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Antimicrobial Agents and Chemotherapy, September 2001, p. 2553-2558, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2553-2558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Limonene Arrests Parasite Development and Inhibits Isoprenylation of Proteins in Plasmodium falciparum

Ivan Cruz Moura,1,dagger Gerhard Wunderlich,1 Maria L. Uhrig,2 Alicia S. Couto,2 Valnice J. Peres,1 Alejandro M. Katzin,1 and Emília A. Kimura1,*

Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil,1 and CIHIDECAR, Departamento de Química Orgánica, Pabellón II, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina2

Received 9 November 2000/Returned for modification 18 January 2001/Accepted 18 June 2001

Isoprenylation is an essential protein modification in eukaryotic cells. Herein, we report that in Plasmodium falciparum, a number of proteins were labeled upon incubation of intraerythrocytic forms with either [3H]farnesyl pyrophosphate or [3H]geranylgeranyl pyrophosphate. By thin-layer chromatography, we showed that attached isoprenoids are partially modified to dolichol and other, uncharacterized, residues, confirming active isoprenoid metabolism in this parasite. Incubation of blood-stage P. falciparum treated with the isoprenylation inhibitor limonene significantly decreased the parasites' progression from the ring stage to the trophozoite stage and at 1.22 mM, 50% of the parasites died after the first cycle. Using Ras- and Rap-specific monoclonal antibodies, putative Rap and Ras proteins of P. falciparum were immunoprecipitated. Upon treatment with 0.5 mM limonene, isoprenylation of these proteins was significantly decreased, possibly explaining the observed arrest of parasite development.

* Corresponding author. Mailing address: Universidade de São Paulo, Av. Professor Lineu Prestes, 1374, CEP 05508-900, São Paulo, Brazil. Phone: (55) (11) 38187330. Fax: (55) (11) 38187417. E-mail: address: eakimura{at}usp.br.

dagger Present address: Institut National de la Santé et de la Recherche Médicale U25, Necker Hôpital, 75743 Paris, France.

Antimicrobial Agents and Chemotherapy, September 2001, p. 2553-2558, Vol. 45, No. 9
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.9.2553-2558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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