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J. Biol. Chem., Vol. 280, Issue 14, 13554-13559, April 8, 2005

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Resistance to a Protein Farnesyltransferase Inhibitor in Plasmodium falciparum^*

Richard T. Eastman, John White, Oliver Hucke¶, Kevin Bauer||, Kohei Yokoyama**, Laxman Nallan**, Debopam Chakrabarti, Christophe L. M. J. Verlinde, Michael H. Gelb**, Pradipsinh K. Rathod**, and Wesley C. Van Voorhis||¶¶

From the Departments of Pathobiology, Biochemistry, ^||Medicine, and ^**Chemistry, University of Washington, Seattle, Washington 98195 and the Department of Molecular Biology and Microbiology, University of Central Florida, Orlando, Florida 32826

The post-translational farnesylation of proteins serves to anchor a subset of intracellular proteins to membranes in eukaryotic organisms and also promotes protein-protein interactions. Inhibition of protein farnesyltransferase (PFT) is lethal to the pathogenic protozoa Plasmodium falciparum. Parasites were isolated that were resistant to BMS-388891, a tetrahydroquinoline (THQ) PFT inhibitor. Resistance was associated with a 12-fold decrease in drug susceptibility. Genotypic analysis revealed a single point mutation in the subunit in resistant parasites. The resultant tyrosine 837 to cysteine alteration in the subunit corresponded to the binding site for the THQ and peptide substrate. Biochemical analysis of Y837C-PFT demonstrated a 13-fold increase in BMS-388891 concentration necessary for inhibiting 50% of the enzyme activity. These data are consistent with PFT as the target of BMS-388891 in P. falciparum and suggest that PFT inhibitors should be combined with other antimalarial agents for effective therapy.

Received for publication, December 2, 2004 , and in revised form, January 11, 2005.

^* This work was supported by the W. M. Keck Foundation Center on Microbial Pathogens at the University of Washington, Medicines for Malaria Venture, and National Institutes of Health Grants AI26912 and AI60360 (to P. K. R.) and AI054384 (to M. H. G.). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY880030, AY880031, AY880032, AY880033, and AY880034.

^¶ Fellow of the German Academy of Natural Scientists Leopoldina (BMBF-LPD 9901/8-77).

Senior Scholar in Global Infectious Diseases, Ellison Medical Foundation.

^¶¶ To whom correspondence should be addressed: Dept. of Medicine, University of Washington, 1959 N.E. Pacific, Seattle, WA 98195-7185. Tel.: 206-543-2447; Fax: 206-685-8681; E-mail: wesley{at}u.washington.edu.

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