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J. Biol. Chem., Vol. 282, Issue 9, 6388-6397, March 2, 2007

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

T. N. C. Ramya¹, Krishanpal Karmodiya, Avadhesha Surolia, Recipient of a grant from the Center of Excellence, DBT^¶2, and Namita Surolia³

From the Indian Institute of Science, Bangalore 560012, India, the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India, and the ^¶National Institute of Immunology, New Delhi 110067, India

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. 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.

Received for publication, November 2, 2006 , and in revised form, December 27, 2006.

^* This work was supported in part by the Dept. of Biotechnology (DBT), Government of India (to N. S. and A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Council of Scientific and Industrial Research Senior Research Fellowship.

² To whom correspondence may be addressed: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Tel.: 91-11-26717102; Fax: 91-11-26717104; E-mail: surolia{at}nii.res.in. ³ To whom correspondence may be addressed: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India. Tel.: 91-80-22082821; Fax: 91-80-22082766; E-mail: surolia{at}jncasr.ac.in.

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