Geranyl pyrophosphate biosynthesis

The enzyme catalyzed reactions that lead to geraniol and farnesol (as their pyrophosphate esters) are mechanistically related to the acid catalyzed dimerization of alkenes discussed m Section 6 21 The reaction of an allylic pyrophosphate or a carbo cation with a source of rr electrons is a recurring theme m terpene biosynthesis and is invoked to explain the origin of more complicated structural types Consider for exam pie the formation of cyclic monoterpenes Neryl pyrophosphate formed by an enzyme catalyzed isomerization of the E double bond m geranyl pyrophosphate has the proper geometry to form a six membered ring via intramolecular attack of the double bond on the allylic pyrophosphate unit... 

Croteau, R. B. In Flavor Precursors Teranishi, R. Takeoka, G. R. Guntert, M., Eds. Monoterpene Biosynthesis cyclization of geranyl pyrophosphate to (+)-sabinene Amercian Chemicd Society Symposium Seriers 490 Washington, DC, 1991, pp. 8-20. 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

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. 

IV. Biosynthesis of cyclic dlterpenes from trans-geranyl-geranyl pyrophosphate." J. Biol. Chem., 19 % 2kh, 3200-3209. 

Croteau, R., Felton, M. and Ronald, R.C. (1980a) Biosynthesis of monoterpenes conversion of the acyclic precursors geranyl pyrophosphate and neryl pyrophosphate to the rearranged monoterpenes fenchol and fenchone by a soluble enzyme preparation from fennel (Foeniculum vulgare). Archives of Biochemistry and Biophysics 200(2), 524-533. 

Borneol, camphene, and a-pinene are made in nature from geranyl pyrophosphate. The biosynthesis of a-pinene and the related camphor is described in the chapter. In the laboratory bornyl chloride and camphene can be made from a-pinene by the reactions described below. Give mechanisms for these reactions and say whether you consider them to be biomimetic. 

Croteau, R. and Purkett, P.T. (1989) Geranyl pyrophosphate synthase characterization of the enzyme and evidence that this chain-length specific prenyltransferase is associated with monoterpene biosynthesis in sage (Salvia officinalis). Arch. Biochem. Biophys., 271,524—35. 

The deuterium labelling established that the y, 5-unsaturated, nitrile 241 equilibrates at room temperature with the iV-allylketene imine 242 through an intramolecular rearrangement mechanism. Deuterium has been applied in the study of the novel palladium(0)-catalysed cyclization of 2,7-octadienyl carbonate containing an allylsilane moiety, 243, to product 244 (in 89%) and some 245 in the presence of phosphite 246 (equation 99). Intramolecular KlEs (Ah/Ad =3.0 and 3.5) have been observed in a bicyclic olefin formation (monoterpinene biosynthesis from [1- H,4- H2]- and [10- H2]-geranyl pyrophosphates) catalysed by pinene synthases from sage (Salvia officinalis). ... 

The previous view on the biosynthesis of monoterpenes is that the cyclization of the geranyl pyrophosphate proceeds via a common cationic precursor, which in turn is further transformed into the various monoterpenes, as shown in Fig. (2). 

Figure 8.4 Biosynthesis of geranyl pyrophosphate from dimethylallyl pyrophosphate.

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. 

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. 

It is possible that an analogous intermediate is involved in phytoene (8) biosynthesis. However, instead of a reductive elimination of pyrophosphate, as in squalene biosynthesis, the 15(15 )-double bond must be derived by elimination. Goodwin and co-workers have shown that both protons of this double bond are labelled by [2- C,3R,5R- H]mevalonic acid. Porter and co-workers have studied the kinetics of an enzyme system from tomatoes for the conversion of geranyl geranyl pyrophosphate (6 n = 3) into phytoene. 

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