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Mol Biochem Parasitol. 2013 Nov-Dec;192(1-2):39-48. doi: 10.1016/j.molbiopara.2013.10.003. Epub 2013 Nov 6.

The effect of fusidic acid on Plasmodium falciparum elongation factor G (EF-G).

Author information

1
Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India.
2
Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, India.
3
Division of Molecular and Structural Biology, CSIR-Central Drug Research Institute, Lucknow, India. Electronic address: saman.habib@gmail.com.

Abstract

Inhibition of growth of the malaria parasite Plasmodium falciparum by known translation-inhibitory antibiotics has generated interest in understanding their action on the translation apparatus of the two genome containing organelles of the malaria parasite: the mitochondrion and the relic plastid (apicoplast). We report GTPase activity of recombinant EF-G proteins that are targeted to the organelles and further use these to test the effect of the EF-G inhibitor fusidic acid (FA) on the factor-ribosome interface. Our results monitoring locking of EF-G·GDP onto surrogate Escherichia coli ribosomes as well as multi-turnover GTP hydrolysis by the factor indicate that FA has a greater effect on apicoplast EF-G compared to the mitochondrial counterpart. Deletion of a three amino acid (GVG) sequence in the switch I loop that is conserved in proteins of the mitochondrial EF-G1 family and the Plasmodium mitochondrial factor, but is absent in apicoplast EF-G, demonstrated that this motif contributes to differential inhibition of the two EF-Gs by FA. Additionally, the drug thiostrepton, that is known to target the apicoplast and proteasome, enhanced retention of only mitochondrial EF-G on ribosomes providing support for the reported effect of the drug on parasite mitochondrial translation.

KEYWORDS:

Apicoplast; Elongation factor-G; Fusidic acid; Mitochondria; Plasmodium falciparum; Thiostrepton

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