Farnesyl pyrophosphate

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... 

The substrate specificity of farnesyl pyrophosphate synthetase has been studied using 3-methyl-2-aIkenyl pyrophosphates (90) as models. When (90) bears a large side-chain i.e. R = C4H9), the reaction with isopentenyl pyrophosphate ceases after the formation of (91) and this reaction has been... 

Bark beetles primarily utilize isoprenoid derived pheromones [100,101] and have been the most studied regarding their biosynthesis [8,98]. Earlier work indicated that the isoprenoid pheromones could be produced by the beetle altering host derived isoprenoids however more recent work indicates that for the most part bark beetles are producing pheromones de novo. The production of isoprenoids follows a pathway outlined in Fig. 4 which is similar to the isoprenoid pathway as it occurs in cholesterol synthesis in mammals. Insects cannot synthesize cholesterol but can synthesize farnesyl pyrophosphate. Insects apparently do not have the ability to cyclize the longer chain isoprenoid compounds into steroids. The key enzymes in the early steps of the isoprenoid... 

Scheme 1. Posttranslational modification of Ras protein with lipid groups (FPP Farnesyl-pyrophosphate, PalCoA Palmitoyl CoA)...

The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. 

Farnesyl pyrophosphate, an intermediate in the pathway, may also be used for ... 

As indicated in Figure 3, the cadlnanes (170 - 187) are formed from the humulane (205) system, which also is the progenitor of the caryophyllanes (206 - 208). Of these last three compounds, caryophyllene (206) itself is of particular Importance, since it can account for 20 - 25% of the essential oil of some samples (lA). Other major constituents in the same sample were copaene (173, another cadinane) and a-humulene (205), each near 15%. It is therefore apparent that the pathway involving initial conversion of Z,E-farnesyl pyrophosphate to the humulane system is dominant in Gossypiwn terpenoid biogenesis. 

The bisabolanes, of which eight have been reported in these studies, also deserve special mention. Again, Z,E-farnesyl pyrophosphate is the putative progenitor. One study (13) reported 3-bisabolol (199) to be about 34% of the volatile alcohol fraction, making it about 5% of the total essential oil. a-Bisabolene (193) is representative of the hydrocarbons of this group. 

This enzyme [EC 2.5.1.40] catalyzes the conversion of trms,trans-fainesyl diphosphate (or, trans,trans-farnesyl pyrophosphate) to aristolochene and diphosphate (or, pyrophosphate). The enzyme-catalyzed reaction proceeds through an initial internal transfer of the farnesyl... 

FTase catalyzes the covalent attachment of a farnesyl moiety via a thioether Unkage to the proteins bearing a C-terminal amino acid sequence known as the CAAX motif (Fig. 2) [12,21]. The farnesyl moiety is derived from farnesyl pyrophosphate (FPP), a 15-carbon isoprenyl intermediate in the mevalonate pathway of cholesterol biosynthesis. The binding of FPP to the enzyme has relatively high affinity (K = 1-lOnM), and FPP binding must precede the binding of the peptide substrate for successful catalysis [22,23]. 

The structure and mechanism of catalysis of FTase were well defined in the late 1990s from several X-ray crystallography and elegant biochemical studies [24,26-30]. The enzyme is a heterodimer of a and P subunits [31,32]. The P subunit contains binding sites for both the farnesyl pyrophosphate and the CAAX protein substrates. A catalytic zinc (Zn " ) identified in the active site of the P subunit participates in the binding and activation of the CAAX protein substrates [28]. The Zn " is coordinated to the enzyme in a distorted tetrahedral geometry and surrounded by hydrophobic pockets [24,27]. Upon binding of the CAAX peptide, the thiol of the cysteine displaces water and is activated for a nucleophilic attack via thiolate on the C-1 carbon atom of farnesyl pyrophosphate [30]. 

Fig. 6 Inhibitors of farnesyl protein transferase, which are competitive for farnesyl pyrophosphate binding...

Further detailed study of the substrate specificity of yeast squalene synthetase has been reported (see Vol. 7, p. 130). The enzyme is very sensitive to changes in substrate. For example, 10,11-dihydrofarnesyl pyrophosphate was converted into 2,3,22,23-tetrahydrosqualene with only 60% of the efficiency of farnesyl pyrophosphate whereas 6,7-dihydro- and 6,7,10,11-tetrahydro-farnesyl pyrophosphates were not metabolized. The first of the two binding sites has a greater preference for farnesyl pyrophosphate and this accounts for the formation of the unsymmetrical squalene product when mixtures of farnesyl pyrophosphate and a modified substrate are used. The importance of the methyl groups, especially that at C-3, for binding is emphasized by the low efficiency of conversion of 3-desmethylfarnesyl, , -3-methylundeca-2,6-dien-l-yl (1), and E,E-7-desmethylfarnesyl pyrophosphates. The prenylated cyclobutanones (2) and (3)... 

Menaquinone. The incorporation of [2- C]mevalonate and [2- C]-2-methyl-l,4-naphthoquinone into MK-4, normally considered a bacterial quinone, has been demonstrated in marine invertebrates such as crabs and starfish." Incorporation into 2,3-epoxy-MK-4 (163) was also observed. Cell-free extracts have been prepared from Escherichia coli which catalyse the conversion of o-succinylbenzoic acid (164) into l,4-dihydroxy-2-naphthoic acid (165) and menaquinones. In the presence of farnesyl pyrophosphate the major menaquinone produced was MK-3. Genetic studies with mutants of E. coli K12 that require (164) offer support for the generally accepted pathway for MK biosynthesis via (164) and (165)." The enzyme system that catalyses the attachment of the polyprenyl side-chain to 1,4-dihydroxy-2-naphthoic acid to form demethylmenaquinone-9 (166) has been isolated from E. colU ... 

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