ISOPRENOID ANALOGS AS CHEMICAL GENETIC TOOLS TO PROVIDE INSIGHTS INTO FARNESYL TRANSFERASE TARGET SELECTION AND CELLULAR ACTIVITY

摘要: Protein farnesylation is an essential post-translational modification required for the function of numerous cellular proteins including oncoprotein Ras. The farnesyl transferase (FTase) catalyzed reaction unique because diphosphate (FPP), group donor reaction, forms a significant portion target protein binding site. major goal this research was to exploit property FTase and determine if changing structure would affect targeting. A small library structural analogues FPP synthesized. Michelis-Menten steady-state kinetic analyses competition reactions were used effect these modifications on We found that did selectivity could be exploited induce unnatural into enzyme. The second proteins. To test we determined whether lipid ablate oncogenic H-Ras biological in Xenopus laevis model system. Several able disrupt while others mimicked activity FPP. These results indicated some may act prenyl inhibitors lead important new class anti-cancer therapeutics. Another use as probes endogenous developed antibodies two study their cell cultureUtilizing alcohol prodrugs incorporated dependent manner. ability permeant live cells enhances chances such molecule modify with inhibitor.