Mevalonic acid-5-diphosphate

The final decarboxylation of mevalonate 5-diphosphate appears unusual because decarboxylations of acids do not typically occur except in /3-keto acids and malonic acids, in which the carboxylate group is two atoms away from an additional carbonyl group (Section 22.7). The function of this second carbonyl group is to act as an electron acceptor and stabilize the charge resulting from loss of CC>2- In fact, though, the decarboxylation of a /3-kelo acid and the decarboxylation of mevalonate 5-diphosphate are closely related. 

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... 

The isoprenoid side chains of quinones are biosynthesized mainly by the mevalonic acid pathway from acetyl-CoA. Another pathway to biosynthesizing isoprenoids is the so-called non-mevalonate ronte by which isopentenyldiphosphate (IPP) is formed from glyceraldehyde 3-phosphate and pyrnvate. The key molecule is the famesyl-diphosphate (FPP) that accepts other IPP molecules to form polyprenyl diphosphates. 

Ginsenosides are bios)mthesized via the isoprenoid pathway in the cytosol with mevalonic acid as the precursor for isopentenyl diphosphate (IFF) and dimethylallyl diphosphate (DMAPP), which are the two C5 starting units in the bios)mthesis of ginsenosides and other terpenoids... 

This enzyme [EC 4.1.1.33] (also known as mevalonic acid 5-pyrophosphate anhydrodecarboxylase, mevalonate-5-diphosphate decarboxylase, and diphosphomevalonate decarboxylase) catalyzes the reaction of ATP with (R)-5-diphosphomevalonate to produce ADP, orthophosphate, isopentenyl diphosphate, and carbon dioxide. 

Fig. 11 Natural rubber is produced from a side branch of the ubiquitous isoprenoid pathway, with 3-hydroxy-methyl-glutaryl-CoA (HMG-CoA) as the key intermediate derived from acetyl-CoA by the general mevalonic-acid pathway. Mevalonate diphosphate decarboxylase (MPP-D) produces IPP, which is isomeiized to DMAPP by IPP isomerase (IPI). IPP is then condensed in several steps with DMAPP to produce GPP, FPP and GGPP by the action of a trani-prenyltransferase (TPT). The cA-l,4-polymeiization that yields natural rubber is catalyzed by cA-prenyltransferase (CPT), which uses the non-allylic IPP as substrate. Reprinted from [248], with permission from Elsevier...

Terpenes, biogenetically, arise from two simple five-carbon moieties. Isoprenyl-diphosphate (IPP) and dimethylallyldiphosphate (DMAPP) serve as universal precursors for the biosynthesis of terpenes. They are biosynthesised from three acetylcoenzyme A moieties through mevalonic acid (MVA) via the so-called mevalonate pathway. About 10 years ago, the existence of a second pathway leading to IPP and DMAPP was discovered involving l-deoxy-D-xylulose-5-phos-phate (DXP) and 2C-methyl-D-erythritol-4-phosphate (MEP). This so-called non-mevalonate or deoxyxylulose phosphate pathway starts off with the condensation of glyceraldehyde phosphate and pyruvate affording DXP. Through a series of reactions as shown in Fig. 4.1, IPP and DMAPP are formed, respectively [3,7, 42, 43]. 

Rubber also contains almost entirely Z double bonds. Consistent with this fact is the finding that the prenyltransferases catalyzing formation of rubber promote loss of the pro-R proton rather than the pro-S proton of mevalonic acid (see Eq. 22-2). There appear to be two types of prenyltransferase in animal mitochondria giving rise to E and Z double bonds, respectively.64 In contrast, the rubber tree contains a 137-residue protein, the rubber elongation factor. This small protein binds to E prenyltransferases causing them to form Z double bonds.65 The bacterium Micrococcus hit cits synthesizes all E polyprenyl alcohol diphosphates up to the 0 5 nonaprenyl compound solanesyl diphosphate.66... 

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]. 

The main problem in this approach is the very low permeability of mevalonic acid to membranes, resulting in very low incorporation. Positive results have been obtained by the use of cell-free systems incubated with [14C]-mevalonic acid,26,27 [14C]isopentenyl diphosphate,28 or [32P]orthophos-phate.29 Incubation of these radioactive lipids with glycosyl nucleotides labelled in the glycosyl group with a different isotope, followed by extraction and cochromatography in different solvent systems, may indicate that both compounds are present in the same molecule. When the lipid moiety becomes labelled from mevalonic acid or isopentenyl diphosphate, chromatography on DEAE-cellulose columns should be performed, in order to avoid confusion with steryl glycosides. 

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... 

Isopentenyl diphosphate isomerase (IPI E.C. 5.3.3.2) catalyzes the isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMADP), a previous and mandatory step to create the electrophilic allylic diphosphates needed for the condensation reaction generating geranyl diphosphate, Fig. (6). Thus, IPI is an essential enzyme in organisms which synthesize IPP through the mevalonic acid pathway as archaea, eukaryota and some Gram-positive bacteria [275, 305]. 

Isopentenyl diphosphate (pyrophosphate) (5.5) provides the isoprene unit of the terpenoids and steroids. There are two major routes by which it is formed (Scheme 5.1). The first involves mevalonic acid (5.4) and the second, quite... 

The ophiobolin carbon skeleton is formed by the cyclization of geranylfar-nesyl diphosphate, as shown in 5.139, although an isomerization of the 2-trans double bond to the cis isomer is required to generate the correct stereochemistry. The incorporation of [2- C]mevalonic acid and geranylfarnesyl diphosphate... 

The early steps in the ergot alkaloid biosynthetic pathway are outlined in Fig. 1. The first determinant and rate-limiting step is the prenylation of tryptophan to 4-(y,y-dimethylallyl)tryptophan (DMAT), catalyzed by dimethy-lallyl-diphosphate L-tryptophan dimethylallyltransferase (DMAT synthase EC 2.5.1.34) (Heinstein et al., 1971 Gebler and Poulter, 1992). The prenyl group for the DMAT synthase reaction is provided in the form of dimethylallyl diphosphate (DMAPP), which is derived from mevalonic acid. After the formation of DMAT, the free amino group of this intermediate is N-methylated with a methyl group donated by S-adenosylmethionine (AdoMet). The N-methylated DMAT is then converted into chanoclavine I by closure of the... 

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