Mevalonate, biosynthesis isopentenyl diphosphate from

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

But we do know those mechanisms Look back at the pathway for the biosynthesis of isopentenyl diphosphate from acetyl CoA, shown in Figure 27.7 on page 1100. It turns out that the rate-limiting step in the pathway is the reduction of 3-hydroxy-3-methylglutaryl CoA (abbreviated HMG-CoA) to mevalonate, brought about by the enzyme HMG-CoA reductase. If that enzyme could be stopped from functioning, cholesterol biosynthesis would also be stopped. 

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).

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. " ... 

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). 

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... 

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. 

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... 

The building unit of vitamin A and other isoprenoids is not isoprene, but its activated forms isopentenyl diphosphate and dimethylallyl diphosphate. Isopentenyl diphosphate is synthesised either from acetylcoenzyme A (an intermediate of its biosynthesis is mevalonic acid) or, alternatively, from 1-deoxy-D-xylulose 5-phosphate via 2-C-methyl-D-erythritol 4-phosphate and isopentenyl diphosphate. Gradual lengthening of the isoprenoid chain yields the immediate precursor of the carotenoids, geranylgeranyl diphosphate, with 20 carbon atoms in the molecule. The subsequent reactions of two molecules of geranylgeranyl diphosphate yield provitamins A (see Section 3.7.4.2). 

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... 

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