Mevalonate biosynthetic pathway

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).

Figure 10.7 All terpenes are derived from allylic diphosphates which are polymers of repeating isopentyl units (IPP) put together by the action of prenyltransferases. In plants, IPP can be derived from the mevalonate biosynthetic pathway (a cytoplasmic pathway) or the methyl erythritol phosphate pathway (a plastidic pathway). Monoterpenes are then derived from the CIO precursor geranyl diphosphate (GPP), sesquiterpenes from the C15 precursor famesyl diphosphate (FPP), and diterpenes from the C20 precursor geranylgeranyl diphosphate (GGPP) by the action of terpene synthases or cyclases, which divert carbon into the specific branch pathways.

In fungi, carotenoids are derived by sequence reactions via the mevalonate biosynthetic pathway. The main product 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) is finally reduced to the mevalonic acid. This two-step reduction of HMG-CoA to mevalonate is highly controlled and is also a major control factor of sterol synthesis (Metzler 2003). 

Bark beetles oxidise toxic monoterpenoid hydrocarbons in their respiratory air, which originate from the resin of the tree they colonise, and thereby circumvent this defense barrier of the tree. Converting these compounds into less toxic secondary metabolites serves another purpose, by providing pheromones to attract insects of the same species, of both sexes. Therefore, an oxygen function is often introduced species-specifically and stereoselectively. European spruce bark beetles oxidise (-)-a-pinene to (S)-cis-verbenol, whereas pine beetles produce (R)-trans-verheno. In the California fivespined engraver Ips paraconfu-sus), myrcene is converted into (S)-ipsdienol and (S)-ipsenol. But Ips pint and Ips paraconfusus are also able to synthesise their pheromones de novo via the classical mevalonate biosynthetic pathway. 

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

Terpenoid substances are of broad distribution and diverse function in insects. One set, elaborated by the mandibular glands of Acanthomyops claviger, acts both as a defensive secretion and as an alarm releaser. When fed Cu-labeled acetate or mevalonate, laboratory colonies of these ants produce radioactive citronellal and citral, providing unambiguous evidence for de novo synthesis of these terpenes by the ant. The incorporations of these precursors implicate the mevalonic acid pathway as the likely biosynthetic route. 

Isoprenoids are intermediates and products of the biosynthetic pathway that starts with mevalonate and ends with cholesterol and other sterols. 

Evidence for de novo synthesis of pheromone components was obtained by showing that labeled acetate and mevalonate were incorporated into ipsdienol by male Ips pini [103,104]. Similarly, labeled acetate and other labeled intermediates were shown to be incorporated into frontalin in a number of Dendroctonus species [105]. Possible precursors to frontalin include 6-methyl-6-hep-ten-2-one, which was incorporated into frontalin by D. ruffipennis [106]. The precursor 6-methyl-6-hepten-2-one also was shown to be converted to bre-vicomin in the bark beetle, Dendroctonus ponderosae [107]. In addition, the expression patterns of HMG-CoA reductase and HMG-CoA synthase are tightly correlated with frontalin production in Dendroctonus jeffreyi [108, 109]. A geranyl diphosphate synthase cDNA from I. pini was also isolated, functionally expressed, and modeled [110]. These data indicate that the de novo isoprenoid biosynthetic pathway is present in bark beetles. A variety of other monoterpene alcohols such as myrcenol, pityol, and sulcitol are probably synthesized through similar pathways [111]... 

Fig. 2 Two possible biosynthetic pathways to pyrethrolone. The [l-13C]D-glucose-derived 13C labels that occur in the mevalonic acid and 2-C-methyl-D-erythritol 4-phosphate (13) pathways are colored in red and green, respectively. The phosphate moiety is indicated as P ...

Formation of mevalonate. The conversion of acetyl CoA to acetoacetyl CoA and then to 3-hydroxy-3-methylglutaryl CoA (3-HMG CoA) corresponds to the biosynthetic pathway for ketone bodies (details on p. 312). In this case, however, the synthesis occurs not in the mitochondria as in ketone body synthesis, but in the smooth endoplasmic reticulum. In the next step, the 3-HMG group is cleaved from the CoA and at the same time reduced to mevalonate with the help of NADPH+H 3-HMG CoA reductase is the key enzyme in cholesterol biosynthesis. It is regulated by repression of transcription (effectors oxysterols such as cholesterol) and by interconversion... 

The endergonic biosynthetic pathway described above is located entirely in the smooth endoplasmic reticulum. The energy needed comes from the CoA derivatives used and from ATP. The reducing agent in the formation of mevalonate and squalene, as well as in the final steps of cholesterol biosynthesis, is NADPH+H ... 

The mevalonate-independent pathway is present in most bacteria and all phototropic organisms. In higher plants and most algae both pathways run independently. The mevalonate pathway is located in the cytoplasm and is responsible for the biosynthesis of most sesquiterpenoids. The mevalonate-independent pathway, in contrast, is restricted to the chloroplasts where plastid-related isoprenoids such as monoterpenes and diterpenes are biosynthesised via this pathway [43-45]. Figure 4.2 illustrates the interrelationships of both biosynthetic pathways connected to Fig. 4.1 [46]. 

Fig. 5.1.1 Isoprenoid biosynthetic pathway. The enzyme mevalonate kinase (black solid bar) is deficient in patients affected with mevalonic aciduria and hyperimmunoglobulinemia D and periodic fever syndrome. -CoA -Coenzyme A, HMG-CoA 3-hydroxy-3-methyl-glutaryl-coenzyme A, -PP -pyrophosphate...

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]. 

Figure 22-5 Structures and partial biosynthetic pathways for a few of the more than 600 known carotenoid compounds. The origin of some hydrogen atoms from mevalonate is shown, using the numbering for mevalonate. The numbering system for C40 carotenoids is also indicated.

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, with the important subgroup of steroids, sometimes singled out as a class in its own right. Monoterpenes, sesquiterpenes, diterpenes and triterpenes are ubiquitous in terrestrial organisms and play an essential role in life, as we know it. Although the study of terrestrial terpenes dates back to the last century, marine terpenes were not discovered until 1955. 

Metabolites of the ergoline type [as (128)], as well as those of type (119), have been isolated from Penicillium roqueforti. The incorporation has been observed of radioactive samples of tryptophan and mevalonate into both series of metabolites, and of histidine into those of type (119).44 Diversion from tryptophan into the two independent biosynthetic pathways is initiated on the one hand by the formation of (122) and on the other by reaction with histidine to give a diketopiperazine precursor for metabolites such as (119). Which route is followed is temperature-dependent. 

A mevalonate-independent isoprenoid biosynthetic pathway occurring only among bacteria, algae, and plants was also identified in/ falciparum and Tgondii.Fosmidomycin, known to inhibit 1-deoxy-D-xylulose-5-phosphate isomerase in this pathway, was found to also inhibit in vitro growth of P falciparum and to cure P vinckei infection in mice. However, the same questions about whether the pathway plays an indispensable role in this parasitic organism and whether fosmidomycin inhibits the parasites by inhibiting the particular enzyme remain to be answered. 

It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). 

The biosynthesis of monoterpenoids and camphor has been described by several authors (108-llU). Ruzicka (115,116) proposed a unified biogenetic scheme for terpenes. The biosynthetic building blocks for these terpenes are iso-prene units. The biosynthetically active isoprene units are isopentenyl pyrophosphate [l] and dimethyl allyl pyrophosphate [2] the compounds that are derived from acetate via mevalonic acid (Scheme V). Geranyl pyrophosphate [3] is the C-10 precursor for the terpenes (117). Banthorpe and Baxendale (ll8) confirmed the biosynthetic pathway of (iamphor via acetate mevalonate by conducting degradation study of camphor, biosynthesized from l c labelled mevalonic acid. The biosynthesis of camphor is summarised in Scheme VI. 

The incorporation of label from mevalonate into ABA, a sesquiterpenoid, has been demonstrated in different parts of plants ( . . 41). This indicates that ABA can be synthesized throughout the plant. In addition to the direct incorporation of three isoprene units, derived from mevalonate, into ABA, an indirect biosynthetic pathway via carotenoids has been proposed. This idea stems from the finding that xanthophylls, in particular violaxanthin, can either photochemically or enzymatically be converted to the neutral inhibitor xanthoxin (42) (Figure 3). When labeled xanthoxin was fed in the transpiration stream to bean or tomato shoots, ca. 10% was converted to ABA over an 8-hr period (43). However, the importance of the biosynthetic route to ABA via xanthophylls and xanthoxin in normal metabolism remains to be established, and most of the evidence favors the direct synthesis route via a precursor (see 2). 

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