isoprenyltransferase

Isoprenyltransferases are enzymes that catalyze the covalent attachment of isoprenoid groups to acceptor molecules, a modification that often promotes membrane association and alters protein interactions. The transfer uses prenyl pyrophosphate donors, such as farnesyl pyrophosphate or geranylgeranyl pyrophosphate, and results in a thioether linkage between the cysteine of the substrate and the isoprenoid chain.

The best known examples are protein farnesyltransferase (FTase) and protein geranylgeranyltransferases type I and II (GGTase I and GGTase II). FTase transfers a farnesyl group from farnesyl pyrophosphate to cysteine within a CaaX motif at the C-terminus of many signaling proteins. GGTase I transfers a geranylgeranyl group from geranylgeranyl pyrophosphate to the same CaaX motif on other substrates. GGTase II, also called Rab geranylgeranyltransferase, transfers two geranylgeranyl groups to Rab GTPases, and requires Rab escort protein (REP) to deliver substrates. Substrate motifs and enzyme specificity determine which proteins receive prenylation.

Structurally, FTase and GGTase I are heterodimers composed of alpha and beta subunits. GGTase II is a heterodimer that associates with REP. The reaction generally involves coordination of catalytic cofactors and the oriented presentation of both donor and acceptor; the result is a lipophilic protein that associates with membranes and participates in signaling or vesicular trafficking.

Biological significance and medical relevance stem from the role of prenylated proteins in growth, differentiation, and intracellular transport. Inhibitors of farnesyltransferase and related enzymes have been explored for therapeutic use, notably in cancer, though clinical outcomes have been variable due to compensatory prenylation pathways and protein-specific requirements.