DIFFERENT ANALOGS OF FARNESYL PYROPHOSPHATE INHIBIT SQUALENE SYNTHASEAND PROTEIN-FARNESYLTRANSFERASE TO DIFFERENT EXTENTS

The inhibitory potency of farnesyl pyrophosphate analogues was investi gated on two farnesyl pyrophosphate-consuming enzymes: squalene syntha se, a secondary regulation site in the cholesterol synthesis pathway, and protein:farnesyl transferase, which plays a role in the function o f Ras-proteins. For the transferase determination a rapid in vitro ass ay, using Sepharose-bound Ras-peptides, was developed. The distinct fa rnesyl pyrophosphate analogues showed a different order of potency in the inhibition of these two enzymes. Using the farnesyl transferase as say with pre-p21(Ha-ras) as substrate the same result was obtained. Th e difference observed in the in vitro assays was also reflected in the inhibition of cholesterol synthesis, protein prenylation in general a nd Ha-ras farnesylation in Rat-1.H-ras13 cells, a rat fibroblast cell line that overproduces human p21(Ha-ras) This work shows that farnesyl pyrophosphate analogues can be developed for specific inhibition of d ifferent processes such as cholesterol synthesis and protein prenylati on.