15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum

Ramya, TNC and Karmodiya, Krishanpal and Surolia, Avadhesha and Surolia, Namita (2007) 15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum. In: Journal of Biological Chemistry, 282 (9). pp. 6388-6397.

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Abstract

15-Deoxyspergualin, an immunosuppressant with tumoricidal and antimalarial properties, has been implicated in the inhibition of a diverse array of cellular processes including polyamine synthesis and protein synthesis. Endeavoring to identify the mechanism of antimalarial action of this molecule, we examined its effect on Plasmodium falciparum protein synthesis, polyamine biosynthesis, and transport. 15-Deoxyspergualin stalled protein synthesis in P. falciparum through Hsp70 sequestration and subsequent phosphorylation of the eukaryotic initiation factor $eIF2\alpha$. However, protein synthesis inhibition as well as polyamine depletion were invoked only by high micromolar concentrations of 15-deoxyspergualin, in contrast to the submicromolar concentrations sufficient to inhibit parasite growth. Further investigations demonstrated that 15-deoxyspergualin in the malaria parasite primarily targets the hitherto underexplored process of trafficking of nucleus-encoded proteins to the apicoplast. Our finding that 15-deoxyspergualin kills the malaria parasite by interfering with targeting of nucleus-encoded proteins to the apicoplast not only exposes a chink in the armor of the malaria parasite, but also reveals new realms in our endeavors to study this intriguing biological process.

Item Type:	Journal Article
Publication:	Journal of Biological Chemistry
Publisher:	American Society for Biochemistry and Molecular Biology
Additional Information:	Copyright of this article belongs to American Society for Biochemistry and Molecular Biology.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	30 May 2008
Last Modified:	19 Sep 2010 04:45
URI:	http://eprints.iisc.ac.in/id/eprint/14130

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