Geranylgeranyl diphosphate cyclization

Their biosynthesis proceeds through geranylgeranyl diphosphate, cyclization and rearrangement of the resulting labdadienyl cation. Antibiotic, antitumor, and insect antifeedant properties have been described. IM. J. Indian Chem. Soc. 75, 552 (1998) (isolation) Nat Prod. Rep. 9, 243 - 287 (1992) Synlett 1998,912 (synthesis) Tetrahedron 44, 6607-6622 (1988) Zechmeister 63, 107-196. 

Koepp, A.E., Hezari, M., Zajicek, J. etal. (1995) Cyclization of geranylgeranyl diphosphate to taxa-4(5),l 1(12)-diene is the committed step of Taxol biosynthesis in Pacific yew. Journal of Biological Chemistry, 270, 8686-8690. 

By using an elegant 13C-labeling study that involved incubation of Phoma sp. with 1-13C and 1,2-13C acetate, Oikawa et al. [9], were able to isolate the proposed biosynthetic intermediate phomactatriene (or Sch 49026), with 13C incorporation from singly labeled acetate units as indicated by in Fig. 8.3. Phomactatriene is strikingly reminiscent of taxadiene, a biosynthetic intermediate for Taxol . The net biosynthesis for both involves geranylgeranyl diphosphate (GGDP) cyclization [9]. It is noteworthy that prior to isolation of phomactins, the only known related structure is cleomeolide, a diterpene from the herb Cleome viscosa [10] that remarkably resembles phomactin H. 

Figure 2.19 Stereochemical mechanism for the cyclization of geranylgeranyl diphosphate (1) via 15-verticilline (2), as a transient intermediate, to taxa-4(5),11(12)-diene (3).

Figure 5.7 Proposed mechanism for the cyclization of geranylgeranyl diphosphate (GGPP) to the diterpene copalyl diphosphate, an example of terpene synthase-catalysed cyclization initiated by double-bond protonation, rather than by hydrolysis of the diphosphate ester. PP indicates a diphosphate moiety.

Two major steps exist in the biosynthesis of diterpene resin acids the formation of the diterpene and the stepwise oxidation of the diterpene to the corresponding acid. Most conifer diterpenes are tricyclic they are biosynthesized by bifunctional di-TPS that first cyclize geranylgeranyl diphosphate to (+)-copalyl diphosphate and then cyclize this intermediate even... 

Williams, D. C., Barroll, B. J., Jin, Q., Rithner, C. D., Lenger, S. R., Floss, H. G., Coates, R. M.,Williams, R. M., Croteau, R., Intramolecular proton transfer in the cyclization of geranylgeranyl diphosphate to the taxa diene precursor of taxol catalyzed by recombinant taxadiene synthase,... 

CHCI3), from roots of Solidago missouriensis and He-lichrysum chionosphaerum. A. is formed by metal ion-dependent cyclization of geranylgeranyl diphosphate as intermediate in the biosynthesis of abietic acid. 

Abietanes may formally be derived from pimaranes by migration of the methyl group C-17 from C-13 to C-15. In plants, however, they emerge from cyclization of geranylgeranyl diphosphate. Related parent diterpene hydrocarbons include 13,16-cycloabietanes, 17(15-16)-aZ)eo-abietanes in which the methyl group C-17 has shifted from C-15 to C-16, and totaranes. The latter formally arise from abietane when the isopropyl group migrates from C-13 to C-14. 

The cyclization of geranylgeranyl diphosphate (A16.1) to taxadiene A16.2 has been thoroughly investigated, and it has been shown that the electrophilic cyclization involves initial closure of the A-ring, followed by an intramolecular transfer of the C-11 proton to the r< -face of C-7 to promote closure of the B/C ring junction, followed by proton elimination from the / -face of C-5 (566). 

Williams DC, Carroll BJ, Jin Q, Rithner CD, Lenger SR, Floss HG, Coates RM, Williams RM, Croteau R (2000) Intramolecular Proton Transfer in the Cyclization of Geranylgeranyl Diphosphate to the Taxadiene Precursor of Taxol Catalyzed by Recombinant Taxadiene Synthase. Chem Biol 7 969... 

Figure 4.50 Proposed mechanism for the cyclization of geranylgeranyl diphosphate by taxadiene synthase.

In that vein, it has been proposed that geranylgeranyl diphosphate and its isomer, geranyllinalyl diphosphate (Scheme 11.71) combine to generate the corresponding tetraterpene (C40) derivative (phytoene), and the latter is isomerized to a carotene and then cleaved (presumably) after cyclization (as noted above) to 2 equivalents of either the aldehyde or the alcohol. 

The next series of steps involves the combination of IPP units to form geranyl diphosphate, famesyl diphosphate, and geranylgeranyl diphosphate, which serve as the precursors of the mono-, sesqui- and diterpene families, respectively [Figure 4.9]. In effect, all of the other members of these families arise from the cyclization or secondary modification of these three precursors. 

It uses a series of enzyme-controlled reactions. The step responsible for the creation of the unusual core is a cyclization reaction which changes geranylgeranyl diphosphate into taxa-4,11-diene. This then undergoes a variety of processes involving oxidation, acylation, and addition of a side chain to form taxol. The structure of the enzyme responsible for this, taxadiene synthase, was reported injanuary 2011. 

---