In the late-1980s, the structures of prenyl groups attached to proteins in mammalian cells were determined by Gelb, Glomset, and their coworkers (3). Protein prenylation involves the attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal cysteine residues of a specific set of proteins. Many of these prenylated proteins are small GTPases including Ras, Rab, Rac, and Rho that play a role in cellular signal transduction and intracellular vesicle trafficking (4). The y-subunits ofheterotrimeic G proteins, nuclear lamins, multiple proteins in the phototransuction cascade, and viral antigens are other examples of prenylated proteins (5). The functions of protein prenyl groups are not fully understood, but they play a role in binding proteins to membranes and to direct interactions with other proteins (4).
The farnesylation of Ras is absolutely essential for the ability of this protein to transform mammalian cells (6). Thus, there is currently intense medicinal interest in protein prenylation. The enzyme that attaches the farnesyl group to proteins, protein farnesyl-transferase (FTase), is a target for anticancer drugs. In fact, several hundred potent FTase inhibitors (FTIs) have been reported over the past few years (7). Clinical trials with FTIs for the treatment of cancer have been initiated because such compounds are much less toxic than expected to normal cells in culture and to experimental animals, and they cause shrinkage of tumors implanted into animals (Chapters 4-9 and 13 of this volume).
There are three protein prenyltransferases in mammals (8,9). FTase transfers the farnesyl group from farnesyl pyrophosphate (FPP) to the cysteine SH ofthe C-terminal protein sequence CAAX (A is usually but not necessarily an aliphatic residue, and X is usually S, M, Q, A). Protein geranylgeranyltransferase I (GGTase I) transfers the 20-carbon geranylgeranyl group from geranylgeranyl pyrophosphate (GGPP) to CAAX (when X is L or F). Finally, GGTase II (also called Rab geranylgeranyltransferase) attaches two geranylgeranyl groups to both cysteines at the end of Rab proteins. The X-ray structures of rat FTase and the complex of the enzyme with substrates and inhibitors have been obtained (10-12). After prenylation ofthe CAAX sequence, the last three residues (AAX) are removed by an endoprotease. The new C-terminal S-prenyl-cysteine is methylated on its a-carboxyl group. Both of these steps occur in the endoplasmic reticulum (13,14).
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