Photoactive analogs of farnesyl pyrophosphate containing benzoylbenzoate esters: Synthesis and application to photoaffinity labeling of yeast protein farnesyltransferase

被引:50
作者
Gaon, I [1 ]
Turek, TC [1 ]
Weller, VA [1 ]
Edelstein, RL [1 ]
Singh, SK [1 ]
Distefano, MD [1 ]
机构
[1] UNIV MINNESOTA,DEPT CHEM,MINNEAPOLIS,MN 55455
关键词
D O I
10.1021/jo9602736
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
Farnesyl pyrophosphate (FPP) is involved in a large number of cellular processes including the prenylation of transforming mutants of Ras proteins implicated in cancer. Photoactive analogs could provide useful information about enzyme active sites that bind farnesyl pyrophosphate; however, the availability of such compounds is extremely limited. Molecules that incorporate benzophenone moieties are attractive photoaffinity labeling reagents because of their useful photochemical properties. Here, the syntheses of two compounds, 3a and 3b, containing para- and meta-substituted benzoylbenzoates are described. Compounds 3a and 3b are competitive inhibitors (with respect to FPP) of yeast protein farnesyltransferase (PFTase) with K-i values of 910 and 380 nM, respectively. Both compounds inactivate PFTase upon photolysis, resulting in as much as 44% inactivation of enzyme activity. Photolysis of PFTase in the presence of [P-32]3a or of [P-32]3b results in preferential labeling of the beta subunit, suggesting that this subunit is involved in prenyl group recognition. These compounds should be valuable tools for studying enzymes that utilize FPP as a substrate.
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页码:7738 / 7745
页数:8
相关论文
共 26 条
[1]  
BABA T, 1985, J BIOL CHEM, V260, P467
[2]   INACTIVATION OF UNDECAPRENYLPYROPHOSPHATE SYNTHETASE WITH A PHOTOLABILE ANALOG OF FARNESYL PYROPHOSPHATE [J].
BABA, T ;
ALLEN, CM .
BIOCHEMISTRY, 1984, 23 (06) :1312-1322
[3]  
Barany G., 1979, PEPTIDES A, V2, P1
[4]  
Bond PD, 1995, METHOD ENZYMOL, V250, P30
[5]   PRENYLATED PROTEINS - A CONVENIENT SYNTHESIS OF FARNESYL CYSTEINYL THIOETHERS [J].
BROWN, MJ ;
MILANO, PD ;
LEVER, DC ;
EPSTEIN, WW ;
POULTER, CD .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (08) :3176-3177
[6]   PHOTOREACTIVE ANALOGS OF PRENYL DIPHOSPHATES AS INHIBITORS AND PROBES OF HUMAN PROTEIN FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE TYPE-I [J].
BUKHTIYAROV, YE ;
OMER, CA ;
ALLEN, CM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (32) :19035-19040
[7]  
BURNNER J, 1993, ANN REV BIOCH, V62, P483
[8]   Farnesyl transferase inhibitors: The successes and surprises of a new class of potential cancer chemotherapeutics [J].
Buss, JE ;
Marsters, JC .
CHEMISTRY & BIOLOGY, 1995, 2 (12) :787-791
[9]  
CHOWDHRY V, 1979, ANNU REV BIOCHEM, V48, P293, DOI 10.1146/annurev.bi.48.070179.001453
[10]   2-DIAZO-3,3,3-TRIFLUOROPROPIONYL CHLORIDE - REAGENT FOR PHOTOAFFINITY LABELING [J].
CHOWDHRY, V ;
VAUGHAN, R ;
WESTHEIMER, FH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1976, 73 (05) :1406-1408