Famesyl diphosphate formation

Fig. 3 Proposed mechanisms for the formation of (+)-5-epi-aristolochene (2) and (-)-premnaspir-odiene (3) from famesyl-diphosphate (6) by the action of TEAS and HPS, respectively...

Draw famesyl diphosphate in the configuration that resembles the product, then draw its allylic isomer (the mechanism for the formation of the isomer is shown in Problem 27.7). In this reaction, a cyclization, followed by loss of a proton to form the double bond, gives helminthogermacrene. 

Now, arrange famesyl diphosphate to resemble the skeleton of oc-cadinene. The first step in the reaction sequence is formation of the allylic isomer of FPP the mechanism was shown in Problem 27.7. 

Schmidt, A. and Gershenzon, J. (2007) Cloning and characterization of isoprenyl diphosphate synthases with famesyl diphosphate and geranylgeranyl diphosphate synthase activity from Norway spruce (Picea abies) and their relation to induced oleoresin formation. Phytochemistry, 68, 2649-59. 

Hemiterpenoids are produced from the isoprenyl diphosphate DMAPP. All other terpenoids are produced from DMAPP and IPP via longer-chain prenyl diphosphate intermediates formed by prenyl transferases. Prenyl transferases (20) catalyze the formation of geranyl diphosphate (GPP), famesyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP) from one molecule of DMAPP and one, two, or three molecules of IPP, respectively (Fig. 1). Isoprenyl diphosphates are the substrates for all TPS, which lead to the hemiterpenoids, monoterpenoids, sesquiterpenoids, and diterpenoids, which will be highlighted with selected examples in the following sections. 

At GlaxoWellcome, an assay was developed for inhibition of squalene synthase in rat liver homogenates. Based on a 96 well microtitre plate format, the assay measured incorporation of [2- C] famesyl diphosphate into squalene. 

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],... 

Biological Formation of Geranyl Diphosphate 1135 Biological Formation of Famesyl Diphosphate 1136 Isomerization of Geranyl Diphosphate to Neryl Diphosphate Synthetic Polymers... 

Isopentenyl pyrophosphate is potentially a bifunctional molecule. Its terminal vinyl group gives a nucleophilic character whereas when it isomerizes to 3,3-dimethylallyl diphosphate, the latter is electrophilic. Thus, longer-chain polyprenyls are formed by a favourable condensation of isopentenyl pyrophosphate first with dimethylallyl pyrophosphate and later with other allylic diphosphates. The initial interconversion of isopentenyl diphosphate and dimethylallyl diphosphate is promoted by an isomerase. The successive condensations yield the Cio compound geranyl diphosphate and then the C15 farnesyl diphosphate. The two molecules of famesyl diphosphate condense to form presqualene pyrophosphate which is reduced by NADPH to give the C30 open chain terpenoid squalene. The condensation reactions with IPP are a rather novel method of C-C bond formation since in the formation of other types of natural products (peptides, sugars, fatty acids, etc.) the reactions involve Claisen- or aldol-type condensations. 

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