Transferase farnesyl

Farnesyl transferase from rat cells is a heterodimer consisting of a 48 kD u-snbnnit and a 46 kD /3-snbnnit. In the structure shown here, helices 2 to 15 of the u-snbnnit are folded into seven short coiled coils that together form a crescent-shaped envelope partially surrounding the /3-snbnnit. Twelve helices of the /3-snl> nnit form a novel barrel motif that creates the active site of the enzyme. Farnesyl transferase inhibitors, one of which is shown here, are potent suppressors of tumor growth in mice, but their value in humans has not been established. 

The structure of 1-739,749, a farnesyl transferase inhibitor that is a potent tumor growth suppressor. 

Rheb Elevated in many tumor cells, Rheb may be the critical target by which farnesyl transferase inhibitors inhibit tumor growth... 

Caliendo G et al. (1999) Synthesis and biological activity of pseudopeptide inhibitors of Ras farnesyl transferase containing unconventional amino acids. Farmaco 54(11-12) 785-790... 

A common way to benefit from the ability to combine different molecular orbital methods in ONIOM is to combine a DFT or ab-initio description of the reactive region with a semi-empirical treatment of the immediate protein environment, including up to 1000 atoms. Due to the requirement for reliable semi-empirical parameters, as discussed in Section 2.2.1, this approach has primarily been used for non-metal or Zn-enzymes. Examples include human stromelysin-1 [83], carboxypeptidase [84], ribonucleotide reductase (substrate reaction) [85], farnesyl transferase [86] and cytosine deaminase [87], Combining two ab-initio methods of different accuracy is not common in biocatalysis applications, and one example from is an ONIOM (MP2 HF) study of catechol O-methyltransferase [88],... 

In another application of coupling proteins to surfaces using click chemistry, Duckworth et al. (2006) carried out prenylation of a protein using a farnesyl azide derivative and the enzyme farnesyl transferase for subsequent chemoselective ligation to alkyne-functionalized agarose beads. The result is a highly discrete, site-specific attachment of the protein to the solid phase at a single location. 

Protein farnesyl transferase also can be used to add a geranylazide derivative to a synthetic peptide by incorporating the enzyme recognition sequence CAAX at the C-terminal of any... 

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

There are several possible explanations to account for this apparent lack of toxicity. Some geranylgeranylated Ras-related proteins might compensate for the loss of Ras function (see, e.g., [46]). Alternatively inhibition of farnesyl transferase may reduce Ras activity below the level required for transformation, yet allow sufficient Ras activity for maintaining normal cell viability [47]. Alternatively, a different signaling pathway may be activated when Ras is not anchored to the plasma membrane. 

Synthesis of Characteristic Lipopeptides of the Human N-Ras Protein and Their Evaluation as Possible Inhibitors of Protein Farnesyl Transferase, P. Stober, M. Schelhaas, E. Nagele, P. Hagenbuch, J. R etey, H. Waldmann, Bioorg. Med. Chem 1997, 5,75-83. 

Sn2 substitution using organocopper reagents is an efficient method for the synthesis of 3-substituted olefins. In the synthesis of farnesyl diphosphate analogues (43, 45) as potential inhibitors of the enzyme protein-farnesyl transferase, for example, organocopper methodology was compared with the Stifle reaction [33] and the Suzuki reaction [34], frequently used in the coupling of vinyl triflates with... 

Scheme 2.45 Synthesis of potential enzyme farnesyl transferase inhibitors.

Perola, E., Xu, K., Kollmeyer, T.M., Kaufmann, S.H., and Prendergast, F.G. Successful virtual screening of a chemical database for farnesyl-transferase inhibitor leads./. Med. 

In order for Ras to function properly, the protein must be localized to the plasma membrane. This is achieved by the addition of a farnesyl group to a cysteine residue near the carboxy terminus, which then acts as a tether to the cellular membrane. Farnesyl transferase, the enzyme that adds the farnesyl moiety to Ras, is also a target for small-molecule intervention. This class of inhibitors is the subject of another chapter (Angibaud et al, in this volume). 

Keywords Farnesyl transferase inhibitor Protein prenylation Ras protein ... 

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