PHOTOREACTIVE ANALOGS OF PRENYL DIPHOSPHATES AS INHIBITORS AND PROBES OF HUMAN PROTEIN FARNESYLTRANSFERASE AND GERANYLGERANYLTRANSFERASE TYPE-I

被引:46
作者
BUKHTIYAROV, YE
OMER, CA
ALLEN, CM
机构
[1] UNIV FLORIDA,J HILLIS MILLER HLTH CTR,DEPT BIOCHEM & MOLEC BIOL,GAINESVILLE,FL 32610
[2] MERCK SHARP & DOHME LTD,RES LABS,DEPT CANC RES,W POINT,PA 19486
关键词
D O I
10.1074/jbc.270.32.19035
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Photoreactive analogues of prenyl diphosphates have been useful in studying prenyltransferases. The effectiveness of analogues with different chain lengths as probes of recombinant human protein prenyltransferases is established here. A putative geranylgeranyl diphosphate analogue, 2-diazo-3,3,3-trifluoropropionyloxy-farnesyl diphosphate (DATFP-FPP), was the best inhibitor of both protein farnesyltransferase (PFT) and protein geranylgeranyltransferase-I (PGGT-I), Shorter photoreactive isoprenyl diphosphate analogues with geranyl and dimethylallyl moieties and the DATFP-derivative of farnesyl monophosphate were much poorer inhibitors. DATFP-FPP was a competitive inhibitor of both PFT and PGGT-I with K-i values of 100 and 18 nM, respectively, [P-32]DATFP-FPP specifically photoradiolabeled the beta-subunits of both PFT and PGGT-I. Photoradiolabeling of PGGT-I was inhibited more effectively by geranylgeranyl diphosphate than farnesyl diphosphate, whereas photoradiolabeling of PFT was inhibited better by farnesyl diphosphate than geranylgeranyl diphosphate. These results lead to the conclusions that DATFP-FPP is an effective probe of the prenyl diphosphate binding domains of PFT and PGGT-I. Furthermore, the beta-subunits of protein prenyltransferases must contribute significantly to the recognition and binding of the isoprenoid substrate.
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页码:19035 / 19040
页数:6
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