Protein geranylgeranyltransferase type 1 (GGTase-I)

Protein geranylgeranyltransferase type 1 (GGTase-I) is a critical prenyltransferase enzyme responsible for the post-translational modification of proteins containing a C-terminal CAAX motif, where 'X' is typically leucine. It catalyzes the transfer of a 20-carbon geranylgeranyl group from geranylgeranyl pyrophosphate (GGPP) to a cysteine residue, a process essential for the membrane anchoring and functional activation of various signal transduction proteins, most notably members of the Rho and Rac GTPase families. In oncology, GGTase-I is a significant therapeutic target because its substrates, such as RhoA, RhoC, and Rac1, are frequently overexpressed or hyperactivated, driving tumor cell proliferation, survival, and metastasis. Therapeutic strategies primarily focus on small-molecule inhibitors known as GGTIs, which aim to block the prenylation of these oncogenic signaling proteins to induce cell cycle arrest and apoptosis. While early clinical candidates like L-778123 faced challenges regarding potency and specificity, newer generation inhibitors like GGTI-2418 have entered clinical trials for solid tumors. Beyond cancer, GGTase-I is also investigated for its roles in inflammatory and cardiovascular diseases, though achieving a therapeutic window that avoids broad systemic toxicity remains a primary challenge in drug development.

Other names

Geranylgeranyltransferase 1PGGT1Protein geranylgeranyltransferase ICAAX geranylgeranyltransferaseType 1 protein geranylgeranyltransferase

Competitive inhibition of the CAAX substrate binding site or the geranylgeranyl pyrophosphate (GGPP) binding site to prevent the attachment of a 20-carbon isoprenoid lipid to target proteins.