasm

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Abstract

The malaria parasite, Plasmodium falciparum, develops within in human erythrocytes while isolated from its environs by the parasitophorous membrane vacuole(PVM). The PVM is a barrier that serves a number of purposes including opening and closing gates that allows the trafficking of both large and small molecules in either direction. We have identified one of the PVM associated etramp molecules as being involved in p-aminobenzoic acid (pABA) transport to the parasite, We demonstrate that the presence of pABA selectively influences the transcription of this PVM associated protein and suggest that this serves as a mechanism to build substrate to support DNA. The work may have important implications for antifolate drug therapy and yield information on the dynamics of the PVM and the control of DNA synthesis in malaria parasites. [unreadable] [unreadable] PABA is a precursor in the synthesis of folates and hence is essential for DNA synthesis. Although the parasites can grow in the absence of PABA it has been proposed that the synthesis of pABA is induced only when there is a need for it and that the parasites synthetic pathway is regulated by the concentration of products. Hence the parasite synthesizes pABA in response to severe conditions. The mechanism of drug action involves competition for the binding site of dihydoropterroate synthase(DHPS), an essential enzyme for DNA synthesis. While resistance could arise that relate to transport of drug through the PVM other possibilities exist including metabolic detoxification, variation of the molecular target or mechanisms to circumvent drug action., Transport defects have been reported and appear to be a major factor in resistance. [unreadable] [unreadable] We isolated a series of auxotrophic mutants that are dependent upon exogenous p-aminobenzoic acid for growth. As a potential mechanism for dependency on exogenous we have screened our bank of PABA dependant clones for transport mutants and have analyzed their response to exogenous PABA/mutant holds the potential of further defining the PVM and a mechanism of uptake of aromatic compounds[unreadable] [unreadable] Plasmodium species face dramatic but predictable environmental changes during their life cycles, to which they must respond. These include predictable changes in temperature and the availability of nutrients. The transmission of Plasmodium falciparum from human to mosquito involves a temperature drop for the parasite. This temperature drop signals the parasites cellular machinery and activates transcriptional change. We used micro-array analysis to monitor the transcriptional changes that are solely related to this temperature change. Expression of one gene was stimulated 135 fold by lowering the temperature of the asexual parasite from 37?C to 26?C. The transcript is a non-coding RNA whose gene is positioned immediately 5? to the S type ribosomal RNA genes and is under the control of a polymerase I promoter. The extent of transcription change is directly related to the extent of temperature change at transmission. The study has implications for understanding how the parasite senses and responds to environmental change.[unreadable] The increase in temperature of the parasite has defined but different effects on the parasite than the cold shock. Intermittent episodes of febrile illness is the most benign and recognized symptom of infection with malaria parasites, although its effect on the parasite survival and virulence remains unclear.