Famesyl diphosphate pyrophosphate

This enzyme [EC 2.5.1.29], also known as geranylgera-nyl-diphosphate synthase, catalyzes the condensation of transqrans-famesyl diphosphate and isopentenyl diphosphate to yield geranylgeranyl diphosphate and pyrophosphate. 

Chain elongation during polymerization of prenyl units can be terminated in one of a number of ways. The pyrophosphate group may be hydrolyzed to a monophosphate or to a free alcohol. Alternatively, two polyprenyl compounds may join "head to head" to form a symmetric dimer. The C30 terpene squalene, the precursor to cholesterol, arises in this way from two molecules of famesyl diphosphate as does phy-toene, precursor of the Qo carotenoids, from E,E,E geranylgeranyl diphosphate. The phytanyl groups of archaebacterial lipids (p. 385) arise rather directly from geranylgeranyl diphosphate by transfer of the poly-... 

IPP and DMAPP are interconverted by isopentenyl-di-phosphate D-isomerase (isopentenyl pyrophosphate dimethylallyl pyrophosphate isomerase isopentenyl pyrophosphate A -A -isomerase EC 5.3.3.2). This enzyme has been isolated from a number of plant sources, such as pumpkin, orange peel, and pine seedlings. Isopenenyl-diphosphate d-isomerase (from the fungus Claviceps) has a molecular weight of 35,000, a requirement for Mg, and an pH optimum of 6.0-8.5, and it is inhibited by geranyl and famesyl diphosphate. 

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. 

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. 

Sesquiterpenes are formed from three C5 units where a further molecule IPP reacts with GPP to form famesyl diphosphate (famesyl pyrophosphate, FPP). FPP is further converted to linear or cyclic products. By cleaving the diphosphate group, an allylic cation is produced that underlies an electrophilic attack on the central or distal double bond leading to cyclization. Due to the increased chain length and an additional double bond, a huge number of structures can be built up. Sesquiterpene cyclase enzymes typically produce a major product accompanied by a range of related structures [44]. 

Fig. 99.1 Proposed biosynthetic pathway of artemisinin in Artemisia annua L. plant. SQS Squalene synthase, ADS amorpha-4,11-diene synthase, FPP Famesyl diphosphate, FPS Famesyl pyrophosphate synthase, GPP Geranyl diphosphate, GPPS Geranyle diphosphate synthase, GS germaciene A synthase, DMAPP Dimethylallyl diphosphate, IPP isopeniraiyl diphosphate, CPS P-caryophyllene synthase, DBR2 double bond reductase 2, ECS epi-cedrol synthase, FPP fanesyl diphosphate, PS (E)-P-famesene synthase (Drawn based on informatitm published by Abdin et al., [18] and Zhang et al., 2005)...

Terpenes are synthesised in organisms by complex mechanisms from isoprene units, isopentenyl phosphate and dimethy-lallyl diphosphate (pyrophosphate). The first product is geranyl diphosphate, which is the universal precursor of monoterpenoids. The reaction of geranyl diphosphate with another molecule of isopentenyl diphosphate yields famesyl diphosphate, which is the precursor of sesquiterpenoids. Further reaction with isopentenyl diphosphate gives geranylgeranyl diphosphate, the precursor of diterpenoids (see Figure 3.10). 

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. 

The first reaction involves a prenyl transfer step in which C(10 of one of the allylic substrates (the donor) is bonded to the C(2)-C(3) double bonds of the other (the receptor) to produce a cyclopropylcarbinyl diphosphate with a CV-2-3 structure (Poulter, 1990). In this manner, famesyl pyrophosphate (8) yields presqualene pyrophosphate (9). Only (/ )-presqualene pyrophosphate has been found in nature. 

Upon the synthesis of IPP (C5) and its isomer DMAPP (C5) by either MVA or DXP pathways, the next step is chain elongation. The carbonium ion is a potent alkylating agent that can react with IPP (three molecules of IPP converted into one molecule of geranyl diphosphate (GPP) by condensation reaction catalyzed by enzyme geranyl diphosphate synthase), to yield geranyl diphosphate (GPP). Famesyl pyrophosphate synthase (EPS) is the prenyltransferase that catalyzes l -4 condensation reactions of IPP with the allylic diphosphates, dimethylallyl diphosphate (DMAPP), to produce famesyl pyrophosphate (FPP). 

IDI, laopentanyl diphosphate Isometase IPK, laopentenyl kinase FPPS, famesyl pyrophosphate synthase GPPS, geran pyrophosphate synthase Me(abo/Ass ... 

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