title: Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds.
abstract: Upon farnesylation by protein farnesyltransferase (FTase), key proteins become compartmentalized in cells. For example, cell membrane localization is essential for the mitogenic role of mutant Ras protein, which acts as a switch for cancer cell proliferation. We report that alpha-dicarbonyl compounds derived from the isoprenoid skeleton or other hydrophobic groups potently obstruct farnesylation of a Ras model peptide by human recombinant FTase in vitro. A geranyl-derived isoprenoid diketone, 5,9-dimethyl-8-decene-2,3-dione, at 17 microM caused a 62% reduction in FTase activity after 30 minutes. A farnesyl-derived isoprenoid diketone, 5,9,13-trimethyl-8,12-tetradecadiene-2,3-dione, at 93 microM caused a 94% reduction after 30 minutes. Other dicarbonyl compounds found to be effective against FTase in vitro were (+/-)-6-(camphorquinone-10-sulfonamido)-hexanoic acid, 4,4'-biphenyldiglyoxaldehyde, dehydroascorbic acid 6-palmitate, 2-oxododecanal, and phenylglyoxal. Higher concentrations of the alpha-dicarbonyl compound resulted in more rapid and more extensive inactivation. These findings demonstrate that alpha-dicarbonyl compounds targeted to FTase interfere with protein farnesylation in vitro and may lead to derivatives that have utility as chemotherapeutic agents.
authors.affiliation: Department of Chemistry and Biochemistry, PO Box 871604, Arizona State University, Tempe, AZ 85287-1604, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Okolotowicz
authors.forename: W J
authors.initials: WJ
authors.lastname: Lee
authors.forename: R F
authors.initials: RF
authors.lastname: Hartman
authors.forename: A Y
authors.initials: AY
authors.lastname: Kim
authors.forename: S R
authors.initials: SR
authors.lastname: Ottersberg
authors.forename: D E
authors.initials: DE
authors.lastname: Robinson
authors.forename: S R
authors.initials: SR
authors.lastname: Lefler
authors.forename: S D
authors.initials: SD
authors.lastname: Rose
mesh_terms: D000475:Alkenes / Q000737:chemistry* / Q000494:pharmacology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D001665:Binding Sites / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics
chemical_list: C433671:5,9-dimethyl-8-decene-2,3-dione; D000475:Alkenes; D004791:Enzyme Inhibitors; D007659:Ketones; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase