Protein Prenyltransferases

Abstract

AbstractProtein prenyltransferases (PPT) are Zn metalloenzymes that catalyze the covalent attachment of farnesyl or geranylgeranyl isoprenoids to the C‐terminal cysteine residue(s) of many cellular proteins involved in signal transduction and intracellular vesicle transport. There are three subfamilies of protein prenyltransferases: protein farnesyltransferase (PFT), protein geranylgeranyltransferase type I (PGGT‐I), and protein geranylgeranyltransferase type II (PGGT‐II) or Rab geranylgeranyltransferase (RabGGT). All members of PPT are heterodimers composed of an α‐ and a β‐subunit. The crystal structures of PFT, RabGGT, and, in particular, the complex structures of PFT with its substrates or product elucidated the active site configuration and substrate‐binding mode of these enzymes. An intrinsically bound Zn ion was found to be coordinated to an aspartate, a cysteine, and a histidine residue from the β‐subunit. This Zn ion has been shown to be directly involved in the catalysis by activating the protein substrate cysteine thiol for the nucleophilic attack on the C1 atom of the farnesyl or geranylgeranyl diphosphate. PFT has been a primary anticancer drug target, and extensive biochemical and structural studies have been conducted on the kinetics and mechanistic aspects of the enzyme. Progress has also been made in the structural and enzymological studies of RabGGT and PGGT‐I.