Prenyl sesquiterpenes

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. 

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)... 

In combination with sesquiterpene lactones, the chromenes and benzofurans are another group of defensive compounds that desert Invertebrates have to detoxify. Indeed, the success of many desert sunflower species Is In part due to their diverse secondary chemistry. Prenylated qulnones, on the other hand seem to be restricted to the Hydrophyllaceae and tropical trees. The qulnones are extremely active chemicals that exhibit Insecticidal activity at concentrations lower than many chromenes. The prenylated qulnones of Phacella are also potent cytotoxlns and allergens. 

One reason that dominant plants are successful in semi-arid and arid ecosystems is due to the high concentration of terpenoids and prenylated phenolics that repel and/or deter feeding by herbivorous insects. Compounds like sesquiterpene lactones and benzopyrans are present in high quantities in the leaves of species of Pjajl t h ij jn, E n c e l i a and D i c o r i a and have been demonstrated to be effective feeding deterrents against known economic insect pests. Ijt vivo experiments are still needed in the field with bioactive constituents to better understand their effects on native phytophagous insects. 

The prenyl diphosphates, GPP, FPP and GGPP, are the central intermediates of terpenoid bios)mthesis. Under the catalysis of monoterpene, sesquiterpene and diterpene synthases, respectively, these substances are transformed into... 

The MVA pathway was accepted as the unique biosynthetic pathway for the formation of aU isoprenoids in aU living organisms. Discrepancies with this general assertion appeared, however, as early as the 1950s (1, 2). For instance, -labeled MVA was not incorporated into chloroplast isoprenoids (e.g., carotenoids 25 and phytol 24 from chlorophylls Fig. 6), whereas it was well incorporated into phytosterols 27 synthesized in the cytoplasm. Unexpected labeling patterns were found in the prenyl chain of ubiquinone 22 in Escherichia coli at incorporation of C-labeled acetate. Finally, the labeling pattern in an isoprene unit from the sesquiterpenic pentalenene 21 series from a Streptomyces species at incorporation of uniformly... 

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). 

With the preceding reviews of the enzymology of monoterpene cyclization and of model studies relevant to the cyclization process, it is possible to formulate a unified stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (Figure 4). The proposal which follows is consistent with the implications of parallel advances in related fields, most notably the contributions of Cane (8,16,24,25,52), Arigoni (67) and Coates (68,69) on the stereochemistry of sesquiterpene and diterpene cyclizations, and of Poulter and Rilling (29,70) on the stepwise, ionic mechanism of prenyl transferase, a reaction type of which several monoterpene, sesquiterpene and diterpene cyclizations are, in a sense, the intramolecular equivalents. 

A further element shared by all sesquiterpene synthases is the need for a divalent metal ion as cofactor. The metal ion is essential for substrate binding but also for product specificity. The metal ions stabihze the negatively charged pyrophosphate group of farnesyl diphosphate as illustrated by the crystal structure of 5-epz-aristolochene synthase [9]. The highly conserved sequence (I, L, V)DDxxD(E) serves to bind the metal ions in all known terpene and prenyl synthases (Fig. 5) [18-22]. A further interesting property among terpene synthases is that the active sites are enriched in relatively inert amino acids, thus it is the shape and dynamic of the active site that determines catalytic specificity [23]. 

He and his associates have Isolated several chromenes, prenylated qulnones, and sesquiterpenes esterlfled with phenolic acids which have repellent and/or cytotoxic activity. 

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). 

In addition an enzymatic prenylation of the sesquiterpene hydroquinone 29 to the corresponding sesterpene 28 might be a possible alternative to the Diels-Alder mechanism. 

About 200 diterpenes are reported in which an isoprenyl (= "prenyl") residue extends one of die side chains of a sesquiterpene, consequently referred to as prenylsesquiterpenes This class of diterpenes is reviewed in Table 5. 

The biosynthesis of sesquiterpenes in plants appears to be isolated from that of either monoterpenes or diterpenes. A prenyl transferase isolated from pumpkin Cucurbita pepo, Cucurbitaceae) converts C5 units into FPP, but not into gera-nylgeranyl pyrophosphate (the precursor to diterpenes). Another enzyme from the same source forms C20 terpenoids from C5 units, but does not accumulate lower homologs (also see Chapters 19 and 22). However, because famesyl pyrophosphate synthetase is a branch-point metabolite for the synthesis of sesquiterpenes, triterpenes, and sterols, this enzyme is ubiquitous in plants (Croteau and Johnson, 1985). 

The multiples of isoprene units in a terpene serve to classify it Cio, monoterpenes C15, sesquiterpenes C20, diterpenes C30, tri-terpenes to which the steroids are closely related C25, sesterpenes. It is a curious thing to note that the isoprene rule, sound and powerfully useful not least for structure elucidation, has unnatural foundations. Isoprene (4.1) is not a naturally occurring compound. Instead the clay from which the terpenes are so orderly fashioned is isopentenyl pyrophosphate (4.14) and dimethylallyl pyrophosphate (4.15). The latter is seen in many natural compounds, e.g. (4.11) as a prenyl ... 

The enzyme, farnesyl pyrophosphate synthetase (prenyl transferase), is responsible for the condensation of (4.14) with (4.15) to give geranyl pyrophosphate (4.41). The same enzyme mediates addition of a further molecule of (4.14) to (4.41) yielding 2- ran5-farnesyl pyrophosphate (4.19). This is the basic unit for the elaboration of the structurally diverse sesquiterpenes. The results obtained on biosynthesis are as interesting as the sesquiterpene structures. The 2 cis... 

Other interesting phenolic wood constituents of napthoquinone type are the prenylated derivatives (42) in the durable wood of Catalpa ovata (Bignoniaceae) (64). Sesquiterpenes of naphthalene type (cadalene type e.g. 43), which occur in... 

---