Document Detail


Inactivation of protein farnesyltransferase by active-site-targeted dicarbonyl compounds.
MedLine Citation:
PMID:  11475909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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    
Affiliation:
Department of Chemistry and Biochemistry, PO Box 871604, Arizona State University, Tempe, AZ 85287-1604, USA.
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MeSH Terms
Descriptor/Qualifier:
Alkenes / chemistry*,  pharmacology*
Alkyl and Aryl Transferases / antagonists & inhibitors*
Binding Sites / drug effects
Enzyme Inhibitors / chemistry*,  pharmacology*
Ketones / chemistry*,  pharmacology*
Kinetics
Chemical
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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