Isoprenoid modifications

Up to 2% of the mammalian proteome is post-translationally modified with isoprenes (Gelb 1997). The first prenylated polypeptides reported were secreted pheromone peptides identified in jelly fungi (Sakagami et al. 1978; Tsuchiya et al. 1978). The structure of these peptides resembled the a-factor mating pheromone from S. cerevisiae and contained a farnesylated cysteine methylester at the C terminus (Anderegg et al. I 988). Several parallel studies by groups working on cholesterol biosynthesis reported that a mevalonic acid derivative, other than cholesterol, could be specifically incorporated into proteins (Maltese and Sheridan 1987; Schmidt et al. 1984 ). Subsequently it became clear that protein prenylation is characterized by the attachment of a farnesyl or a geranylgeranyl moiety to one or two C-terminal cysteine residues via a thioether linkage. Three different protein prenyltransferases have been identified in eukaryotes: farnesyltransferase (FTase), geranylgeranyltransferase- l(GGTase-l), andRabgeranylgeranyltransferase(RabGGTase) (Casey and Seabra 1996; Maurer-Stroh et al. 2003). FTase and GGTase-I recognize their substrates via a short C-terminal recognition sequence, referred to as the CAAX box, where C is a cysteine, A is an aliphatic amino acid and X is variable but bi(;lsed depending on the prenyltransferase (Table I . l ). In contrast to FTase and GGTase-1, protein substrate recognition by RabGGTase is more complex, requiring a partner protein, Rab escort protein (REP) for substrate recruitment (Fig. 1.1 )