Natural inhibitors for protein prenyltransferase

Farnesyl protein transferase (FPT) catalyzes the posttranslational farnesylation of the cysteine residue located in the carboxyl-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for membrane association and cell transforming activities of Ras. Inhibitors of FPT have been demonstrated to inhibit Ras-dependent cell transformation and thus represent a potential therapeutic strategy for the treatment of human cancers (1). In the present study, the inhibitory principles for protein prenyltransferases were isolated and identified from Ganoderma lucidum and garlic. The inhibitors from Ganoderma lucidum were identified as ganoderic acid A and ganoderic acid C by comparison with the reported spectral data. Ganoderic acid A has an IC50 value of 100 mu M against FPT and its methyl ester (methyl ganoderate A) has an IC50 value of 38 mu M for the same enzyme. These inhibitors appear to be competitive with farnesyl pyrophosphate (FPP), and K-i values of ganoderic acid A and methyl ganoderate A are 54 mu M and 20 mu M, respectively. The inhibitors from garlic were identified as diallyl thiosulfinate (allicin), methyl allyl thiosulfinate, and allyl methyl thiosulfinate. These inhibitors are more effective against geranylgeranyl protein transferase (GGPT) than FPT and IC50 values of allicin, methyl allyl thiosulfinate, and allyl methyl thiosulfinate for GGPT were 43 mu M, 57 mu M, and 53 mu M, respectively, Methyl allyl thiosulfinate appears to be competitive with geranylgeranyl pyrophosphate (GGPP) and its K-i was determined to be 15 mu M. The molecular structures of triterpenes and thiosulfinates are expected to be useful in designing lead compounds for new potent antitumour agents.