Prenyl transferase, inhibition

Fig. 22 Monophosphate prodrugs that inhibit prenyl transferases...

Inhibition of Isopentenyl Pyrophosphate Isomerase and Prenyl Transferase... 

GGTase-I [5], The specificities of FTase and GGTase are not absolute, and cross prenylation occurs which can be observed more readily for some substrates when one of the enzyme is inhibited. For example, K-Ras and N-Ras, which are the usual substrates for FTase, can be geranylgeranylated when the activity of FTase is suppressed [6]. The second and last steps of the modification process occur on the ER membrane and are catalyzed by Ras converting enzyme 1 (Reel) and isoprenylcysteine carboxylmethyl transferase (Icmt), both unique enzymes modify both farnesylated and geranylgeranylated proteins [1,7]. 

Consequences for the so-called segregation model ofisoprenoid biosynthesis The presence of such alternative pathways as outlined above could provide a further explanation for the observations obtained with the HMGR inhibitor mevinolin, viz. its great efficiency in blocking cytoplasmic sterol biosynthesis, but its low efficiency to affect ubiquinone biosynthesis, and its practically complete inefficiency to block the accumulation of isoprenoids and prenyl lipids of the chloroplast (summarized and discussed earlier 14, 17]. It could also explain the puzzling observation that, in contrast to phytosterols, prenyl-subsituted coumarins were not labeled from [2- ]acetate or [2- C]MVA in elicitor-treated cultures oiAmnd majus, suggesting that the DMAPP needed for the (plastid ) umbelliferone dimethylallyl transferases (EC 2.5.1.3) is formed from IPP synthesized de novo within the plastid, rather than from IPP imported into the plastid from the cytosol [86]. Elicitor-induced inhibition of phytosterol biosynthesis should occur by specific inhibition of one of the enz)ones on the c) osolic pathway from MVA to DMAPP. 

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