Isopentenyl diphosphate, biosynthesis terpenoids from

Figure 27.8 An overview of terpenoid biosynthesis from isopentenyl diphosphate.

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). 

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. 

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]. 

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). 

As artemisinin has a terpenic structure, its biosynthesis starts in the formation of isopentenyl diphosphate GPP)> as in all the natural terpenoids. In plants, IPP is synthesized either via the mevalonate pathway in the cytosol or via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway in the plastid. The IPP derived from the mevalonate pathway is generally used in the biosynthesis of sesquiterpenes (such as artemisinin), phytosterols, and triterpenes, and the IPP derived from the non-mevalonate pathway is employed in the biosynthesis of monoterpenes, diterpenes, and tetraterpenes (Fig. 89.15). 

The importance of terpenoids to life is highlighted by the fact that two separate pathways have been found to produce the terpenoid precursor C5 units isopentenyl diphosphate (IDP) and dimethylaUyl diphosphate (DMADP). The mevalonic acid (MVA) pathway is functional in archae, animals and fungi, 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway is found in green algae, and terpenoids are produced by both pathways in bacteria and plants [2]. In plants the MVA pathway is active in the cytosol and it provides C5 units for sesquiterpene, triterpene and polyterpene biosynthesis whereas the MEP pathway occurs in plastids and produces C5 units for isoprene, monoterpenes, diterpenes and carotenoids [1]. Recent reports have indicated metabolic crosstalk between biosynthesis pathways and e.g., the homoterpene DMNT may originate from both pathways. 

Vitamin E, as well as vitamin K, plastoquinones and ubiquinones, is formed, in principle, from shikimic acid via 4-hydroxyphenylpyruvic and homogentisic acid. The terpenoid side chain k synthesised from isopentenyl diphosphate, or more precisely from geranylgeranyl diphosphate, which is gradually reduced to phytyl diphosphate. The primary product of biosynthesis is 5-tocopherol other tocopherok are products of its methylation. The biosynthesis of tocotrienok lies in the condensation of homogentisic acid with geranylgeranyl diphosphate. Vitamin E k only synthesised by plants and some cyanobacteria. 

Although, terpenoids show enormous chemical and structural diversity, their backbones are synthesized from only two universal precursors isopentenyl pyrophosphate (IPP) and its highly electrophilic allyUc isomer dimethylaUyl pyrophosphate (DMAPP) [25]. IPP is isomerized to DMAPP by the enzyme isopentenyl pyrophosphate isomerase. The mevalonate pathway for the biosynthesis of terpenoids has been illustrated in Fig. 86.3. To summarize, the active isoprene unit (IPP) is repetitively added to DMAPP or a prenyl diphosphate in sequential head-to-tail... 

Carotenoids are synthesized from the basic C5 terpenoid precursor isopentenyl pyrophosphate (IPP) and dimethylallyl diphosphate (DMAPP). These precursors can be obtained from two distinct pathways the mevalonate pathway (MVA) and the non-MVA pathway also known as 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway [84, 85]. All eukaryotes use the MVA pathway, whereas plant plastids and most bacteria use the MEP pathway [86,87]. Some bacteria also use the MVA pathway [84]. In the MEP pathway, the first step in IPP biosynthesis is the formation of l-deoxy-D-xylulose-5-phosphate (DXP) from pyruvate and glyceraldehyde-3-phosphate catalyzed by DXP synthase (Figure 10.7). DXP is then reduced to MEP by DXP reductase. Additional MEP pathway enzymes are then used in subsequent reactions for converting MEP to IPP, which is isomer-ized to DMAPP by the enzyme IPP isomerase. The MVA pathway begins with the conversion of three molecules of acetyl-CoA to MVA through acetoacetyl-CoA... 

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