Abbreviated Journal Title
J. Biol. Chem.
Keywords
GERANYLGERANYLTRANSFERASE TYPE-I; MALARIA PARASITES; CRYSTAL-STRUCTURE; DRUG-RESISTANCE; BETA-SUBUNIT; TRANSFERASE; EXPRESSION; BINDING; CLONING; DESIGN; Biochemistry & Molecular Biology
Abstract
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 beta subunit in resistant parasites. The resultant tyrosine 837 to cysteine alteration in the beta 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.
Journal Title
Journal of Biological Chemistry
Volume
280
Issue/Number
14
Publication Date
1-1-2005
Document Type
Article
Language
English
First Page
13554
Last Page
13559
WOS Identifier
ISSN
0021-9258
Recommended Citation
Eatman, Richard T.; White, John; Hucke, Oliver; Bauer, Kevin; Yokoyama, Kohei; Nallans, Laxman; Chakrabarti, Debopam; Verlinde, Christophe L. M. J.; Gelb, Michael H.; Rathod, Pradipsinh K.; and Van Voorhis, Wesley C., "Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum" (2005). Faculty Bibliography 2000s. 5154.
https://stars.library.ucf.edu/facultybib2000/5154
Comments
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