Farnesyl diphosphate

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... 

Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate ger-anyl diphosphate (Figure 26-2). A further condensation with isopentenyl diphosphate forms farnesyl diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule. 

Farnesyl Diphosphate Gives Rise to Dolichol Ubiquinone... 

The polyisoprenoids dolichol (Figure 14-20 and Chapter 47) and ubiquinone (Figure 12-5) are formed from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3-7 (ubiquinone) isopentenyl diphosphate residues, respectively. Some GTP-binding proteins in the cell membrane are prenylated with farnesyl or geranylgeranyl (20 carbon) residues. Protein prenylation is believed to facilitate the anchoring of proteins into lipoid membranes and may also be involved in protein-protein interactions and membrane-associated protein trafficking. 

IPP = isopentenyl diphosphate GPP = geranyl diphosphate FPP = farnesyl diphosphate ... 

Figure 17.21 An azido-farnesyl diphosphate derivative can be added to cells to obtain farnesylated proteins containing terminal azide groups that can be targeted in a Staudinger ligation reaction. Biotinylation of these post-translationally modified proteins can be done in vivo using a biotin-phosphine derivative.

Mevalonate kinase deficiency. Mevalonate kinase and farnesyl-diphosphate synthase are localized in the peroxisome and are involved in the synthesis of isoprenoids. Mevalonate kinase deficiency causes severe developmental delay, dysmorphic features and early death. Mevalonate deficiency has also been observed in the hyperimmuno-globulinemia-and periodic fever syndrome. 

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]. 

Protein prenylation (also called isoprenylation) attaches a 15-carbon, farnesyl diphosphate or a 20-carbon geranylgeranyl diphosphate to the cysteine residue near the C termini of the target proteins (Overmeyer et al., 1998 Rodrfguez-Concepcion et al., 1999a). This reaction is conserved both in animals and plants. The functions of the target proteins include signal transduction, nuclear architecture, and vesicular transport. 

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... 

Fig. 11.3 Biosynthesis of the homoterpenes (a) DMNT (4,8-dimethyl-l,3,7-nonatriene) and (b) TMTT (4,8,12-trimethyltrideca-l,3,7,l 1-tetraene). (b) Two putative reaction mechanisms for the conversion of (ii,Zi)-geranyUinalool to TMTT catalyzed by a P450 enzyme activity are shown. FPP, farnesyl diphosphate GGPP, geranylgeranyl diphosphate...

Geranyl diphosphate and farnesyl diphosphate are analogues of dimethylallyl diphosphate that contain two and three C5 subunits respectively they can undergo exactly the same SnI reactions as does dimethylallyl diphosphate. In all cases, a carbocation mechanism is favoured by the resonance stabilization of the allylic carbocation. Dimethylallyl diphosphate, geranyl diphosphate, and farnesyl diphosphate are precursors for natural terpenoids and steroids. 

An exactly analogous process can then occur, in which geranyl diphosphate provides the allylic cation, and a further molecule of isopentenyl diphosphate adds on, giving farnesyl diphosphate this can subsequently yield geranylgeranyl diphosphate. 

The compounds geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate are biochemical precursors of monoterpenes, sesquiterpenes, and diterpenes respectively, and virtually all subsequent modifications of these precursors involve initial formation of an allylic cation through loss of diphosphate as the leaving group. 

By far the most impressive example of electrophilic addition in natural prodnct formation is in the biosynthesis of steroids. The snbstrate sqnalene oxide is cyclized to lanosterol in a process catalysed by a single enzyme. Lanosterol is then converted into the primary animal-steroid cholesterol. Sqnalene oxide comes from sqnalene, which is itself formed throngh a combination of two molecules of farnesyl diphosphate. 

Formation of squalene. Isopentenyl diphosphate undergoes isomerization to form dimethylallyl diphosphate. The two C5 molecules condense to yield geranyl diphosphate, and the addition of another isopentenyl diphosphate produces farnesyl diphosphate. This can then undergo dimerization, in a head-to-head reaction, to yield squalene. Farnesyl diphosphate is also the starting-point for other polyisoprenoids, such as doli-chol (see p. 230) and ubiquinone (see p. 52). 

Geranyl diphosphate Farnesyl diphosphate Sgualene Cholesterol Pregnenolone (T 17-OH-Pregnenolone... 

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