Inhibitors of Protein Prenylation: An Overview

Authors: Banerjee, Saswati; McGeady, Paul

Source: Current Enzyme Inhibition, Volume 1, Number 2, June 2005 , pp. 183-206(24)

Publisher: Bentham Science Publishers

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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

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1573408054022225

Affiliations: 1: Department of Chemistry, Clark Atlanta University, 223 James P. Brawley DR S.W. Atlanta, GA 30314, USA.

Publication date: 2005-06-01

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Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.

Inhibitors of Protein Prenylation: An Overview

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