Famesyl diphosphate, biosynthesis

Propose a mechanism for the biosynthesis of the sesquiterpene trichodiene from famesyl diphosphate. The process involves cyclization to give an intermediate secondary carbocation, followed by several carbocation rearrangements. 

Finally, Jommi et al. addressed the question of the hydrogen shift following the ring closure of famesyl diphosphate to the cyclodecadiene within the biosynthesis of tutin (11) (232). 

Ramosvaldivia, A.C., Vanderheijden, R. and Verpoorte, R. (1997a) Elicitor-mediated induction of anthraquinone biosynthesis and regulation of isopentenyl diphosphate isomerase and famesyl diphosphate synthase activities in cell suspension cultures of Cinchona robusta How. Planta, 203, 155-61. 

Catalysis with [Rh2(55-mepy)4] was extended from styrene to other olefins, for which excellent results were dso obtained. By using this chiral catalyst, it has recently been possible to fix the three stereocenters in the cyclopropane ring of (+)-( R,2R,3/ )presqualene diphosphate (Structure 9), an intermediate in the biosynthesis of squalene from famesyl diphosphate [25]. 

HsR H4RH2R H2S 4RH2R H2S H4R Scheme 5.2 Stereochemistry of the biosynthesis of famesyl diphosphate. 

Fig. 1.4 Outline of terpenoid biosynthesis from isopentenyl diphosphate (IPP) via dimethylallyl diphosphate (DMAPP), gcranyl diphosphate (GPP), famesyl diphosphate (FPP) and geranylgcranyl diphosphate (GGPP). These reactions are catalyzed by isoprenyl diphosphate synthases and terpene synthases. The major products of the monoterpene, sesquiterpene, and diterpene pathways that constitute the oleoresm of Picea abies are listed. The general precursor IPP is derived either from the plastidial methylerythritol phosphate (MEP) pathway or the cytosolic mevalonaic pathway.

Biosynthesis The biosynthesis proceeds by the general pathway to triterpenoids from "acetyl-CoA via mevalonate to famesyl diphosphate (C,j). The tail-to-tail condensation of two molecules of the latter furnishes "squalene . 

The biosynthesis of rubber may be divided into three steps (1) initiation, which requires an allylic diphosphate molecule, (2) elongation, in which IPP units are added to a Z-l,4-polyisoprene chain, and (3) termination, in which the polymer is released from the rubber transferase enzyme (Cornish, 1993). In plants, the elongation of Z-l,4-polyiso-prene (natural rubber) requires a small -allylic diphosphate initiator (less than or equal to C20). Famesyl pyrophosphate (FPP) is an effective initiator of polyisoprene biosynthesis (Light et al, 1989) further, because only one molecule of FPP is needed for each molecule of rubber formed, small traces of this substance that are inadvertently present complicate biosynthetic studies. The E-allylic diphosphates are hydrophilic cytosolic compounds, whereas Z-l,4-polyisoprene is hydrophobic and compartmentalized in subcellular rubber particles. A soluble E-prenyl transferase from the latex of Hevea brasiliensis serves as a famesyl diphosphate synthase and plays no direct role in elongation of Z-l,4-polyisoprene (Cornish, 1993). Because the hydro-phobic rubber molecule is produced inside a rubber particle but is formed from hydrophilic precursors from the cytoplasm, the polymerization reaction must take place at the particle surface. 

Biosynthesis. The initiating species in C. biosynthesis in Hevea brasiliensis is a derivative of trans-tram-famesyl diphosphate (i.e. a C15 allylic diphosphate), which is presumably modified at the methyl carbon of the dimethylallyl group. [Y. Tanaka etal. Initiation of Rubber Biosjmthesis in Hevea brasiliensis Characterization of Initiating Species by Structural Analysis Phytochemistry 41 (19 ) 1501-1505]... 

In the biosynthesis of steroids lanosterol and cycloartenol, the building blocks DMAPP and IPP are first joined through famesyl diphosphate synthase to form geranyl pyrophosphate (GPP) and then to form FPP, presqualene pyrophosphate, squalene, and (S)-squalene-2,3-epoxide by corresponding enzymes, sequentially. The product (S)-squalene-2,3-epoxide is used to synthesize the sterols lanosterol (in animals) and cycloartenol (in plants) by lanosterol synthase and cycloartenol synthase, respectively [3]. Further, lanosterol and cycloartenol are converted into other steroids through steroidogenesis. 

Famesyl diphosphate (FPP) is the starting molecule for the committed step in sesquiterpene biosynthesis, so artemisinin is synthesized from FPP via the mevalonate pathway in the cytosol (Fig. 89.15). A rational approach has enhanced artemisinin yields by the overexpression of famesyl diphosphate synthase... 

Biosynthesis of the sesquiterpene antibiotic albaflavenone in Streptomyces codicolor A3(2) was studied in detail. The mechanism and stereochemistry of the enzymatic formation of epi-isozizaene by multistep cyclization of famesyl diphosphate was investigated [101] and a P450 (CYP170A1) was identified to carry out two sequential allylic oxidations to convert epi-isozizaene to an epimeric mixture of albaflavenols and thence to albaflavenone [102],... 

Fig. 26 Schematic overview of terpene biosynthesis in plants. DMAPP, dimethylallyl diphosphate DXP, desoxyxylulose phosphate FPP, famesyl diphosphate GGPP, geranylgeranyl diphosphate GPP, geranyl diphosphate IPP, isopentenyl diphosphate MVA, mevalonate...

Figure 27.12 An overview of steroid biosynthesis from famesyl diphosphate.

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