Isopentenyl- diphosphate

Two SN1 reactions occur during the biosynthesis of geraniol, a fragrant alcohol found in roses and used in perfumery. Geraniol biosynthesis begins with dissociation of dimethylallyl diphosphate to give an allylic carbocation, which reacts with isopentenyl diphosphate (Figure IT 15). From the viewpoint of isopentenyl diphosphate, the reaction is an electrophilic alkene addition, but from tile viewpoint of dimethylallyl diphosphate, the process in an Sjjl reaction in which the carbocation intermediate reacts with a double bond as the nucleophile. 

In plants, terpenes (see Chapter 6 Focus On) are biosynthesized by a pathway that involves loss of CO2 from 3-phosphomevalonate 5-diphosphate to yield isopentenyl diphosphate. Use curved arrows to show the mechanism of this reaction. 

In the Chapter 6 Focus On, "Terpenes Naturally Occurring Alkenes," we looked briefly at terpenoids, a vast and diverse group of lipids found in all living organisms. Despite their apparent structural differences, all terpenoids are related. All contain a multiple of five carbons and are derived biosynthetically from the five-carbon precursor isopentenyl diphosphate (Figure 27.6). Note that formally, a... 

Terpenoids are classified according to the number of five-carbon multiples they contain. Monoterpenoids contain 10 carbons and are derived from two isopentenyl diphosphates, sesquiterpenoids contain 15 carbons and are derived from three isopentenyl diphosphates, diterpenoids contain 20 carbons and are derived from four isopentenyl diphosphates, and so on, up to triterpenoids (C30) and tetraterpenoids (C40). Monoterpenoids and sesquiterpenoids are found primarily in plants, bacteria, and fungi, but the higher terpenoids occur in both plants and animals. The triterpenoid lanosterol, for example, is the precursor from which steroid hormones are made, and the tetraterpenoid /3-carotene is a dietary source of vitamin A (Figure 27.6). 

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids arise primarily from the mevalonate pathway, whereas monoterpenoids, diterpenoids, and tetraterpenoids are biosynthesized by the 1-deoxyxylulose 5-phosphate (DXP) pathway. In bacteria,... 

The mevalonate pathway for the biosynthesis of isopentenyl diphosphate from three molecules of acetyl CoA. Individual steps are explained in the text. 

O Phosphorylation of the tertiary hydroxyl and diphosphorylation of the primary hydroxyl, followed by decarboxylation and simultaneous expulsion of phosphate, gives isopentenyl diphosphate, the precursor of terpenoids,... 

Step 4 of Figure 27.7 Phosphorylation and Decarboxylation Three addition reactions are needed to convert mevalonate to isopentenyl diphosphate. Th first two are straightforward phosphorylations that occur by nucleophilic sul stitution reactions on the terminal phosphorus of ATP. Mevalonate is first cor verted to mevalonate 5-phosphate (phosphomevalonate) by reaction wit ATP in a process catalyzed by mevalonate kinase. Mevalonate 5-phosphat then reacts with a second ATP to give mevalonate 5-diphosphate (diphosphc mevalonate). The third reaction results in phosphorylation of the tertiar hydroxyi group, followed by decarboxylation and loss of phosphate ion. 

Problem 27.6 1 Studies of the conversion of mevalonate 5-phosphate to isopentenyl diphosphate have shown the following result. Which hydrogen, pro-R or pro-S, ends up cis to the methyl group, and which ends up trans ... 

The conversion of isopentenyl diphosphate (IPP) to terpenoids begins with its isomerization to dimethylallyl diphosphate, abbreviated DMAPP and formerly called dimethylallyl pyrophosphate. These two C5 building blocks then combine to give the C10 unit geranyl diphosphate (GPP). The corresponding alcohol, geraniol, is itself a fragrant terpenoid that occurs in rose oil. 

Figure 27.8 An overview of terpenoid biosynthesis from isopentenyl diphosphate.

The isomerization of isopentenyl diphosphate to dimethylally diphos phate is catalyzed by JPP isomerase and occurs through a carbocation pathway Protonation of the IPP double bond by a hydrogen-bonded cysteine residue ir the enzyme gives a tertiary carbocation intermediate, which is deprotonated b a glutamate residue as base to yield DMAPP. X-ray structural studies on the enzyme show that it holds the substrate in an unusually deep, well-protectec pocket to shield the highly reactive carbocation from reaction with solvent 01 other external substances. 

Figure 27.9 Mechanism of the coupling reaction of dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP), to give geranyl diphosphate (GPP).

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

Diterpenoids are derived biosynthetically from geranylgeranyl diphosphate (GGPP), which is itself biosynthesized by reaction of farnesvl diphosphate with isopentenyl diphosphate. Show the structure of GGPP, and propose a mechanism for its biosynthesis horn FPP and IPP. 

Methyl-l-propanol, l3C NMR spectrum of. 453 2-Methylpropene, heat of hydrogenation of. 187 Mevalonate, decarboxylation of, 1075 isopentenyl diphosphate from, 1072-1075... 

Step 2—Formation of Isoprenoid Units Mevalonate is phosphorylated sequentially by ATP by three kinases, and after decarboxylation (Figure 26-2) the active isoprenoid unit, isopentenyl diphosphate, is formed. 

Isopentenyl diphosphate is isomerized by a shift of the double bond to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate ger-anyl diphosphate (Figure 26-2). A further condensation with isopentenyl diphosphate forms farnesyl diphosphate. Two molecules of farnesyl diphosphate condense at the diphosphate end to form squalene. Initially, inorganic pyrophosphate is eliminated, forming presqualene diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule. 

The polyisoprenoids dolichol (Figure 14-20 and Chapter 47) and ubiquinone (Figure 12-5) are formed from farnesyl diphosphate by the further addition of up to 16 (dolichol) or 3-7 (ubiquinone) isopentenyl diphosphate residues, respectively. Some GTP-binding proteins in the cell membrane are prenylated with farnesyl or geranylgeranyl (20 carbon) residues. Protein prenylation is believed to facilitate the anchoring of proteins into lipoid membranes and may also be involved in protein-protein interactions and membrane-associated protein trafficking. 

Since carotenoids are isoprenoids, they share a common early pathway with other biologically important isoprenoids such as sterols, gibberellins, phytol and the terpenoid quinones (Fig. 13.3). In all cases, these compounds are derived from the C5 isoprenoid, isopentenyl diphosphate (IPP). Until a few years ago it was believed that a single pathway from the Cg precursor mevalonic acid (MVA) formed IPP, which itself was synthesised from hydroxymethylglutaryl coenzyme A (HMG CoA) by the action of HMG... 

IPP = isopentenyl diphosphate GPP = geranyl diphosphate FPP = farnesyl diphosphate ... 

KAJIWARA s, FRASER p D, KONDO K and MISAWA N (1997) Expressiou of an exogenous isopentenyl diphosphate isomerase gene enhances isoprenoid biosynthesis in Escherichia coli Biochem J, 324, 421-6. 

Subsequent cyclizations, dehydrogenations, oxidations, etc., lead to the individual naturally occurring carotenoids, but little is known about the biochemistry of the many interesting final structural modifications that give rise to the hundreds of diverse natural carotenoids. The carotenoids are isoprenoid compounds and are biosynthesised by a branch of the great isoprenoid pathway from the basic C5-terpenoid precursor, isopentenyl diphosphate (IPP). The entire biosynthesis takes place in the chloroplasts (in green tissues) or chromoplasts (in yellow to red tissues). 

Cunningham, EX. Jr. and Gantt, E., Identification of multi-gene families encoding isopentenyl diphosphate isomerase in plants by heterologous complementation in Escherichia coli. Plant Cell Physiol. 41, 119, 2000. 

Enfissi, E.M.A. et al., Metabohc engineering of the mevalonate and non-mevalonate isopentenyl diphosphate-forming pathways for the production of health-promoting isoprenoids in tomato. Plant Biotechnol. J. 3, 17, 2005. 

Kim, S.-W. and Keasling, J.D. (2001) Metabolic engineering of the nonmevalonate isopentenyl diphosphate synthesis pathway in Escherichia coli enhances lycopene production. Biotechnology and Bioengineering, 12, 408-415. 

Rodriguez-Concepcion, M., Campos, N., Lois, L.M. et al. (2000) Genetic evidence of branching in the isoprenoid pathway for the production of isopentenyl diphosphate and dimethylallyl diphosphate in Escherichia coli. FEBS Letters, 473, 328-332. 

Figure 73. The carotenoid biosynthetic pathway. Enzymes are named according to the designation of their genes Ccs, capsanthin-capsorubin synthase CrtL-b, lycopene-b-cyclase CrtL-e, lycopene-e-cyclase CrtR-b, b-ring hydroxylase, CrtR-e, e-ring hydroxylase DMADP, dimethylallyl diphosphate GGDP, geranylgeranyl diphosphate Ggps, geranylgeranyl-diphosphate synthase IDP, isopentenyl diphosphate Ipi, IDP isomerase Pds, phytoene desaturase Psy, phytoene synthase Vde, violaxanthin de-epoxidase Zds, z-carotene desaturase Zep, zeaxanthin epoxidase. (From van den Berg and others 2000.)...

McClard, R.W., Fujita, T.S., Stremler, K.E., and Poulter, C.D., Novel phospho-nylphosphinyl (P-C-P-C-) analogues of biochemically interesting diphosphates. Syntheses and properties of P-C-P-C- analogues of isopentenyl diphosphate and dimethylallyl diphosphate, ]. Am. Chem. Soc., 109,5544,1987. 

The biosynthesis of monoterpenes, the major components of peppermint essential oils, can be divided into four stages (Fig. 9.4). Stage 1 includes the formation of isopentenyl diphosphate (IPP) and dimethylallyl alcohol (DMAPP). In plants, two separate pathways are utilized for the synthesis of these universal C5 intermediates, with the cytosolic mevalonate pathway being responsible for the formation of sterols and certain sesquiterpenes, and the plastidial mevalonate-independent pathway being involved in the biosynthesis of isoprene, monoterpenes, certain sesquiterpenes, diterpenes, tetraterpenes, as well as the side chains of chlorophyll and plastoquinone.16 In peppermint oil gland secretory cells, however, the mevalonate pathway is blocked and the biosynthesis of monoterpenoid essential... 

Figure 9.4 Monoterpene biosynthesis in peppermint oil gland secretory cells. The enzymes involved in this pathway are (1) 1-deoxy-D-xylulose 5-phosphate synthase, (2) 2-C-methyl-D-erythritol 4-phosphate reductoisomerase, (3) 2-C-methyl-D-erythritol 4-phosphate cytidyltransferase, (4) 4-(cytidine 5 -diphospho)-2-C-methyl-D-erythritol kinase, (5) 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, (6) isopentenyl diphosphate isomerase, (7) geranyl diphosphate synthase, (8)...

LANGE, B.M., CROTEAU, R., Isopentenyl diphosphate biosynthesis via a mevalonate-independent pathway isopentenyl monophosphate kinase catalyzes the terminal enzymatic step, Proc. Natl. Acad. Sci. USA, 1999,96,13714-13719. 

McCASKILL, D., CROTEAU, R., Monoterpene and sesquiterpene biosynthesis in glandular trichomes of peppermint Mentha x piperita) rely exclusively on plastid-derived isopentenyl diphosphate, Planta, 1995,197,49-56. 

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