Inhibition of farnesyl-protein transferase by gliotoxin and acetylgliotoxin.

Ras p21 proteins have been shown to be posttranslationally farnesylated on a specific carboxyterminal cysteine1 ^. Inhibition of this isoprenylation would alter membrane localization and activation of ras oncogene40. Therefore during our screening for farnesyl-protein transferase (FTase) inhibitors of microbial origin we have isolated gliotoxin (GT) and acetylgliotoxin (AGT) from the fermentation broth of a fungus. GT and AGT are known as fungal epipolythiodiketopiperazine toxin5) and showed a broad spectrum of activity including inhibition of fungi, bacteria and viruses6). This paper reports the inhibition of FTase by GT and AGTlikely in their reduced form. In addition we show that bisdethiobis(methylthio)-GT and bisdethiobis(methylthio)-AGT chemically prepared from GT and AGT failed to inhibit FTase. GT and AGT(Fig. 1) were isolated from the culture of fungus strain FO2047. After fermentation at 27°C for 4 days, the whole broth (20 liters) was extracted with CHC13(20 liters). The extract was concentrated to dryness and the residue (28.4 g) was applied to a silica gel column. The active