Protein-S-isoprenylcysteine methyltransferase (ICMT) (ICMT)

Protein-S-isoprenylcysteine methyltransferase (ICMT) is an integral membrane enzyme located in the endoplasmic reticulum that catalyzes the final step in the post-translational modification of CaaX proteins, such as Ras and Rho GTPases [UniProt, NIH]. This process involves the S-adenosyl-L-methionine-dependent methylation of the C-terminal prenylated cysteine residue, which increases the protein's hydrophobicity and facilitates its attachment to cellular membranes [PubMed, NIH]. Proper membrane localization is critical for the biological function and signaling of these proteins, many of which are key regulators of cell growth and survival [BenchChem, NIH]. In cancer, oncogenic Ras mutations require ICMT-mediated modification to promote tumor growth and metastasis, making ICMT a high-value target for anti-cancer drug development [NIH, ACS]. Additionally, ICMT inhibition has shown promise in treating Hutchinson-Gilford Progeria Syndrome by preventing the membrane anchoring of progerin, a toxic protein that causes premature aging [NIH, PubMed]. Although no ICMT inhibitors are currently FDA-approved, experimental compounds like cysmethynil and UCM-13207 have demonstrated significant therapeutic potential in preclinical studies by disrupting oncogenic signaling and improving disease hallmarks [ACS, NIH].

Other names

Isoprenylcysteine carboxylmethyltransferasePrenylcysteine carboxyl methyltransferaseProtein carboxylmethyltransferasePCPMHSTE14Ste14 homolog

Inhibition of the carboxyl methylation of prenylated CaaX proteins, preventing their proper membrane localization and functional activation.