Protein prenyltransferase

Protein prenyltransferase refers to a family of enzymes that catalyze the covalent attachment (prenylation) of isoprenoid groups (farnesyl or geranylgeranyl) to specific cysteine residues at the C-terminus of target proteins, typically at a CAAX motif[1][3][4][7]. The main subclasses in humans are farnesyltransferase (FTase), geranylgeranyltransferase type I (GGTase-I), and Rab geranylgeranyltransferase (GGTase-II)[3][4]. Prenylation is an irreversible lipid modification that enables proteins, especially small GTPases like those in the Ras superfamily, to associate with cell membranes, thereby regulating localization, protein–protein interactions, signal transduction, and activity[3][4][6]. Dysregulation or aberrant prenylation contributes to numerous diseases, notably cancer, since mutant Ras proteins require prenylation for membrane attachment and oncogenic activity[3][6]. This has made protein prenyltransferases attractive, though challenging, drug targets for cancer and other indications including cardiovascular, neurodegenerative, parasitic, and bone diseases[3]. Inhibitors of FTase (FTIs) and GGTase (GGTIs) have been developed and assessed as potential therapeutics, though resistance mechanisms and off-target effects have limited their clinical impact[3][6]. The mechanism involves transfer of the isoprenoid moiety from its diphosphate donor (FPP or GGPP) to the cysteine residue of substrate proteins via a thioether linkage, leading to altered membrane association and function of those proteins[3][4][1].

Other names

FarnesyltransferaseGeranylgeranyltransferaseProtein farnesyltransferaseProtein geranylgeranyltransferaseProtein prenyl transferase

Inhibition of farnesylation or geranylgeranylation of proteins (especially Ras or Rho family GTPases), Disruption of membrane localization and cellular signaling, Blocking small GTPase activity