Document Detail

Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds.
MedLine Citation:
PMID:  11475909     Owner:  NLM     Status:  MEDLINE    
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.
K J Okolotowicz; W J Lee; R F Hartman; A Y Kim; S R Ottersberg; D E Robinson; S R Lefler; S D Rose
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archiv der Pharmazie     Volume:  334     ISSN:  0365-6233     ISO Abbreviation:  Arch. Pharm. (Weinheim)     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-07-30     Completed Date:  2001-08-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0330167     Medline TA:  Arch Pharm (Weinheim)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  194-202     Citation Subset:  IM    
Department of Chemistry and Biochemistry, PO Box 871604, Arizona State University, Tempe, AZ 85287-1604, USA.
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MeSH Terms
Alkenes / chemistry*,  pharmacology*
Alkyl and Aryl Transferases / antagonists & inhibitors*
Binding Sites / drug effects
Enzyme Inhibitors / chemistry*,  pharmacology*
Ketones / chemistry*,  pharmacology*
Reg. No./Substance:
0/5,9-dimethyl-8-decene-2,3-dione; 0/Alkenes; 0/Enzyme Inhibitors; 0/Ketones; EC 2.5.-/Alkyl and Aryl Transferases; EC 2.5.1.-/p21(ras) farnesyl-protein transferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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