Farnesyl

Hydrolysis of the pyrophosphate ester group converts farnesyl pyrophosphate to the corresponding alcohol farnesol (see Figure 26 6 for the structure of farnesol)... 

A repetition of the process just shown produces the diterpene geranylgeraniol from farnesyl pyrophosphate... 

The higher terpenes are formed not by successive addition of C5 units but by the coupling of simpler terpenes Thus the triterpenes (C30) are derived from two mole cules of farnesyl pyrophosphate and the tetraterpenes (C40) from two molecules of ger anylgeranyl pyrophosphate These carbon-carbon bond forming processes involve tail to tail couplings and proceed by a more complicated mechanism than that just described... 

Analogous processes involving cyclizations and rearrangements of carbocations derived from farnesyl pyrophosphate produce a rich variety of structural types m the... 

FIGURE 9.19 Proteins containing the C-terminal sequence CAAX can undergo prenylation reactions that place thioether-linked farnesyl or geranylgeranyl groups at the cysteine side chain. Prenylation is accompanied by removal of the AAX peptide and methylation of the carboxyl group of the cysteine residue, which has become the C-terminal residue. 

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 farnesylation and subsequent processing of the Ras protein. Following farnesylation by the FTase, the carboxy-terminal VLS peptide is removed by a prenyl protein-specific endoprotease (PPSEP) in the ER, and then a prenylprotein-specific methyltransferase (PPSMT) donates a methyl group from S-adenosylmethionine (SAM) to the carboxy-terminal S-farnesylated cysteine. Einally, palmitates are added to cysteine residues near the C-terminus of the protein. 

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

Farnesol forms an acetate, farnesyl acetate, which is a nearly odourless oil, boiling at 169° to 170° at 10 mm. 

Further combination of GPP with another IPP gives the C15 unit farnesyl diphosphate (FPP), and so on, up to C25. Terpenoids with more than 25 carbons—that is, triterpenoids (C30) and tetraterpenoids (C40)—ate synthesized by dimerization of Cj5 and C2q units, respectively (Figure 27.8). Triterpenoids and... 

Steroids are heavily modified triterpenoids that are biosynthesized in living organisms from farnesyl diphosphate (Cl5) by a reductive dimerization to the acyclic hydrocarbon squalene (C30), which is converted into lanosterol (Figure 27.12). Further rearrangements and degradations then take place to yield various steroids. The conversion of squalene to lanosterol is among the most... 

Figure 27.12 An overview of steroid biosynthesis from farnesyl diphosphate.

Propose a biosynthetic pathway for the sesquiterpene helminthogermacrene from farnesyl diphosphate. 

S-prenylation is the most recent of the four major types of lipid modifications to be described. As with -acylation, S-prenylation is posttranslational. The lipid substrates for these modifications are farnesyl diphosphate and geranylgeranyl diphosphate. The mechanism... 

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

B. l0-Bromo-ll-hydroxy-10,ll-dihydrofarnesyl Acetate [2,6-Dodeca-diene-1,11-diol, 10-bromo-3,7, -trimethyl-, 1-acetate, (E,E)-]. Farnesyl acetate (29 g., 0.11 mole) is dissolved in 1 1. of /erf-butyl alcohol (Note 4) contained in a 3-1. Erlenmeyer flask. Water is added (500 ml.), and the solution is cooled to about 12° using an external ice water bath. Maintaining this temperature, rapid magnetic stirring is begun, and more water is added until a saturated solution is obtained. The second addition of water may be rapid initially, but the saturation point must be approached carefully, like the end point of a titration. A total of about 1200 ml. of water is required for the above amounts of farnesyl acetate and ferf-butyl alcohol. The solution must remain clear and homogeneous at about 12°, and if the saturation point is accidentally passed by adding too much water, ferf-butyl alcohol should be added to remove the turbidity. 

Concentration of the ethereal solution at reduced pressure gives the epoxyacetate as a colorless oil more viscous than water. The overall yield based on farnesyl acetate is near 60% (Note 11). This material is reasonably pure if the preparation has been executed carefully, but it can be further purified by column chromatography (Note 12) or distillation (Note 13). 

Fractions may be monitored by thin-layer chromatography on silica gel, developing with 10% v/v ethyl acetate in hexane and visualizing with iodine vapor. The following Rf values were observed famesol, 0.07 farnesyl acetate, 0.35 bromohydrin acetate, 0.20. 

Farnesyl, 10-bromo-10,l 1-dihydro-l 1-hydroxy-, acetate [2,6-Dodecadiene-1,11-diol, 10-bromo-3,7,11-trimethyl-, 1-acetate, ( , )-], 113 Ferrocene, 28... 

The use of chiral dirhodium carboxamidates has made possible the highly enantioselective synthesis of presqualene alcohol (4) from farnesyl diazoacetate (14) through cyclopropane 15 [9] (Eq. 1). Highly enantiomerically en-... 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

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