Geranyl pyrophosphate scheme

The biosynthesis of monoterpenoids and camphor has been described by several authors (108-llU). Ruzicka (115,116) proposed a unified biogenetic scheme for terpenes. The biosynthetic building blocks for these terpenes are iso-prene units. The biosynthetically active isoprene units are isopentenyl pyrophosphate [l] and dimethyl allyl pyrophosphate [2] the compounds that are derived from acetate via mevalonic acid (Scheme V). Geranyl pyrophosphate [3] is the C-10 precursor for the terpenes (117). Banthorpe and Baxendale (ll8) confirmed the biosynthetic pathway of (iamphor via acetate mevalonate by conducting degradation study of camphor, biosynthesized from l c labelled mevalonic acid. The biosynthesis of camphor is summarised in Scheme VI. 

Cyclization of an allylic pyrophosphate is a key step in the biosynthesis of most monoterpenes. Early hypotheses concerning the nature of the acyclic precursor and the cyclization process are first described, and chemical models for the cyclization presented. Following a review of several representative cyclase enzymes and the reactions that they catalyze, a series of stereochemical and mechanistic experiments with partially purified cyclases are reported. The results of these studies have allowed a detailed description of events at the active site and the formulation of a unified stereochemical scheme for the multistep isomerization-cyclization reaction by which the universal precursor geranyl pyrophosphate is transformed to cyclic monoterpenes. 

Consideration of chemical models, now largely in hindsight, allows broad outlines of a cyclization scheme to be delineated. Reaction of geranyl pyrophosphate is initiated by ionization which is assisted by low pH and divalent metal ion. Conversion of the geranyl to the linalyl system precedes cyclization to the monocyclic intermediate by the established stereochemical course. The overall process occurs stepwise via a series of... 

With the preceding reviews of the enzymology of monoterpene cyclization and of model studies relevant to the cyclization process, it is possible to formulate a unified stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (Figure 4). The proposal which follows is consistent with the implications of parallel advances in related fields, most notably the contributions of Cane (8,16,24,25,52), Arigoni (67) and Coates (68,69) on the stereochemistry of sesquiterpene and diterpene cyclizations, and of Poulter and Rilling (29,70) on the stepwise, ionic mechanism of prenyl transferase, a reaction type of which several monoterpene, sesquiterpene and diterpene cyclizations are, in a sense, the intramolecular equivalents. 

As noted in an earlier section, the labeling patterns of several monoterpenes derived in vivo from basic precursors such as [2-ll C]mevalonic acid are consistent with the basic cyclization scheme (Figure 1). More recently, the labeling patterns of antipodal bornane and pinene monoterpenes from [1-3H]geranyl pyrophosphate have been determined ((+)- and (-)-bornyl... 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

The following scheme shows how some of the many monoterpenes could be synthesized from geranyl pyrophosphate ... 

Previous results on helicobasidin (51) have suggested that y-bisabolene (54) is not a precursor. A similar conclusion has been reached for trichodermol (52) and trichothecin (53). Hanson and co-workers showed that tritium from [2- H,2- C]geranyl pyrophosphate (4 n = 1) is incorporated into all three bicyclic sesquiterpenoids. The suggested explanation is that the tritium atom is transferred by a 1,4-shift as shown in Scheme 6. The involvement of trichodiene (50) was confirmed by Machida and Nozoe. They also isolated deshydroxy-trichodermol and trichodiol A (55), which may be a precursor of the tricyclic system (see arrows). Bisabolene derivatives, as expected, were not incorporated. ... 

The biogenetic pathway of formation of cleomeolide may be envisaged to arise either by the oxidative cyclization of geranyl linalool expoxide [10] as outlined in Scheme 1 or via head-to-tail cyclization of geranyl geranyl pyrophosphate [11] as shown in Scheme 2. However, one would be tempted to prefer the former considering the oxygenation pattern in the molecule. 

Scheme 2 Head-to-tail cyclisation of geranyl geranyl pyrophosphate.

IPP and DMAPP react as shown in Scheme 102.4 to generate geranyl pyrophosphate (GPP), whose further reaction with IPP produce famesyl pyrophosphate (FPP) that reacts with another molecule of IPP to afford geranylgeranyl pyrophosphate (GGPP), representing the linear diterpene C20 precursor. 

The preceding discussion has indicated the sequence of squalene 4.8) biosynthesis as mevalonate 4.13) isopentyl pyrophosphate 4.14) dimethylallyl pyrophosphate 4.15) geranyl pyrophosphate 4.41) farnesyl pyrophosphate 4.19) squalene 4.8). Each stage involves stereochemical change at one or two carbon atoms. The presence of several prochiral centres in the molecules of this sequence meant that for stereochemical changes to be monitored they had to be chirally labelled with deuterium or tritium e.g. the condensation of isopentenyl pyrophosphate 4.14) with dimethylallyl pyrophosphate 4.15) (see Scheme 4.10) involves loss of one of the... 

Fig. 2. Scheme for the enzymatic isomerization-cyclizatlon of geranyl pyrophosphate. 

Fig. 3. Stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (GPP) to bornyl pyrophosphate (BPP) via linalyl pyrophosphate (LPP).

Aspergillus stellatus. This supports its biosynthesis via cyclisation of geranyl-farnesyl pyrophosphate followed by rearrangement as shown in Scheme 3 [10]. Surprisingly, the folding pattern must be different from that involved in the biosynthesis of stellatic acid (4), a previously isolated sesterterpene metabolite of A. stellatus [11]. 

Bacterial ([ ]3,[Z]7)-undecaprenol phosphate (Und-P)(42), has been synthesized from traw-geranyl sulfone and isoprenoid building blocks and then conjugated with prototypical glycan chains through pyrophosphate to Und-PP-linked derivatives (43-45, Scheme 9). °... 

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