GGTase

Geranylgeranyltransferase (GGTase) refers to a family of enzymes that catalyze the transfer of the 20-carbon geranylgeranyl group from geranylgeranyl pyrophosphate (GGPP) to cysteine residues on select substrate proteins. This lipid modification, known as geranylgeranylation, increases protein hydrophobicity and promotes stable association with cellular membranes, which is often required for proper localization and signaling activity. It is distinct from gamma-glutamyl transferase, a liver enzyme involved in glutathione metabolism.

GGTase I is a heterodimer consisting of a catalytic subunit and a regulatory subunit. It prenylates proteins bearing a CaaX motif at their C-terminus, attaching a geranylgeranyl group to the cysteine residue. Classical substrates include members of the Rho family of small GTPases and several kinases and cytoskeletal regulators. The reaction uses GGPP as the donor and is typically followed by proteolytic processing and methylation to produce the mature membrane-anchored protein.

GGTase II, or Rab geranylgeranyltransferase, is another heterodimer that requires Rab escort proteins (REPs) to deliver Rab GTPases to the enzyme. It modifies Rab family members, often with CXC or CC motifs at their C-termini, thereby promoting their proper membrane anchoring and participation in vesicular trafficking. The reaction also uses GGPP as the donor substrate.

Geranylgeranylation is essential for many cellular processes, including signal transduction, cytoskeletal organization, and vesicular transport. Dysregulation of GGTase activity has been linked to cancer and neurodegenerative diseases, making prenyltransferases targets for therapeutic intervention. Specific GGTase inhibitors have been described and studied in research settings, though clinical development has faced challenges related to toxicity and compensatory pathways.