Isopentenyl diphosphate terpenoids from

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,... 

Figure 27.8 An overview of terpenoid biosynthesis from isopentenyl diphosphate.

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. 

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... 

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). 

Isoprene itself is not the true biological precursor of terpenoids.. As we ll see in Chapter 27, nature instead uses two "isoprene equivalents"—isopentenyl diphosphate and dimethylallyl diphosphate—which are themselves made by two different routes depending on the organism. Lanosterol, in particular, is biosynthesized from acetic acid by a complex pathway that has been workeo out in great detail. 

Assume that the three terpenoids in Problem 27.24 are derived bio.syntheti-cally from isopentenyl diphosphate and dimethylalhi diphosphate, each of w hich w as isotopically labeled at the diphosphate-bearing carbon atom (Cl). At what positions w ould the terpenoids be i.sotopicallv labeled ... 

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. 

Most terpenoids are derived from mevalonic acid (MVA) through the universal precursor isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP). Thus, the vast majority of terpenoids contain the basic structural residue 2-methylbutane, often less precisely referred to as isoprene units. These C5 hemiterpene units combine with... 

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. 

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