Isoprenoid mevalonic acid pathway

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. 

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...

Processes affecting the carbon-isotopic compositions of isoprenoid lipids. The isoprene carbon skeleton is indicated schematically in Figure 27. The corresponding biosynthetic reactant—equivalent in its role to acetyl-CoA—is isopentenyl pyrophosphate. As shown in Figure 29, this compound can be made by two different and fully independent pathways. The mevalonic-acid pathway was until recently thought to be the only route to isoprenoids. The deoxyxylulose-phosphate, or methylerythritol-phosphate, pathway was first discovered in Bacteria by Rohmer and coworkers (Flesch and Rohmer... 

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... 

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

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... 

In the past decade, eight inherited disorders have been linked to specific enzyme defects in the isoprenoid/cholesterol biosynthetic pathway after the finding of abnormally increased levels of intermediate metabolites in tissues and/or body fluids of patients (Table 5.1.1) [7, 9, 10]. Two of these disorders are due to a defect of the enzyme mevalonate kinase, and in principle affect the synthesis of all isoprenoids (Fig. 5.1.1) [5]. The hallmark of these two disorders is the accumulation of mevalonic acid in body fluids and tissues, which can be detected by organic acid analysis, or preferably, by stable-isotope dilution gas chromatography (GC)-mass spectrometry (GC-MS) [2]. Confirmative diagnostic possibilities include direct measurement of mevalonate kinase activities in white blood cells or primary skin fibroblasts [3] from patients, and/or molecular analysis of the MVK gene [8]. 

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]. 

Isoprenoid structures for carotenoids, phytol, and other terpenes start biosynthetically from acetyl coenzyme A (89) with successive additions giving mevalonate, isopentyl pyrophosphate, geranyl pyrophosphate, farnesyl pyrophosphate (from which squalene and steroids arise), with further build-up to geranyl geranyl pyrophosphate, ultimately to a- and /3-carotenes, lutein, and violaxanthin and related compounds. Aromatic hydrocarbon nuclei are biosynthesized in many instances by the shikimic acid pathway (90). More complex polycyclic aromatic compounds are synthesized by other pathways in which naphthalene dimerization is an important step (91). 

Several metabolic pathways for the biosynthesis of aromatic compounds are now known, (a) The aromatization of alicyclic and isoprenoid compounds derived from mevalonic acid, as in the formation of estrone (I) from testosterone (II). A very common example of this process, which has not yet been experimentally demonstrated, is probably the aromatization of a O OH... 

The so-called acetate-malonate pathway leads to three different kinds of natiu al products depending on the detailed pathway followed. Fatty acids result from a reductive pathway to be described here, but acetate and malonate are also precursors for the isoprenoids (terpenes and sterols) produced via mevalonic acid (Ce) and... 

The diverse, widespread and exceedingly numerous class of natural products that are derived from a common biosynthetic pathway based on mevalonate as parent, are synonymously named terpenoids, terpenes or isoprenoids. Essentially, they are derived from the basic 5-carbon isoprene unit, biosynthetically as isopentenyl pyrophosphate, which is itself derived from aeetate via mevalonic acid. They may be classified into diverse groups according to the number of isoprene units, e.g.. 

The natural precursors of any flavourings of this group are isopentenylpyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). In the classic pathway these are synthesised from three molecules acetyl/malonyl-CoA via mevalonic acid (MA). Recently a second pathway of the isoprenoid biosynthesis has been detected, in which IPP and DMAPP are synthesised from pyruvate and glyceraldehyde 3-phosphate via deoxyxylulose (DOX) 5-phosphate [322-324],... 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

Figure 2. The mevalonic acid biosynthetic pathway. The transformation of hy-droxymethyl-coenzyme A (HMG-CoA) to mevalonic acid is the first committed step of the pathway. The enzyme, HMG-CoA reductase, catalyzes this step and is inhibited by the compounds, mevinolin and compactin. Note that farnesyl-pyrophosphate (Farnesyl-PP), the substrate of the protein, farnesyltransferase, can be used to make cholesterol or elongated to make geranylgeranyl-pyrophosphate (Geranylgeranyl-PP). The later compound is the substrate for the protein, geranylgeranyltransferase, or is further elongated to make the long-chain isoprenoids, dolichols, ubiquinones, and isoprenoic acids.

Like all steroids, brassinosteroids derive from a single common precursor mevalonic acid. Some phytohormones are synthesized totally or in part via the isoprenoid pathway, such as absdsic acid, gibberellins and cytokinins. The importance of this biosynthetic pathway in processes involved with cell cycle regulation and tumorigenesis in mammals is well documented. Having in mind the similarities between certain regulatory systems in plants and animals the question arose whether brassinosteroids as putative plant steroid hormones would show a specific effect on plant tumor cells. 

The mevalonate pathway in the cytosol is responsible for biosynthesis of sterols, sesquiterpenes, and triterpenoids. After conversion of mevalonic acid to isopentenyl pyrophosphate, three C5 units can be joined head to tail to produce a C15 compound, famesyl pyrophosphate. Two famesyl pyrophosphates are then united head to head to form squalene, the progenitor of the C30 isoprenoids from which sterols are derived. The plant squalene synthetase, like its mammalian homologue, is found in the ER and the reaction proceeds via a presqualene pyrophosphate intermediate (Chapter 14). In the last step prior to cyclization, squalene is converted to squalene 2,3-epoxide. 

Interest in enzyme stereospecificity and the stereochemistry of prochiral centres, such as the methylene groups of mevalonic acid, has necessitated more precise definitions of the stereochemistry of the various molecules involved and of the enzymological consequences. The use of multiply labelled mevalonic acid in terpenoid and steroid biosynthesis has been reviewed by Hanson. The Proceedings of the 1970 Phytochemical Society symposium have been published. They include a general discussion of terpenoid pathways of biosynthesis by Clayton and specific chapters on monoterpenoids, diterpenoids, eedysones, carotenoids, isoprenoid quinones, and chromanols. Other reviews concerning biosynthesis have appeared on furanocoumarins, indole alkaloids, monoterpenoids, and diterpenoids. ... 

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). 

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