Protein prenylation inhibitors

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 ... 

The phenolics include anthocyanins, anthraquinones, benzofurans, chromones, chromenes, coumarins, flavonoids, isoflavonoids, lignans, phenolic acids, phenylpropanoids, quinones, stilbenes and xanthones. Some phenolics can be very complex in structure through additional substitution or polymerization of simpler entities. Thus xanthones can be prenylated and flavonoids, lignans and other phenolics can be glycosylated. Condensed tannins involve the polymerization of procyaninidin or prodelphinidin monomers and hydrolysable tannins involve gallic acid residues esterified with monosaccharides. As detailed in this review, representatives of some major classes of plant-derived phenolics are potent protein kinase inhibitors. 

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. 

Dursina, B., ct al. (2006). Identification and specificity profihng of protein prenyltransfer-ase inhibitors using New flnorescent phosphoisoprenoids./Am Chem Soc 128 2822-2835. Liu, X., and Prestwich, G.D. (2002). Didehydrogeranylgeranyl (DDGG) a flnorescent probe for protein prenylation. J Am Chem Soc 124 20-21. 

However, there are a number of topics that we could not cover in the two volumes (Vols. 29 and 30) due to space constraints. For example, we could not include a discussion of protein prenylation in pathogenic fungi and trypanosomes and the development of inhibitors for therapeutic applications. In addition, we did not sufficiently discuss proteins that recognize and interact with prenylated proteins and the biological functions of these protein-protein interactions. Future areas to cover should also include expanded discussion on the roles that prenylated proteins play in plants... 

Furthermore, the interaction of prenylated Rah GTPase with REP and GDP dissociation inhibitor (GDI) protein could be studied and analyzed. ... 

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