Monoterpenes mevalonate

In plant plastids, GGPP is formed from products of glycolysis and is eight enzymatic steps away from central glucose metabolism. The MEP pathway (reviewed in recent literature - ) operates in plastids in plants and is a preferred source (non-mevalonate) of phosphate-activated prenyl units (IPPs) for plastid iso-prenoid accumulation, such as the phytol tail of chlorophyll, the backbones of carotenoids, and the cores of monoterpenes such as menthol, hnalool, and iridoids, diterpenes such as taxadiene, and the side chains of bioactive prenylated terpenophe-nolics such as humulone, lupulone, and xanthohumol. The mevalonic pathway to IPP that operates in the cytoplasm is the source of the carbon chains in isoprenes such as the polyisoprene, rubber, and the sesquiterpenes such as caryophyllene. 

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]... 

The biosynthesis of monoterpenes, the major components of peppermint essential oils, can be divided into four stages (Fig. 9.4). Stage 1 includes the formation of isopentenyl diphosphate (IPP) and dimethylallyl alcohol (DMAPP). In plants, two separate pathways are utilized for the synthesis of these universal C5 intermediates, with the cytosolic mevalonate pathway being responsible for the formation of sterols and certain sesquiterpenes, and the plastidial mevalonate-independent pathway being involved in the biosynthesis of isoprene, monoterpenes, certain sesquiterpenes, diterpenes, tetraterpenes, as well as the side chains of chlorophyll and plastoquinone.16 In peppermint oil gland secretory cells, however, the mevalonate pathway is blocked and the biosynthesis of monoterpenoid essential... 

Table 9.2 Incorporation rate of [2-14C]-pyruvate into monoterpenes of isolated peppermint oil gland secretory cells in the presence of fosmidomycin, a specific inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an enzyme of the mevalonate-independent pathway of isoprenoid biosynthesis.

Previously, the 14C-labeled mevalonic acid (12) was shown to be incorporated into the acid moiety [28, 29]. However, monoterpenes are generally biosynthesized via the MEP but not the mevalonate pathway. Hence, the author employed [1-13C] D-glucose (Fig. 2) as the precursor to examine whether the acid moiety is produced... 

It is well established that the iridoids are derived from two units of mevalonic acid (97), which itself is derived from acetyl-CoA. Mevalonate is also known to be a metabolic product of leucine (172), and the latter is a precursor of the monoterpene linalool (173). Wigfield and Wen (174) pursued the incorporation of leucine into the monoterpene unit in both vindoline (3) and catharanthine (4), where levels of 0.07 and 0.02%, respectively, were found, irrespective of the amount of precursor fed. This was important because, although initial results were obtained with [2- C] leucine, the specificity of incorporation was determined with 2- C-la-beled precursor. Two carbons in vindoline (3), C-8 and C-24, were en-... 

The incorporation of acetate into the monoterpene unit of the indole alkaloids has recently been reexamined (176). Using [l,2- C2]acetate it was established that no intact incorporation occurred, and a similar labeling pattern to that from [2- C2]acetate was observed, i.e., C-3, C-4, C-20, C-22, and C-23. Extensive scrambling of the acetate occurred via the Krebs cycle to label the 1 and 2 positions of acetate prior to incorporation. [2- C]Mevalonate was incorporated equally into C-17 and C-22 of ajmalicine (39), indicating that an equilibration occurs at some point in the pathway, as had been established previously with radiolabeled precursors 176). 

It is well known that the steroid hormones in mammals are biosynthesized from cholesterol. This compound is derived from the acetate-mevalonate pathway through the monoterpene geranyl pyrophosphate, which undergoes several enzymatic reactions to form the triterpene squalene. 

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]. 

It is generally agreed that mevalonate is the precursor to sterols in higher plants as well as in animals and is also the precursor to plant carotenoids. However, it is poorly incorporated into monoterpenes and into some diterpenes such as those of the taxane group.26 27 The alternative glyceraldehyde 3-... 

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. 

Battersby and Co-workers (25-28), Money et al (29) and Leete et al (30) all reported the specific incorporation of [2- C] mevalonic acid and [2- C] geraniol into representative examples of the corynanthe, aspidosperma and iboga groups of alkaloids, and in each case the distribution of radioactivity was in full agreement with the monoterpene hypothesis developed by Thomas (23) and Wenkert (2U), and according to the biogenetic isoprene rule that monoterpene are formed in nature by suitable modification of geranyl pyrophosphate (31). 

Low incorporations of bicarbonate, acetate, and mevalonate into the halogenated monoterpene metabolites (e.g., Structure 2.75) of Plocamium cartilagineum have been reported.82 In contrast to... 

Thus far no sex pheromone has been described in the Phasmida. Some phasmids produce toxic monoterpenes in typical Class III integumentary glands located behind the head (e.g. Happ et al., 1966). The glands exhibit lipid reserves, carboxylic esterases, phosphatases, alcohol dehydrogenase, and a mevalonate kinase, all of which are suggested to be involved in the production of the toxic compounds (Happ et al., 1966). 

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.

The IBP and its products are displayed in Figure 12.1. HMG-CoA, ultimately derived from acetyl-CoA is converted to mevalonate via the enzyme HMG-CoA reductase (HMGR) [8]. This reaction is the rate-limiting step in the pathway. Mevalonate is then phosphorylated via mevalonate kinase (MK) to yield 5-phosphomevalonate [9]. IPP is formed following additional phosphorylation and decarboxylation steps [10]. Isomerization of IPP via the enzyme IPP isomerase yields DMAPP [11]. In mammals, the enzyme farnesyl pyrophosphate synthase (FDPS) catalyzes the synthesis of both GPP and FPP [12]. In plants, a separate GPP synthase has been identified [13]. GPP is a key intermediate in plants as it serves as the precursor for all monoterpenes. In animals, however, GPP appears to serve only as an intermediate in the synthesis of FPP. Very low basal levels of GPP have been measured in cell culture, although cellular GPP levels can become markedly increased in the setting of FDPS inhibition [14]. 

Keywords biosynthesis genes monoterpenes sesquiterpenes diterpenes mevalonate pathway methylerythritol phosphate pathway... 

The non-mevalonate route to terpenoids appears to be localized in the plas-tids. In plant cells, terpenoids are manufactured both in the plastids and the cytosol (Gray, 1987 Kleinig, 1989). As a general rule, the plastids produce monoterpenes, diterpenes, phytol, carotenoids and the side chains of plas-toquinone and a-tocopherol, while the cytosol/ER compartment produces sesquiterpenes, sterols and dolichols. In the studies discussed above, nearly all of the terpenoids labelled by deox30cylulose (Sagner et al, 1998b Eisenreich et al, 2001) and 2-G-methyl erythritol feeding (Duvold et al, 1997) or... 

It is now firmly established that green plants use both iso-prenoid biosynthesis pathways (52). More specifically, sterols and triterpenes are generated in the cytoplasm via the mevalonate pathway, whereas monoterpenes and diterpenes are... 

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). 

C(4) to C(8) (equation 3). The in vivo labeling patterns of i/-3-thujone (48), sabinene (55) and other thujane-type monoterpenes derived from [2- C]mevalonic acid (56a) in various species are consistent with Ruzicka s hypothesis in which the double bond of the... 

---