Plants squalene from

The mevalonate pathway in the cytosol is responsible for biosynthesis of sterols, sesquiterpenes, and triterpenoids. After conversion of mevalonic acid to isopentenyl pyrophosphate, three C5 units can be joined head to tail to produce a C15 compound, famesyl pyrophosphate. Two famesyl pyrophosphates are then united head to head to form squalene, the progenitor of the C30 isoprenoids from which sterols are derived. The plant squalene synthetase, like its mammalian homologue, is found in the ER and the reaction proceeds via a presqualene pyrophosphate intermediate (Chapter 14). In the last step prior to cyclization, squalene is converted to squalene 2,3-epoxide. 

The low polarity of carbon dioxide appears as a limitation to its use in extraction technologies requiring a total lipid extract, because more polar lipids cannot be extracted. Many of the extraction protocols used for these applications rely on a modified solvent system based on the addition of small volumes of a polar organic solvent (methanol or ethanol) to the extraction system. Such application for the extraction of lipids in the food industry is widespread, particularly with plant-based oils. However, the potential problems with the extraction of total lipids by SF has also yielded specific applications in the selective extraction or concentration of lipid components. Examples exist of the separation of FA from triacylglycerols (TAG) and squalene from sterols. 

Lanosterol and cycloartenol are two tetracyclic triterpenoids found in animals and plants, respectively, from which all steroids are derived. Tiiterpenoid squalene is the first precursor in the biosynthesis of phytostanols and phytosterols in plants and... 

The path from squalene (114) to the corresponding oxide and thence to lanosterol [79-63-0] (126), C qH qO, cholesterol [57-88-5] (127), and cycloartenol [469-38-5] (128) (Fig. 6) has been demonstrated in nonphotosynthetic organisms. It has not yet been demonstrated that there is an obligatory path paralleling the one known for generation of plant sterols despite the obvious stmctural relationships of, for example, cycloartenol (128), C qH qO, to cyclobuxine-D (129), C25H42N2O. The latter, obtained from the leaves of Buxus sempervirens E., has apparentiy found use medicinally for many disorders, from skin and venereal diseases to treatment of malaria and tuberculosis. In addition to cyclobuxine-D [2241-90-9] (129) from the Buxaceae, steroidal alkaloids are also found in the Solanaceae, Apocynaceae, and LiUaceae. 

Steroids are plant and animal lipids with a characteristic tetracyclic carbon skeleton. Like the eicosanoids, steroids occur widely in body tissues and have a large variety of physiological activities. Steroids are closely related to terpenoids and arise biosynthetically from the triterpene lanosterol. Lanosterol, in turn, arises from cationic cyclization of the acyclic hydrocarbon squalene. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Plant terpenes may deter herbivores and attract pollinators. They may participate in competition among plants and may act as antibiotics, called phytoalexins, to protect plants from bacteria and fungi.84 In invertebrate animals terpenes serve as hormones, pheromones, and defensive repellants (Figs. 22-3,22-4). The terpene squalene is the precursor to sterols. Some terpenes are toxic. For example, thujone (Fig. 22-3), which is present in the liqueur absinthe, causes serious chronic poison-... 

In green plants, which contain little or no cholesterol, cydoartenol is the key intermediate in sterol biosynthesis.161-1623 As indicated in Fig. 22-6, step c, cydoartenol can be formed if the proton at C-9 is shifted (as a hydride ion) to displace the methyl group from C-8. A proton is lost from the adjacent methyl group to close the cyclopropane ring. There are still other ways in which squalene is cyclized,162/163/1633 including some that incorporate nitrogen atoms and form alkaloids.1631 One pathway leads to the hop-anoids. These triterpene derivatives function in bacterial membranes, probably much as cholesterol does in our membranes. The three-dimensional structure of a bacterial hopene synthase is known.164 1643 Like glucoamylase (Fig. 2-29) and farnesyl transferase, the enzyme has an (a,a)6-barrel structure in one domain and a somewhat similar barrel in a second domain. 

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

The earliest steps (MVA to GGPP) for polyisoprenoid biosynthesis are identical for all plants and animals (12,13). They involve the well-known diterpene pathway, MVA — MVAP — MVAPP — IPP + DMAPP — GPP — FPP — GGPP. The enzymes catalyzing these steps have been studied extensively, especially from animals (liver) and yeast, and to a more limited extent from higher plants. In some cases the enzymes have been purified to homogeneity most have been only partially purified. In both plants and animals a major branch at FPP leads to the production of squalene and the steroids. In plants, three major branches occur at GGPP, of which one leads to the carotenoids via phyto-ene, a second to the phytyl group of chlorophyll, and a third to the GAs. 

Plant sterols inhibit the intestinal absorption of cholesterol and so have a useful hypocholesterolemic action. They also inhibit endogenous synthesis of cholesterol, by inhibiting and repressing the regulatory enzyme of cholesterol synthesis, hydroxymethylglutaryl (HMG)-CoA reductase. Other compounds synthesized from mevalonate also inhibit and repress HMG-CoA reductase and have a hypocholesterolemic action, including squalene (found in relatively large amounts in olive oil), ubiquinone (Section 14.6), and the tocotrienols (Section 4.1). 

Figure 6.1 Chemical structures of plant metabolites synthesized from squalene-2,3-epoxide.

Interestingly, /3,7-unsaturated a-diazoketones are also sources of cyclo-butanones when they are exposed to protic acid. For example, compound XI furnished XII in high yield upon contact with concentrated sulfuric acid (see Scheme 42.3). In a conceptually analogous reaction, /S.y-unsaturated a-diazoketones proved to be useful in the constmction of cyclopentanones XIV" in a polyolefinic cationic cyclization process reminiscent of the mechanism by which plants in nature build their polycyclic triterpenoid metabolites from squalene, that is, XV - XVI. 

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