Farnesyltransferase (FTase), Geranylgeranyltransferase (GGTase), & Methyltransferase Inhibitors
Prenylation is carried out by cytoplasmic enzymes known as geranylgeranyltransferases and farnesyltransferases that covalently attach 20-carbon (geranylgeranyl) or 15-carbon (farnesyl) isoprenoids to the C-terminus of intracellular proteins via thioether linkages. Protein farnesyltransferase I (FTase I) and protein geranylgeranyltransferase I (GGTase I) recognize a CAAX motif as substrate, where C is cysteine, A represents any aliphatic amino acid, and X is either serine or methionine (FTase I), or leucine (GGTase I). The Rab GGTase II attaches geranylgeranyl groups to proteins that terminate in either CC or CXC motifs. Many proteins in signal transduction pathways are prenylated. Perhaps the best-characterized farnesylation products are the Ras ATPases. Ras is a guanine nucleotide binding protein that transduces growth and differentiation signals from receptor tyrosine kinases to the nucleus. Mammalian cells express four types of Ras; H-, N-, KA-, and KB-Ras. Mutated or oncogenic forms of Ras require farnesylation for their ability to transform cells. Peptidomimetics designed against the Ras CAAX motif have been shown to reverse oncogenic transformation by H-Ras and inhibit growth of H-Rastransformed cells. Hence, several types of FTase inhibitors have been designed for use as potential anticancer agents. Since Ras proteins are posttranslationally modified by FTase and carboxymethylation and they act as a common focal point for signals from growth factor receptors, use of FTase inhibitors is likely to interfere with their action and impede cell proliferation. These inhibitors can be divided into four groups based on the mechanism of their action: (1) competitive inhibitors of farnesyl PPi, (2) peptidomimetic inhibitors based on the CAAX motif, (3) bisubstrate inhibitors, and (4) inhibitors with unknown mechanisms. CAAX peptidomimetics can either function as alternative substrates in the FTase catalyzed reaction, or they can competitively inhibit FTase without serving as substrates.
References:
Mazieres, J., et al. 2004. Cancer Lett. 206, 159.
Sebti, S.M., and Adjei, A.A. 2004. Semin. Oncol. 31 (Suppl 1), 28.
Head, J.E., and Johnston, S.R. 2003. Expert Opin. Emerg. Drugs 8, 163.
Casey, P.J., and Seabra, M.C. 1996. J. Biol. Chem. 271, 5289.
Lerner, E.C., et al. 1995. J. Biol. Chem. 270, 26802.
Kelloff, G.J., et al. 1997. Cancer Epidemiol. Biomarkers Prev. 6, 267.
