Isopentenyl diphosphate biosynthesis from

Kuzuyama T, Takagi M, Takahashi S, Seto H (2000) Cloning and characterization of 1-deoxy-D-xylulose 5-phosphate synthase from Streptomyces sp. Strain CL190, which uses both the mevalonate and nonmevalonate pathways for isopentenyl diphosphate biosynthesis. J Bacteriol 182 891... 

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. 

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

Figure 27.8 An overview of terpenoid biosynthesis from isopentenyl diphosphate.

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. 

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). 

Fig. 2. Schematic representation of paclitaxel biosynthesis. Dimethylallyl-diphosphate and isopentenyl-diphosphate are condensed through geranylgeranyl diphosphate synthase activity to render geranylgeranyl-diphosphate (GGPP). GGPP is converted into taxa-4(5), 11 (12)-diene in a reaction catalyzed by the taxane synthase (TS). A series of reactions catalyzed by cytochrome P450 monoxygenases lead to the production of a taxane intermediate that is further converted to baccatin III through enzymes-driven oxidation and oxetane ring formation. The side chain moiety of paclitaxel is derived from L-phenylalanine. Three consecutive arrows mean multiple steps. Ac, acetyl Bz, benzoyl.

The second pathway leads from acetyl-CoA to isopentenyl diphosphate active iso-prene ), the basic component for the isoprenoids. Its biosynthesis is discussed in connection with biosynthesis of the isoprenoid, cholesterol (see p. 172). 

The terpenes, carotenoids, steroids, and many other compounds arise in a direct way from the prenyl group of isopentenyl diphosphate (Fig. 22-1).16a Biosynthesis of this five-carbon branched unit from mevalonate has been discussed previously (Chapter 17, Fig. 17-19) and is briefly recapitulated in Fig. 22-1. Distinct isoenzymes of 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase) in the liver produce HMG-CoA destined for formation of ketone bodies (Eq. 17-5) or mevalonate.7 8 A similar cytosolic enzyme is active in plants which, collectively, make more than 30,000 different isoprenoid compounds.910 However, many of these are formed by an alternative pathway that does not utilize mevalonate but starts with a thiamin diphosphate-dependent condensation of glyceraldehyde 3-phosphate with pyruvate (Figs. 22-1,22-2). 

Until 1993, all terpenes were considered to be derived from the classical acetate/mevalonate pathway involving the condensation of three units of acetyl CoA to 3-hydroxy-3-methylglutaryl CoA, reduction of this intermediate to mevalonic acid and the conversion of the latter to the essential, biological isoprenoid unit, isopentenyl diphosphate (IPP) [17,18,15]. Recently, a totally different IPP biosynthesis was found to operate in certain eubacteria, green algae and higher plants. In this new pathway glyceradehyde-3-phosphate (GAP) and pyruvate are precursurs of isopentenyl diphosphate, but not acetyl-CoA and mevalonate [19,20]. So, an isoprene unit is derived from isopentenyl diphosphate, and can be formed via two alternative pathways, the mevalonate pathway (in eukaryotes) and the deoxyxylulose pathway in prokaryotes and plant plastids [16,19]. 

Figure 6.10 De novo biosynthesis of isoprenoid pheromone components by bark and ambrosia beetles through the mevalonate biosynthetic pathway. The end products are hemiterpenoid and monoterpenoid pheromone products common throughout the Scolytidae and Platypodidae (Figure 6.9A). The biosynthesis is regulated by juvenile hormone III (JH III), which is a sesquiterpenoid product of the same pathway. The stereochemistry of JH III is indicated as described in Schooley and Baker (1985). Although insects do not biosynthesize sterols de novo, they do produce a variety of derivatives of isopentenyl diphosphate, geranyl diphosphate, and farnesyl diphosphate. Figure adapted from Seybold and Tittiger (2003).

Figure 27 Four possible pathways for ABA biosynthesis. Open and closed circles show the 13C label from [1-13C]-d-glucose in the mevaloic acid pathway and the MEP pathway, respectively. DAP, dihydroxyacetone phosphate DXP, 1-deoxy-xylulose-5-phosphate FDP, farnesyl diphosphate GAP, glyceraldehyde-3-phosphate GGDP, geranylgeranyl diphosphate HMG-CoA, 3-hydroxy-3-methylglutaryl CoA IDP, isopentenyl diphosphate MEP, 2-C-methyl-D-erythritol-4-phosphate.

All isoprenoids are biosynthesized from two isomeric 5-carbon compounds, isopentenyl diphosphate (IPP, 86) and dimethylallyl diphosphate (DMAPP, 87) (Fig. 11). The mammalian pathway for the biosynthesis of these key biosynthetic precursors from three acetyl-CoA units (83) via mevalonate (85) had been elucidated in the 1950s (51). In the wake of that pioneering work, it became established dogma that all terpenoids are invariably of mevalonate origin, even in the face of significant aberrant findings. 

The carbon skeleton of isoprenoids is derived from the branched C5 skeleton of isoprene. Isopentenyl diphosphate and dimethylallyl diphosphate represent the biologic equivalents of isoprene. From research on cholesterol biosynthesis in liver tissues and on ergosterol in yeast, mevalonate was accepted as the universal precursor of isoprenoids. However this assertion is inaccurate. Incorporation of labeled acetate and glucose isotopomers into bacterial isoprenoids and into diterpenes of ginkgo embryos indicated fortuitously the existence of an alternative mevalonate-independent route. Its full elucidation required experiments using and H-labeled precursors followed by extensive nuclear magnetic resonance analyses as well as a combination of biochemical and molecular biology methods. These additional studies revealed a complete set of novel unsuspected enzymes. 

Terpenoids are derived from the cytosolic mevalonate pathway or from the plastidial 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway (see also Terpenoid Biosynthesis). Both pathways lead to the formation of the C5 units isopentenyl diphosphate and its allylic isomer dimethylallyl diphosphate, which are the basic terpenoid biosynthesis building blocks (Fig. 1). Although increasing evidence suggests that exchange of intermediates occurs between these compartments, the cytoplasmic mevalonate pathway is generally considered to supply the precursors for the production of sesquiterpenes and triterpenes (including sterols) and to provide precursors for protein prenylation and for ubiquinone and heme-A production in mitochondria. In the plastids, the MEP pathway supplies the precursors for the production of isoprene, monoterpenes, diterpenes (e.g., GAs), and tetraterpenes (e.g., carotenoids). 

Mevalonate diphosphate decarboxylase (MVP EC4.1.1.33) catalyzes the conversion of mevalonate diphosphate to isopentenyl diphosphate, a key building block for a large family of functionally important terpenoids. Fig. (6). This reaction is the third step in the biosynthesis of steroids and terpenoids from the mevalonate pathway, and the last well characterized step in the mevalonate pathway for the biosynthesis of isopentenyl pyrophophaste, the isoprenoids precursor [296-298]. Some reports showed that MVP is located predominantly in the cytosolic fraction and its expression is independent of peroxisome proliferation [299-300]. 

Of the nine complementation groups, coq2—coq8 are involved in the synthesis of the benzoquinone, while coql participates in the synthesis of the prenyl side chain. The isopentenyl diphosphate (IPP), required for the biosynthesis of the side chain precursor, hexaprenyl diphosphate (HexPP), for the yeast Q 6 unlike that of E. coli, is derived from the mevalonate pathway. " ... 

Fig. 1.4 Outline of terpenoid biosynthesis from isopentenyl diphosphate (IPP) via dimethylallyl diphosphate (DMAPP), gcranyl diphosphate (GPP), famesyl diphosphate (FPP) and geranylgcranyl diphosphate (GGPP). These reactions are catalyzed by isoprenyl diphosphate synthases and terpene synthases. The major products of the monoterpene, sesquiterpene, and diterpene pathways that constitute the oleoresm of Picea abies are listed. The general precursor IPP is derived either from the plastidial methylerythritol phosphate (MEP) pathway or the cytosolic mevalonaic pathway.

The isoprenoids are derived from mevalonic acid (MVA), which is formed from three molecules of acetyl-CoA (Fig. 3). Two molecules of acetyl-CoA are condensed, yielding acetoacetyl-CoA. Subsequently, this product is coupled with another molecule of acetyl-CoA to yield 35-hydroxy-3-methylglutaryl-CoA (HMG-CoA). By reduction of HMG-CoA MVA is obtained. MVA is further converted in some steps to yield the Cs-unit isopentenyl diphosphate (IPP), which is then isomerized to dimethy-lallyl diphosphate (DMAPP), the starter molecule of the isoprenoid pathway. Coupling of DMAPP with one or more IPP molecules yields the basic structures which form the backbone of terpenoid biosynthesis. A number of reviews on the early steps in the terpenoid biosynthesis have been published (70-77). 

Biosynthesis The biosynthesis of the C. proceeds in chloroplasts or chromoplasts in analogy to other iso-prenoids by way of 3-isopentenyl diphosphate ( active isoprene ). The colorless 15-cis-phytoene (C40) is formed from 2 molecules of geranylgeranyl diphosphate, further transformations furnish, wiaall-trans- -carotene (colored), all-trans- ycopenc. Subsequent cy-clization reactions allow the formation of other carotinoids. Xanthophvlls are formed from C. by incorporation of oxygen... 

The introduction to Section 24.8 pointed out that mevalonic acid is the biosynthetic precursor of isopentenyl diphosphate. The early steps in the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those in fatty acid biosynthesis (see Section 24.3) except that they do not involve acyl carrier protein. Thus, the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A. 

The early stages of carotenoid biosynthesis are common to the biosynthesis of all isoprenoids. The characteristic isoprenoid precursor, mevalonic acid (MVA) is converted into the C5 compound isopentenyl diphosphate (IDP), some of which is isomerized to dimethyallyl diphosphate (DMADP). The isoprenoid chain is then built from these precursors by means of prenyl transferase enzymes to give, successively, the Ciq geranyl... 

Tetraterpenes or carotenoids are synthesized from mevalo-nate precursors. Those involved in photosynthesis are synthesized in the chloroplast, but the enzymes specific for carotenoid biosynthesis are encoded in the nucleus, synthesized in cytoplasmic ribosomes, and transported into the chloroplast (Britton, 1993). Chloroplasts at different stages in development seem to differ in their ability to synthesize carotenoids autonomously from CO2 or by importation of isopentenyl pyrophosphate (isopentenyl diphosphate) (Britton, 1993). 

A proteinaceous inhibitor of rubber biosynthesis was purified from the C-serum of Hevea brasiliensis latex. The protein inhibited the incorporation of isopentenyl diphosphate into rubber. Purification was achieved by employing three column chromatography methods Sephadex G-150 gel filtration, DEAE-Cellulose ion exchange chromatography and Phenyl Sepharose CL-4B hydrophobic interaction chromatography. 21 refs. 

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