Title

Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum

Authors

Authors

R. T. Eastman; J. White; O. Hucke; K. Bauer; K. Yokoyama; L. Nallan; D. Chakrabarti; Clmj Verlinde; M. H. Gelb; P. K. Rathod;W. C. Van Voorhis

Comments

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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

WOS:000228095500047

ISSN

0021-9258

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