Isopentenyl pyrophosphate formation

In keeping with its biogenetic origin m three molecules of acetic acid mevalonic acid has six carbon atoms The conversion of mevalonate to isopentenyl pyrophosphate involves loss of the extra carbon as carbon dioxide First the alcohol hydroxyl groups of mevalonate are converted to phosphate ester functions—they are enzymatically phosphorylated with introduction of a simple phosphate at the tertiary site and a pyrophosphate at the primary site Decarboxylation m concert with loss of the terti ary phosphate introduces a carbon-carbon double bond and gives isopentenyl pyrophos phate the fundamental building block for formation of isoprenoid natural products... 

The principal steps in the mechanism of polyisoprene formation in plants are known and should help to improve the natural production of hydrocarbons. Mevalonic acid, a key intermediate derived from plant carbohydrate via acetylcoen2yme A, is transformed into isopentenyl pyrophosphate (IPP) via phosphorylation, dehydration, and decarboxylation (see Alkaloids). IPP then rearranges to dimethylaHyl pyrophosphate (DMAPP). DMAPP and... 

It is immediately clear that Acanthomyops need not rely on dietary sources of terpenes but can synthesize citronellal and citral from either acetate or mevalonate. The higher total activity of the citronellal as compared with the citral probably reflects the natural preponderance of citronellal (ca. 90%) in the ant secretion. As the specific activities show, these results are consistent with a common biogenetic origin of both terpenes. In the mevalonic acid pathway as described from other organisms (13), the radioactive carbon of l-C14-mevalonate is lost upon formation of isopentenyl pyrophosphate. 

The substrate specificity of farnesyl pyrophosphate synthetase has been studied using 3-methyl-2-aIkenyl pyrophosphates (90) as models. When (90) bears a large side-chain i.e. R = C4H9), the reaction with isopentenyl pyrophosphate ceases after the formation of (91) and this reaction has been... 

Formation of the biological isoprene unit from mevalonic acid has been shown to proceed by stepwise phosphorylation of both alcohol groups, then elimination and decarboxylation to yield 3-methyl-3-butenyl pyrophosphate, 9 (often called A3-isopentenyl pyrophosphate) ... 

A quantum chemical investigation of the biosynthesis of farnesyl pyrophosphate through the condensation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate suggests that the mechanism is concerted, although the transition state has carbocationic character.164 Quantum chemical calculations were performed on the cyclization of the farnesyl cation to the sesquiterpene pentalenene.165 Two distinct pathways with similar activation barriers were identified, each differing from previous proposed mechanisms, and each involving unusual carbocationic intermediates. Mechanisms previously proposed for enzyme-catalysed formation of the sesquiterpene trichodiene involve carbocation intermediates with a 1,4-hydride transfer as the key step, e.g. (89) -> (90) - (91).166 Quantum chemical calculations, however, show a... 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

Sesquiterpenes have 15 carbons. The parent for this family is famesyl pyrophosphate, which is produced by the addition of the carbocation derived from geranyl pyrophosphate to isopentenyl pyrophosphate. This reaction is very similar to the formation of geranyl pyrophosphate shown in Figure 28.2. 

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). 

Unexpected results have come to light bearing on monoterpenoid biosynthesis (Chapter 1). Banthorpe s group have shown that in the formation of the thujane and camphor skeletons, activity from labelled mevalonic acid can appear predominantly in the C5 unit supposedly derived from isopentenyl pyrophosphate and only to a minor extent in the dimethylallyl pyrophosphate-derived portion. Banthorpe has also presented evidence for a chrysanthemyl intermediate, analogous to presqualene alcohol, in the biosynthesis of artemesia ketone. 

J Isopentenyl pyrophosphate arises biosynthetically by loss of CO2 from nevalonale, which itself results from a reaction of acetate with 3-ketobutyrate. Show the mechanism, and tell what kind of reaction is occurring in the formation of mevalonate. (Sec Section 29.5.)... 

A proposal for the formation of l -deoxy-o-xylulose-5-phosphate and its conversion to isopentenyl pyrophosphate is outlined in Fig. 43 [183, 185]. None of the enzymes involved have yet been cloned or characterized. 

The answer is d. (Murray, pp 505-626. Scrivei, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In the first stage ol cholesterol formation, acetyl coenzyme A condenses to form mevalonate, which is then phosphorylated and decarboxylated to form isopentenyl pyrophosphate. Half of the isopentenyl pyrophosphate isomerizes to form dimethylallyl pyrophosphate. These two isomeric C5 pyrophosphate units (isopentenyl pyrophosphate and dimethylallyl pyrophosphate) condense to form a CIO compound called geranyl pyrophosphate. Isopentenyl pyrophosphate then condenses with geranyl pyrophosphate to form the C15 compound farne-syl pyrophosphate. Finally, two farnesyl pyrophosphates condense in the presence of NADPH to form the C30 compound squalene. Squalene is ultimately cyclized through a series of steps to form cholesterol. Thus, the correct sequence of events leading from C5 units to C30 squalene is sequential condensation of 5-carbon units until a 15-carbon unit is formed, then condensation of two 15-carbon units to form squalene. 

Cholesterol is synthesized mainly in the liver by a three-stage process. All 27 carbon atoms in the cholesterol molecule are derived from acetyl-CoA. The first stage is the synthesis of the activated five-carbon isoprene unit, isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate then condense to form squalene in a sequence of reactions that also synthesize isoprenoid intermediates that are important in protein isoprenylation modifications. The characteristic four-ring structure of cholesterol is then formed by cycUzing of the linear squalene molecule. Several demethylations, the reduction of a double bond, and the migration of another double bond result in the formation of cholesterol. Figure 34-1 provides an overview of cholesterol biosynthesis. 

The above results strongly suggest that in the biological formation of the furanoquinoline alkaloids an isoprene unit (probably as isopentenyl pyrophosphate) is introduced into 2,4-dihydroxyquinoline to give (35). Cyclisation of this intermediate leads to isopropylidene-furanoquinolines e.g. platydesminium salt (36). Then elimination of the side chain gives the dictamnine (37) type. 

The isoprenoids are a vast array of biomolecules that contain repeating five-carbon structural units known as isoprene units (Figure 11.10). Isoprenoids are not synthesized from isoprene (methylbutadiene). Instead, their biosynthetic pathways all begin with the formation of isopentenyl pyrophosphate from acetyl-CoA (Chapter 12). 

Terpenoids do not necessarily contain exact multiples of five carbons and allowance has to be made for the loss or addition of one or more fragments and possible molecular rearrangements during biosynthesis. In reality the terpenoids are biosynthesized from acetate units derived from the primary metabolism of fatty acids, carbohydrates and some amino acids (see Fig. 2.10). Acetate has been shown to be the sole primary precursor of the terpenoid cholesterol. The major route for terpenoid biosynthesis, the mevalonate pathway, is summarized in Fig. 2.16. Acetyl-CoA is involved in the generation of the C6 mevalonate unit, a process that involves reduction by NADPH. Subsequent decarboxylation during phosphorylation (i.e. addition of phosphate) in the presence of ATP yields the fundamental isoprenoid unit, isopentenyl pyrophosphate (IPP), from which the terpenoids are synthesized by enzymatic condensation reactions. Recently, an alternative pathway has been discovered for the formation of IPP in various eubacteria and plants, which involves the condensation of glyceraldehyde 3-phosphate and pyruvate to form the intermediate 1-deoxy-D-xylulose 5-phosphate (Fig. 2.16 e.g. Eisenreich et al. 1998). We consider some of the more common examples of the main classes of terpenoids below. 

Mevalonate is first phosphorylated and decarboxylated through four steps to give isopentenyl pyrophosphate and dimethylallyl pyrophosphate. Through three new steps these compounds react with each other to give squalene, an aliphatic hydrocarbon with 30 carbons and 6 double bonds. A hydroxyl group is introduced into squalene and formation of the typical ring system of the sterols takes place (Figure 5.1). 

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