Isoprenoid biosynthetic pathway

Vitamins are classified by their solubiUty characteristics iato fat-soluble and water-soluble groups. The fat-soluble vitamins A, E, and K result from the isoprenoid biosynthetic pathway. Vitamin A is derived by enzymic cleavage of the symmetrical C q beta-carotene, also known as pro-vitamin A. Vitamins E and K result from condensations of phytyldiphosphate (C2q) with aromatic components derived from shikimic acid. Vitamin D results from photochemical ring opening of 7-dehydrocholesterol, itself derived from squalene (C q). 

Fig. 4 Proposed biosynthetic pathways for the production of ipsdienol in I. pini and frontalin in D. spp. Both pathways utilize an isoprenoid biosynthetic pathway to produce geranyl diphosphate...

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]... 

It appears that, in beetles, pheromone production is regulated by JH III, despite the variations in biosynthetic pathways. JH apparently regulates pheromone production in beetles that utilize both fatty acid and isoprenoid biosynthetic pathways [8,98]. Environmental and physiological factors will in turn regulate production of JH. The endocrine regulation of pheromone production in the beetles has been best studied with regard to the bark beetles. 

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...

Fig. 5.1.2 Cholesterol biosynthesis branch of the isoprenoid biosynthetic pathway. Enzymes are numbered as follows 1 squalene synthase 2 squalene epoxidase 3 2,3-oxidosqua-lene sterol cyclase 4 sterol A24-reductase (desmosterolosis) 5 sterol C-14 demethylase 6 sterol A14-reductase (hydrops-ectopic calcification-moth-eaten, HEM, dysplasia) 7 sterol C-4 demethylase complex (including a 3/ -hydroxysteroid dehydrogenase defective in congenital hemidyspla-sia with ichthyosiform nevus and limb defects, CHILD, syndrome) 8 sterol A8-A7 isomerase (Conradi-Hunermann syndrome CDPX2) 9 sterol A5-desaturase (lathosterolosis) 10 sterol A7-reductase (Smith-Lemli-Opitz syndrome). Enzyme deficiencies are indicated by solid bars across the arrows...

An extensive overview of the biochemistry and molecular biology of the isoprenoid biosynthetic pathway in plants is given by Chappell [17]. 

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. 

As presented in Table 1.2, over half of reported marine natural products are derived from the isoprenoid biosynthetic pathway (56%), with the remainder split mainly between amino acid (19%) and acetogenin (20%) pathways. Secondary metabolites falling into the categories of nucleic acids and carbohydrates comprise only 1%. Such low levels are somewhat surprising given the fundamental importance of such classes of compounds as primary metabolites. 

Fig. 12.1. The isoprenoid biosynthetic pathway. Intermediates and products are shown in black and enzymes in blue. Components of the mevalonate-mdependent DOXP pathway are shown in green. The HMGR inhibitors (statins) are shown m red.

Fig. 12.2. Timeline of milestones involving the isoprenoid biosynthetic pathway and statins. 

Holstein, S.A., Tong, H., and Hohl, R.J. (2010). Differential activities of thalidomide and isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells. LeukRes 34 344-351. Tong, H., Wiemer, A.J., Neighbors, J.D., and Hohl, R.J. (2008). Quantitative determination of farnesyl and geranylgeranyl diphosphate levels in mammalian tissue. Anal Biochem 378 138-143. 

Lewis, K.A., Holstein, S.A., and Hohl, R.J. (2005). Lovastatin alters the isoprenoid biosynthetic pathway in acute myelogenous leukemia cells in vivo. Leuk Res 29 527-533. 

Liu Y, Wang H, Ye HC, Li GF. Advances in the plant isoprenoid biosynthetic pathway and its metabolic engineering. J. Integr. Plant Biol. 2005 47 769-782. 

Terpenoids, which are also known as isoprenoids, constitute the most abundant and structurally diverse group of plant secondary metabolites, consisting of more than 40,000 different chemical structures. The isoprenoid biosynthetic pathway generates both primary and secondary metabolites that are of great importance to plant growth and survival. Among the primary metabolites produced by this pathway are phytohormones, such as gibberellic acid (GA), abscisic acid (ABA), and cytokinins the carotenoids, such as chlorophylls and plastoquinones involved in photosynthesis the ubiquinones required for respiration and the sterols that influence membrane stmcture (see also Steroid and Triterpene Biosynthesis) (Fig. 1). Monoterpenoids (CIO), sesquiterpenoids (Cl5), diterpenoids (C20), and... 

Of the two existing isoprenoid biosynthetic pathways (Fig. 3), DXP is used by most prokaryotes for production of IPP and dimethylallyl diphosphate (DMAPP) [65,66]. With the available knowledge of the genes involved in the DXP pathway, several groups have studied the impact of changed expression levels of these genes on the production of reporter terpenoids. Farmer and liao reconstructed the isoprene biosynthetic pathway in Escherichia coli (E. colt) to produce lycopene, which was used as an indication... 

Isoprenoid biosynthetic pathways produce an astonishing variety of products in different cell types and different species. Despite this diversity, the beginning of isoprenoid biosynthesis appears to be identical in most of the species investigated (e.g., yeast, mammals, and plants). (HMG-CoA = / -hydroxy-/3-methylglutaryl-CoA)... 

Relatively little is known about plant sterols. (Most of the research effort in steroid metabolism has been expended in the investigation of steroid-related human diseases.) It appears, however, that the initial phase of plant sterol synthesis is very similar to that of cholesterol synthesis with the following exception. In plants and algae the cyclization of squalene-2,3-epoxide leads to the synthesis of cycloartenol (Figure 12.30) instead of lanosterol. Many subsequent reactions in plant sterol pathways involve SAM-mediated methylation reactions. There appear to be two separate isoprenoid biosynthetic pathways in plant cells the ER/cyto-plasm pathway and a separate chloroplast pathway. The roles of these pathways in plant isoprenoid metabolism are still unclear. 

Another special class of terpene formed by the isoprenoid biosynthetic pathway are the carotenoids. Carotenoids are important compounds in photosynthesis for harvesting of light energy as well as in the protection of cyanobacteria from excessive amounts of UV radiation. The carotenoids present in cyanobacteria are similar to those found in higher life-forms along with some glycosylated derivatives (see Chapters 1.15-1.18). 

The biosynthesis of sterols takes place via the protracted sterol/isoprenoid biosynthetic pathway (Chapter 1). Although the major portion of the carbon flux through this pathway is normally directed into sterols, several branches exist leading to the production of other isoprenoid compounds needed by the cell, such as ubiquinone, dolichol and isopentenyl adenine. Total carbon flux is regulated through the enzymes of the early, or common, portion of the pathway of which the most important is HMG-CoA reductase. Distribution of carbon between the various end products is regulated at later stages of the pathway. 

Alterations in the levels of each of the enzymes of the early, or common portion of the sterol/isoprenoid biosynthetic pathway (acetyl-CoA isopentenyl pyrophosphate) have been observed in response to certain physiological stimuli. These alterations usually parallel those in HMG-CoA reductase. For example ... 

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