Geranyl pyrophosphate, synthesis

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-... 

In the synthesis of a-terpineol or limonene, for example, geranyl pyrophosphate isomerizes at one double bond to form neiyl pyrophosphate, a stereoisomer (Step [1] in the following reaction sequence). Neryl pyrophosphate then cyclizes to a 3° carbocation by intramolecular attack (Steps [2]-[3]). Nucleophilic attack of water on this carbocation yields a-terpineol (Step [4]) or loss of a proton yields limonene (Step [5]). Both products are cyclic monoterpenes. 

Figure 26.9. Condensation Mechanism in Cholesterol Synthesis. The mechanism for joining dimethylallyl pyrophosphate and isopentenyl pyrophosphate to form geranyl pyrophosphate. The same mechanism is used to add an additional isopentenyl pyrophosphate to form famesyl pyrophosphate.

Cholesterol is a steroid component of eukaryotic membranes and a precursor of steroid hormones. The committed step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (derived from acetyl CoA and acetoacetyl CoA). Mevalonate is converted into isopentenyl pyrophosphate (C5), which condenses with its isomer, dimethylallyl pyrophosphate (C5), to form geranyl pyrophosphate (Cjo)- The addition of a second molecule of isopentenyl pyrophosphate yields famesyl pyrophosphate (C15), which condenses with itself to form squalene (C30). 

Two pinene cyclases have been isolated from sage (19,35). Electrophoretically pure pinene cyclase I converts geranyl pyrophosphate to (+)-a-pinene and to lesser quantities of (+)-camphene and (+)-limonene, whereas pinene cyclase II, of lower molecular weight, converts the acyclic precursor to (-)-B-pinene and to lesser quantities of (-)-a-pinene, (-)-camphene and (-)-limonene. Both purified enzymes also utilize neryl and linalyl pyrophosphate as alternate substrates for olefin synthesis. The availability of enzyme systems catalyzing formation of enantiomeric products from a common, achiral substrate has provided an unusual opportunity to examine the stereochemistry of cyclization. 

The five-carbon compound used for the synthesis of ter-penes is isopentenyl pyrophosphate. The reaction of dimethylallyl pyrophosphate (formed from isopentenyl pyrophosphate) with isopentenyl pyrophosphate forms geranyl pyrophosphate, a 10-carbon compound. Geranyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate, a 15-carbon compound. Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound. Squalene is the precursor of cholesterol. Farnesyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form geranylgeranyl pyrophosphate, a 20-carbon compound. Two geranylgeranyl pyrophosphates join to... 

Conifers exhibit resistance to bark beetle attack and fungal invasion because of an Induced synthesis and flow of secondary resin which contains high levels of volatile monoterpenes. Monoterpene olefin synthases (geranyl pyrophosphate cyclases) were found in higher levels in fungus-infected lodgepole pine seedlings than in uninfected controls. 

Cholesterol, which is present in brain and in almost all tissues, is synthesised from isopentenyl pyrophosphate via squalene, farnesyl and geranyl pyrophosphates. The synthesis of squalene commences with the isomerisation of isopentenyl pyrophosphate to dimethylallyl pyrophosphate, after which successive condensations take place according to Equation 11.118. The hydrocarbon squalene is then transformed into the tetracyclic steroidal configuration of lanosterol by appropriate enzymes, and this is followed by conversion into cholesterol. Cholesterol is the precursor to most other steroids in the body. 

M. are biosynthesized from geranyl pyrophosphate (see Terpenes) via its isomer neryl pyrophosphate (Fig.). Aliphatic M. arise by hydrolysis of the phosphate bond, or the elimination of pyrophosphate (synthesis of 3,7-dimethyloctane type). Cyclic M. usually arise by nucleophilic substitution at Cl of the neryl pyrophosphate with loss of pyrophosphate. Iridoid compounds arise from the reductive cyclization of neryl pyrophosphate. 

If a further unit of IPP is now added to geranyl pyrophosphate, far-nesyl pyrophosphate, a sesquiterpene, is obtained. The addition occurs head to tail the CH2 group, the head of IPP, adds to the pyrophosphate end, the tail, of geranyl pyrophosphate. The resulting farnesyl pyrophosphate can be joined tail to tail to form an open chain triterpene. The latter, in turn, serves as the starting material for the synthesis of the cyclic triterpenes which include the steroids, compounds that are essential for all living organisms. 

Overhand, M., et al. (1998). Inhibitors of protein farnesyltransferase and protein geranyl-geranyl transferase I Synthesis of homologous diphosphonate analogues of isoprenylated pyrophosphate. Bioorg Chem 26 269-282. 

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). 

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