Isoprene pathway

The isoprene pathway produces a diverse range of natural products such as terpenes and steroids. A number of complex biochemical transformations are involved, many of which have been proposed to involve short-lived carbocation intermediates. Two recent studies provide a brief introduction. 

Carotene is a highly conjugated hydrocarbon with an orange-red color. Its biosynthesis occurs via the isoprene pathway (Special Topic E in WileyPLUS), and it is found in, among other sources, pumpkins. One of the chemical syntheses of /3-carotene was accomplished near the turn of the twentieth century by W. Ipatiew Ber. 1901, 34, 594-596). The first few steps of this synthesis involve chemistry that should be familiar to you. Write mechanisms for all of the reactions from compounds 2 to 5, and from 8 to 9 and 10. 

The biosynthesis of plant sterols and saponins proceeds via the isoprene pathway with the cyclization and subsequent rearrangement of a C30 2,3-oxidosqualene precursor, as discussed in reviews by Haralampidis et al. [107], Benveniste [108, 109], Kreis and Miiller-Uri [110], and Osbourn et al. [111]. Following cyclization of 2,3-oxidosqualene (in the chair-boat-chair conformation), the resultant... 

Precursor selection An important step in designing a microbial labeling process is the identification of one or more suitable labeled precursors. Generally, secondary metabolites are biosynthesized via primary metabolites from five metabolic sources. These are amino acids, shikimic acid (shikimic acid pathway), acetate and its homologues (polyketide pathway), mevalonic acid (isoprene pathway) and carbohydrates. Selection of a suitable precursor is primarily influenced by the biosynthetic pathway(s) involved, but also depends on the desired position of label in the product and the availability of labeled precursors. 

Isoprene itself is not the true biological precursor of terpenoids. As we ll see in Chapter 27, nature instead uses two "isoprene equivalents"—isopentenvl diphosphate and dimethylallyl diphosphate—which are themselves made by two different routes depending on the organism. Lanosterol, in particular, is biosynthesized from acetic acid by a complex pathway that has been worked out in great detail. 

NMHC. A large number of hydrocarbons are present in petroleum deposits, and their release during refining or use of fuels and solvents, or during the combustion of fuels, results in the presence of more than a hundred different hydrocarbons in polluted air (43,44). These unnatural hydrocarbons join the natural terpenes such as isoprene and the pinenes in their reactions with tropospheric hydroxyl radical. In saturated hydrocarbons (containing all single carbon-carbon bonds) abstraction of a hydrogen (e,g, R4) is the sole tropospheric reaction, but in unsaturated hydrocarbons HO-addition to a carbon-carbon double bond is usually the dominant reaction pathway. 

IPP and its DMAPP structural isomer are produced from glycolytic products by the methyl erythritol phosphate (MEP) pathway (Figure 5.3.1, Pathway 1). These isoprene units are condensed in a stepwise fashion to form the precursor to all carotenoids, geranylgeranyl di-phosphate (GGPP). GGPP is not solely metabolized to make carotenoids, but is a precursor for many other primary and secondary metab-... 

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. 

Rohmer, M., Seemann, M., Horbach, S. et al. (1996) Glyceraldehyde 3-phosphate and pyruvate as precursors of isoprenic units in an alternative non-mevalonate pathway for terpenoid biosynthesis. Journal of the American... 

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... 

Rohmer M (2007) Diversity in isoprene unit biosynthesis the methylerythritol phosphate pathway in bacteria and plastids. Pure Appl Chem 79 739-751... 

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)... 

Carotenoids are lipid-soluble terpenoids derived from the isoprenoid pathway and are located in hydrophobic areas of cells. All have a 40-carbon isoprene backbone with a variety of ring structures at one or both ends (Fig. 8.2) [25]. The carbon skeleton is derived from five-carbon isoprenoid groups and contains alternating conjugated double bonds. There are two kinds of carotenoids (Fig. 8.2) carotenes composed of carbon and hydrogen and xanthophylls composed of carbon, hydrogen, and oxygen. 

In pepper as in many plants, there are two sources of isoprene monomers the mevalonic acid pathway and the plastidal pool from pymvate and glyceraldehyde-3-phosphate [26], Pepper carotenoid biosynthesis uses the plastidal pathway for the isopentyl pyrophosphate monomers and the resident terpenoid synthases and transferases [27], Using the 5-carbon isoprene pool, the prenyl transferases sequentially... 

From activated isoprene, the metabolic pathway leads via dimerization to activated geraniol (1 = 2) and then to activated farnesol = 3). At this point, the pathway divides into two. Further extension of farnesol leads to chains with increasing numbers of isoprene units—e.g., phytol (1 = 4), dolichol (1 = 14-24), and rubber = 700-5000). The other pathway involves a head-to-head linkage between two farnesol residues, giving rise to squalene (1 = 6), which, in turn, is converted to cholesterol (1 = 6) and the other steroids. 

The pentose phosphate pathway (PPP, also known as the hexose monophosphate pathway) is an oxidative metabolic pathway located in the cytoplasm, which, like glycolysis, starts from glucose 6-phosphate. It supplies two important precursors for anabolic pathways NADPH+H+, which is required for the biosynthesis of fatty acids and isopren-oids, for example (see p. 168), and ribose 5-phosphate, a precursor in nucleotide biosynthesis (see p. 188). 

The direct displacement reaction can be used to prepare many of the common diphosphate esters in the isoprene biosynthetic pathway, Including isopentenyl diphosphate The yields are typically 60-90% from the... 

The reduced risk of CHD achieved with the statins may also be due to drug actions independent of lowering blood cholesterol. Many important molecules besides cholesterol are generated by intermediates in the complex cholesterol synthesis pathway. These include the isoprenes geranylgeranyl and farnesyl, which are covalently attached to some proteins (isoprenylation) and target them to membranes where they function. The re-... 

FIGURE 16.10 A biosynthetic pathway proposed for the formation of the chalcone-isoprene Diels-Alder adduct, sanggenon R (182), after Hano et The fate of the diene is indicated in bold type. 

FIGURE 6.3 Some major pathways in the reaction of OH with isoprene (adapted from Carter and Atkinson, 1996). 

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