Linalyl pyrophosphate

Two pinene cyclases have been isolated from sage (19,35). Electrophoretically pure pinene cyclase I converts geranyl pyrophosphate to (+)-a-pinene and to lesser quantities of (+)-camphene and (+)-limonene, whereas pinene cyclase II, of lower molecular weight, converts the acyclic precursor to (-)-B-pinene and to lesser quantities of (-)-a-pinene, (-)-camphene and (-)-limonene. Both purified enzymes also utilize neryl and linalyl pyrophosphate as alternate substrates for olefin synthesis. The availability of enzyme systems catalyzing formation of enantiomeric products from a common, achiral substrate has provided an unusual opportunity to examine the stereochemistry of cyclization. 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

Curiously, certain cyclases, notably (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase, are capable of cyclizing, at relatively slow rates, the 3S-linalyl pyrophosphate enantiomer to the respective antipodal products, (-)-bornyl pyrophosphate and (+)-endo-fenchol (74,75). Since both (+)-bornyl pyrophosphate cyclase and (-)-endo-fenchol cyclase produce the designated products in optically pure form from geranyl, neryl and 3R-linalyl pyrophosphate, the antipodal cyclizations of the 3S-linalyl enantiomer are clearly abnormal and indicate the inability to completely discriminate between the similar overall hydrophobic/hydrophilic profiles presented by the linalyl enantiomers in their approach from solution. The anomalous cyclization of the 3S-enantiomer by fenchol cyclase is accompanied by some loss of normal regiochemical control, since aberrant terminations at the acyclic, monocyclic and bicyclic stages of the cationic cyclization cascade are also observed (74). The absolute configurations of these abnormal co-products have yet to be examined. 

Figure 5. Stereochemistry at Cl of geranyl pyrophosphate and neryl pyrophosphate in the cyclization, via linalyl pyrophosphate, to bornyl pyrophosphate. "Reproduced with permission from Ref. 76. Copyright 1985, Journal of Biological Chemistry".

Because the coupled isomerization-cyclization of geranyl pyrophosphate proceeds without detectable free intermediates, no ready means has been available to examine the isomerization to linalyl pyrophosphate in isolation. In an attempt to dissect the normally cryptic isomerization step from the tightly coupled reaction sequence, a non-cyclizable analog of geranyl... 

In the Figures, GPP indicates geranyl pyrophosphate, NPP indicates neryl pyrophosphate, LPP indicates linalyl pyrophosphate, and BPP indicates bornyl pyrophosphate. 

Working with orange juice vesicles. Potty and Bruemmer have isolated an enzyme, geraniol dehydrogenase, that maintains the equilibrium between aldehyde and alcohol. The presence of a second enzyme that saturates one of the double bonds in this system to citronellal and citronellol is inferred. The same authors have also demonstrated the presence of enzymes which convert mevalonate to linalyl pyrophosphate, suggesting that citrus fruits synthesise terpenoids from mevalonate by this route. 

Nerol (5) and related compounds with a 2-Z double bond occur in many plants. Although GPP is a precursor to many other groups of terpenoid compounds and is highly reactive in biological systems, despite earlier reports, neither neryl and linalyl pyrophosphates serve as intermediates in monot-erpene biosynthesis (Croteau, 1984). Present evidence suggests that geranyl pyrophosphate (GPP) is the preferred precursor of most compounds of this series (Croteau, 1984). 

Geranyl pyrophosphate is cyclized without preliminary conversion to NPP or linalyl pyrophosphate (LPP) (8). An isomerase system is not involved (Croteau, 1984). This im... 

In studies with a geranyl pyrophosphate (- )-endo-fo.n chol cyclase from fennel Foeniculum vulgare, Apiaceae), (3/ )-linalyl pyrophosphate (18) had a lower than that obtained with geranyl pyrophosphate (3) and a relative velocity nearly three times higher. These results suggest that the isomerization step is rate limiting (Johnson and Croteau, 1987). 

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

A large number of insect pheromone compounds are either simple terpenes or are derived from them. The few examples of monoterpenes given in Figure 6.4 illustrates the variety of structures that can be made from geranyl pyrophosphate or linalyl pyrophosphate without much further reaction. Both the Coleoptera and the Hymenoptera make frequent use of terpenes as secretory substances. Bark beetles have particularly employed monoterpenes in their aggregation pheromones. 

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