Abstract
Protein prenylation is a type of lipid modification involving attachment of either a farnesyl (15- carbon) or geranylgeranyl (20-carbon) isoprenoid group via thioether linkages to the cysteine residues at or near the C-terminus of various eukaryotic proteins. According to their substrate specificity the three known types of prenyltransferases can be categorized in two classes: the farnesyltransferase and geranylgeranyltransferase- I recognize CAAX motifs whereas geranylgeranyltransferase-II recognizes a non-CAAX motif. Protein substrates of prenyltransferases include G-proteins and small GTP-binding proteins, which are critical intermediates of cell signaling and cytoskeletal organization including the Ras protein. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that is involved in cell proliferation. Because farnesylation of Ras is needed for its transforming and proliferative activity, protein-farnesyltransferase inhibitors (FTIs) provide a rational target of anticancer therapy. Like FTIs, geranylgeranyltransferase inhibitors can also be used as antitumor agents and are more effective as a part of combinational therapy with taxanes in blocking the proliferation of tumor cells. FTIs can also be used to treat several viral diseases like Hepatitis delta virus and Herpes simplex virus. FTIs can inhibit the growth of trypanosomal and malarial parasites. Inhibitors have been designed based on both the protein substrate and the isoprenoid diphosphate substrate.
Keywords: ras, prenylation, farnesyltransferase, geranylgeranyltransferase, farnesyltransferase inhibitor, geranylgeranyltransferase inhibitor, peptidomimetics
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