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Modulation of Palmitoylation
Besides farnesylation and geranylgeranylation, palmitoylation constitutes a major posttranslational lipid modification of proteins, which plays a key role in determining membrane
association, intracellular distribution and activities of many proteins. The major biological role of palmitoylation is the postranslational modification of a subset of signaling molecules, which are associated with the plasma membrane, including the receptor tyrosine kinases, Gprotein- linked receptors, heterotrimeric G-proteins, endothelium nitric oxide synthase (eNOS), adenylyl cyclase, and Ras (Mumby). Palmitoylation is mediated by enzymes such as the palmityl Palmitate is bound to cysteine residues through a thioester linkage, resulting in a reversible and highly dynamic addition of the fatty acid. By contrast, protein prenylation and N-myristoylation constitute irreversible linkages of prenyl groups and myristate groups through stable bonds (Magee). Typically palmitoylation is found in the proximity of other lipid modifications, such as prenyl groups, myristate or close to hydrophobic stretches of amino acids. Often the presence of the first lipid modification provides a sufficient increase in protein hydrophobicity to allow a transient membrane association, suggesting a synergistic effect of fatty acid or lipid adduction (Peitzsch). Conversely, inhibitors of selective fatty acid adduction may severely influence the probability of further lipid modification and thus induce profound effects on signal transduction and membrane distribution of proteins. Palmitoylation plays a major role in targeting signaling molecules to membrane microdomains, as well as to the specialized caveolae, which allows a rapid and efficient coupling of receptors and their effector molecules. In fact, mutagenesis of palmitoylable cysteine residues of eNOS prevented compartmentation to caveolae (Garcia-Cardena). As described in chapter 4, the activity of certain Ras proteins is dependent upon palmitoylation, which forms part of a series of post-translational modifications targeting the protein to the plasma membrane. The initial step is the farnesylation at the C-terminal CAAX box by the enzyme FPTase, which is followed by carboxy methylation of the C-terminus . The final modification of both H and N-Ras constitutes of a reversible palmitoylation of cysteine residues upstream of the farnesylated cysteine by the enzyme PPTase (Buss). By contrast,K-Ras, which is not palmitoylated, has an increased predilection to plasma membrane localization due to the presence of a polybasic stretch of lysine residues. The plasma membrane localization of Ras is a prerequisite for the transmission of signals transmitted via tyrosine kinase receptors. However, in contrast to N-myristoylation, very little is known about the enzymes and the biochemistry of protein palmitoylation. Two thioesterases, PPT1 and APT1, have been identified that deacylate palmitoylated Ras proteins and G Protein alpha in vitro (Duncan). However, the enzymes which catalyze the attachment of palmitate to proteins have not been definitively identified. Recently, enzymes with palmitoyl acyl transferase (PAT) activities have been purified from human erythrocytes (Das), and nonenzymatic palmitoylation has been reported (Bano).

Recently, the natural product cerulenin ([2R,3S]-2,3-epoxy-4-oxo-7,10-trans,transdodecadienamide) was demonstrated to inhibit both fatty acid synthase and protein palmitoylation (Lawrence). Currently, two cerulenin analogs 9C (cis-2,3-epoxy-4- oxododecanamide) and 16C (cis-2,3-epoxy-4-oxononadecanamide) have become available, which show increased selectivity for protein palmitoylation inhibition (Lawrence). These compounds were shown to exhibit profound antiproliferative effects on several tumor cell
lines, including bladder carcinomas, breast adenocarcinomas, breast medulla carcinoma, pancreatic epitheloid carcinoma, colon adenocarcinoma, kidney carcinoma, and hepatocellular carcinoma (De Vos).

Recently, long chain fatty acids were shown to inhibit protein fatty acylation. Of these, the polyunsaturated fatty acids (PUFAs), particularly the n-3 series, have been used as
immunosuppressive agents, and in the treatment of inflammatory diseases. Recently, it was reported that PUFAs inhibit T cell signal transduction by displacing Fyn and Lck from the rafts (Stulnig). Moreover, the PUFAs arachidonic acid (20:4) and eicoapentanoic acid (20:5) act as specific inhibitors of Fyn palmitoylation and membrane targeting (Webb). The palmitic acid analogue 2-Bromopalmitate similarly inhibits Fyn palmitoylation, but also inhibits Lck and LAT palmitoylation, which is associated with impaired membrane association and signalling through the TCR (Webb).

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