The two primary subclasses of prenyltransferases are farnesyltransferases (FTases) and geranylgeranyltransferases (GGTases), which differ in their substrate specificity. FTases transfer a farnesyl group (C15) to cysteine residues near the carboxyl terminus of target proteins, often Ras family GTPases, facilitating their membrane association. GGTases, on the other hand, can be further divided into type I (GGTase-I) and type II (GGTase-II) enzymes. GGTase-I transfers a geranylgeranyl group (C20) to the C-terminal cysteine of proteins such as Rab GTPases, while GGTase-II, also known as Rab geranylgeranyltransferase, catalyzes the addition of two geranylgeranyl groups to the two C-terminal cysteines of Rab proteins.
Prenyltransferases are typically heterodimeric enzymes composed of an α-subunit and a β-subunit, with the β-subunit providing the catalytic activity. The specificity of these enzymes is determined by the α-subunit, which recognizes and binds to the target protein. Dysregulation of prenyltransferase activity has been implicated in various diseases, including cancer, where aberrant prenylation of signaling proteins can promote oncogenic transformation. Consequently, prenyltransferase inhibitors have been explored as potential therapeutic agents, particularly in targeting Ras mutations that drive tumor growth.
Structurally, prenyltransferases share a conserved fold that facilitates the transfer of the isoprenoid moiety from the pyrophosphate donor to the acceptor protein. The reaction mechanism involves nucleophilic attack by the cysteine residue of the target protein on the α-carbon of the prenyl pyrophosphate, leading to the formation of a thioether linkage. Understanding the biochemical properties and regulation of prenyltransferases continues to be an active area of research, with implications for both fundamental biology and disease treatment.