Farnesyltransferases

Lane KT, Beese LS (2006) Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J Lipid Res 47 681-699... 

Waldmann H, Thutewohl M (2000) Ras-Farnesyltransferase-Inhibitors as Promising Anti-Tumor Drugs. 211 117-130 Wang G-X, see Chow H-F (2001) 217 1-50 Weil T, see Wiesler U-M (2001) 212 1-40... 

Waldmann H, Thutewohl M (2000) Ras-Farnesyltransferase-Inhibitors as Promising Anti-Tiimor Drugs. 211 117-130... 

Park HW et al (1997) Crystal structure of protein farnesyltransferase at 2.25 angstrom resolution. Science 275(5307) 1800-1804... 

Ras is strictly localized to the inner side of the plasma membrane. A lipid anchor covalently attached to the C-terminus of Ras penetrates into the lipid bilayer. This membrane anchorage is essential for the biological activity of Ras. Hence, the inhibition of anchor attachment has become an attractive pharmacological target [ 13]. See Waldmann H, Thutewohl M,Ras-Farnesyltransferase-inhibitors as promising anti-tumor drugs, this volume. 

Ras-Farnesyltransferase-Inhibitors as Promising Anti-Tumor Drugs... 

Farnesyltransferase is a heterodimeric protein composed of an a- and a /1-sub-unit, and zinc and magnesium ions are required for its activity [7,8]. A closely related heterodimeric enzyme is geranylgeranyltransferase I (GGTase I). It also recognizes proteins with a CAAX-box when X is leucine. Both enzymes share the same a-subunit and the requirement for Zn2+ and Mg2+ but the /1-subunits are different. The similarity of these enzymes highlights the importance of selectivity of farnesyltransferase (FT)-inhibitors. 

Although FTase inhibitors influence the farnesylation of Ras they are likely to interfere with the posttranslational modifications of other CAAX-containing proteins as well. Apart from the approximately 20 farnesylated proteins that are known today, farnesylation is also required for normal Ras function which in turn is critical for normal cell viability. For these reasons farnesyltransferase... 

Toxicity and effectivity studies have often been performed in rodent fibroblast cells containing oncogenic H-Ras. However, prenylation of K-Ras B and N-Ras are not as effectively blocked by the farnesyltransferase inhibitors as H-Ras [48] (see below). Thus normal cells may be less sensitive to these drugs because they express K-Ras 4B and N-Ras. In this context it should be noted that H-Ras mutations are relatively uncommon in human tumors [49]. Rather, the K-Ras gene is the most frequently mutated in solid human cancers, whereas N-Ras is prevalent in leukemias. Thus the preclinical evaluation of the farnesylation inhibitors has yet to be critically re-evaluated for trials in humans. 

In normal cells, the GDP/GTP-binding proteins, after protein synthesis, move to the cell membrane to which they become hooked by a hydrophobic farnesyl group. The y-subunit is anchored in the membrane by a post-translational modification of the C-terminal CAAX sequence (C - cystein, AA - aliphatic amino acids, X - methionine). This protein is first enzymatically farnesylated by a specific farnesyltransferase, then the AAX part is cleaved by specific proteases and finally the cystein residue is converted to a methyl ester. 

The molecular elements of that pathway were mapped with photoaffinity labeling by different investigators. Farnesyltransferase contains a and heterodimer subunits, and binds to both protein and farnesyl diphosphate. The main recognition elements for the protein is the C-terminal CAAX motif. Coleman et al. attached two benzophenones to the recognition sequence and the resulting photoprobe (38, Fig. 14) specifically labeled both subunits [125]. 

Aminopyrrolidinone farnesyltransferase inhibitors design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. Journal of Medicinal Chemistry, 45, 2388-2409. 

Farnesyltransferase inhibitor, IC5Q 25 pM from structure-based virtual screening... 

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