title: Resistance to a protein farnesyltransferase inhibitor in Plasmodium falciparum.
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.
authors.affiliation: Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Oliver
authors.initials: O
authors.lastname: Hucke
authors.forename: Kevin
authors.initials: K
authors.lastname: Bauer
authors.forename: Kohei
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Laxman
authors.initials: L
authors.lastname: Nallan
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D016415:Sequence Alignment
chemical_list: D007093:Imidazoles; D021122:Protein Subunits; D015800:Protozoan Proteins; D011804:Quinolines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase