Proteins prenylation

Gelb, M. H., 1997. Protein prenylation, et cetera Signal transdnction in two dimensions. Science 275 1750-1751. 

PPCs Prenylation is the post-translational addition of 15- or 20-carbon isoprenyl lipids to the C-terminus of proteins. Prenylation is an irreverable modification that anchors proteins to the membrane fraction of cells. 

The polyisoprenoids dolichol (Figure 14-20 and Chapter 47) and ubiquinone (Figure 12-5) are formed from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3-7 (ubiquinone) isopentenyl diphosphate residues, respectively. Some GTP-binding proteins in the cell membrane are prenylated with farnesyl or geranylgeranyl (20 carbon) residues. Protein prenylation is believed to facilitate the anchoring of proteins into lipoid membranes and may also be involved in protein-protein interactions and membrane-associated protein trafficking. 

Zhang FL, Casey PJ Protein prenylation Molecular mechanisms and functional consequences. Annu Rev Biochem 1996 65 241. 

Fig. 14. Photoaffinity probes studying biomolecular targets in protein prenylation...

Protein prenylation (also called isoprenylation) attaches a 15-carbon, farnesyl diphosphate or a 20-carbon geranylgeranyl diphosphate to the cysteine residue near the C termini of the target proteins (Overmeyer et al., 1998 Rodrfguez-Concepcion et al., 1999a). This reaction is conserved both in animals and plants. The functions of the target proteins include signal transduction, nuclear architecture, and vesicular transport. 

Overmeyer, J., Erdman, R., and Maltese, W. (1998). Membrane targeting via protein prenylation. Methods Mol. Biol. 88, 249-263. 

Rodriguez-Concepcion, M., Yalovskyy, S., and Gruissem, W. (1999a). Protein prenylation in plants old friends and new targets. Plant Mol. Biol. 39, 865-870. 

Protein prenylation leads to an increased hydrophobicity of proteins, typically resulting in an increased affinity for membranes. In 2004 studies on the cellular location of prenylated RhoB proteins showed that RhoB can undergo farnesylation (RhoB-F) as well as geranylgeranylation (RhoB-GG). With the aid of specific prenyl transferase inhibitors, it was revealed that RhoB-GG is localized to multivesicular late endosomes. 

Keywords Farnesyl transferase inhibitor Protein prenylation Ras protein ... 

In addition to protein farnesylation, two other pathways exist for protein prenylation. As mentioned above, GGTase I also utilizes the C-terminal... 

Suzuki, T., Ito, M., Ezine, T., Shikata, M., Ando, E., Utsumi, T., Tsimasawa, S., and Nishimura, O. (2007) Protein prenylation in an insect cell-free protein synthesis system and identification of products by mass spectrometry. Proteomics , 1942-1950. 

Prenylation (covalent attachment of an isoprenoid see Fig. 27-30) is a common mechanism by which proteins are anchored to the inner surface of cellular membranes in mammals (see Fig. 11-14). In some of these proteins the attached lipid is the 15-carbon farnesyl group others have the 20-carbon geranylgeranyl group. Different enzymes attach the two types of lipids. It is possible that prenylation reactions target proteins to different membranes, depending on which lipid is attached. Protein prenylation is another important role for the isoprene derivatives of the pathway to cholesterol. 

Gelb, M.H., Brunsveld, L., Hrycyna, C.A., MichaeUs, S., Tamanoi, F., Van Voorhis, W.C., and Waldmann, H. (2006). Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol 2 518-528. 

Yokoyama, K., Zimmerman, K., Scholten, J., and Gelb, M.H. (1997). Differential prenyl pyrophosphate binding to mammalian protein geranylgeranyltransferase-I and protein farnesyltransferase and its consequence on the specificity of protein prenylation. J Biol Chem 272 3944-3952. 

DeGraw, A.J., Hast,M.A.,Xu, J., Mullen,D., Beese, L.S., Barany, G., andDistefano, M.D. (2008). Caged protein prenyltransferase substrates tools for understanding protein prenylation. Chem Biol Drug Des 72 171-181. 

Benetka, W., Koranda, M., and Eisenhaber, F. (2006). Protein prenylation an (almost) comprehensive overview on discovery history, enzymology, and significance in physiology and disease. Monat Fur Chem 137 1241-1281. 

Gelb, M.H., et al. (2006). Therapeutic intervention based on protein prenylation and associated modifications. Nat Chem Biol 2 518-528. 

Schafer, W.R., and Rine, J. (1992). Protein prenylation genes, enzymes, targets, and functions. Annu Rev Genet 26 209-237. 

CaldweU, G.A., Naider, F., and Becker, J.M. (1995). Fungal lipopeptide mating pheromones a model system for the study of protein prenylation. Microbiol Rev 59 406-422. 

Omer, C.A., and Gibbs, J.B. (1994). Protein prenylation in eukaryotic microorganisms genetics, biology and biochemistry. Mol Microbiol 11 219-225. 

Fu, H.W., and Casey, P.J. (1999). Enzymology and biology of CaaX protein prenylation. Recent Prog Harm Res 54 315-342, discussion 342-313. 

Synthetic derivatives and analogs of prenyl diphosphates have historically played a key role in defining key featnres of the mechanism of enzymes that ntilize these key intermediates in the isoprenoid pathway. This has also been the case with the investigation of the protein prenyl-transferases. A brief introduction to the protein prenyltransferase enzymes is given along with outlines on the previous use of prenyl diphosphate tools and key aspects of their synthesis. The development of prenyl diphosphate-based FTase inhibitors is described. The use of prenyl diphosphate derivatives as mechanistic and structural probes is next discussed. In particular, the use of fluorinated, isotopically labeled, and photoaffinity derivatives is presented. An overview of the extensive work on the determination of FTase isoprenoid substrate specificity is then given, and the chapter concludes with a section on the development of prenyl diphosphate tools for proteomic studies. 

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