Squalene, biosynthesis lanosterol from

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

The first enantioselective polyene tetracydization starting with a chiral epoxide was reported by Corey et al. in 1997 [8a]. The silylated enol ether 3 (Scheme 1) was converted into the tetracycle 4 by treatment with the Lewis acid MeAlCl2 at -90 °C. The synthetic route is modeled on the biosynthesis of lanosterol from (3S)-squalene 2,3-epoxide and has also been applied to the biomimetic synthesis of tetracyclic polyprenoids from sediment bacteria [8b]. 

Fig. 8 is a schematic diagram of a cell which shows the known sites in which sterol carrier proteins are involved in cholesterol biosynthesis, utilization and intracellular transfer. SCP, participates in the conversion of squalene to lanosterol and SCP2 participates in the conversion of lanosterol to cholesterol, the conversion of cholesterol to cholesterol ester by ACAT, and probably also in the conversion of cholesterol to 7a-hydroxycholesterol. SCPj transfers cholesterol from cytoplasmic lipid inclusion droplets to mitochondria in the adrenal and SCPj also translocates cholesterol from the outer to the inner mitochondrial membrane. 

A schematic of fungal ergosterol biosynthesis starting from squalene is shown in Figure 40.1. The biosynthetic pathway has been simplified to emphasize steps important to the action of currently employed antifungal drugs. The last nonsteroidal precursor to both ergosterol and cholesterol is the hydrocarbon squalene. Squalene is converted to squalene epoxide by the enzyme squalene epoxidase. Squalene epoxide is then cyclized to lanosterol, the first steroid in the biosynthetic pathway. The... 

The biosynthesis of lanosterol from squalene has intrigued chemists since its discovery. It is now possible, for example, to synthesize polycyclic compounds from acyclic or monocyclic precursors by reactions that form several C - C bonds in a single reaction mixture. 

The biosynthesis of the steroid alkaloids takes the usual paths of tri-terpene synthesis, i.e. via farnesyl pyrophosphate, squalene, and lanosterol or cycloartenol. The nitrogen probably comes from ammonia or ammonium compounds. 

Figure 7.6 Outline of the biosynthesis of the triterpenoid lanosterol from acetate and mevalonate via squalene...

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

The evidence is strong that the biosynthesis of lanosterol actually proceeds by a route of this type. With squalene made from either methyl- or carboxyl-labeled ethanoate, all the carbons of lanosterol and cholesterol are labeled just... 

The two remaining reactions in the biosynthesis of lanosterol are shown in figure 20.9. In the first of these reactions, squalene-2,3-oxide is formed from squalene. As can be seen in figure 20.8, squalene is a symmetrical molecule, hence the formation of squalene oxide can be initiated from either end of the molecule. The oxide is converted into lanosterol. The reaction can be formulated as proceeding by means of a protonated intermediate that undergoes a concerted series of trans-1,2 shifts of methyl groups and hydride ions to produce lanosterol (see fig. 20.9). 

Holotoxin Ai inhibits the RNA biosynthesis in Candida albicans and Saccharomyces carlsbergensis, as indicated by the decrease in incorporation of C-uridine to the acid-insoluble fraction of the cells. Similar results were obtained for glycoside fractions of 14 species of Pacific sea cucumbers [132]. Apparently the inhibition of RNA biosynthesis in Saccharomyces carlsbergensis is related to nucleotide loss from yeast cells after treatment with glycosides. Holotoxin Ai also inhibits biosyntheses of squalene, lanosterol and ergosterol in S. carlsbergensis [133]. Mitosis is arrested and DNA synthesis inhibited in onion root bulbs by crude holothurin [134]. 

The present state of knowledge of terpenoid biosynthesis does not allow many detailed conclusions to be reached on its taxonomic importance. However, some gross differences at the phyla level are apparent. This review has already commented on differences observed in the formation of steroidal A - and A -double bonds, 24-alkyl groups, and whether lanosterol or cycloartenol is formed from squalene epoxide. 

In addition to cholesterol and 5a-cholest-7-en-3y8-ol, many C2g and C29 conventional sterols are present in Echinodermata. These sterols are probably derived from the diet. However, echinoderms are able to synthesize sterols. Thus, [ C]mevalonic acid was incorporated into squalene, lanosterol and desmosterol by the sea urchin. Echinus esculentus [87]. The ability of ophiurpids to synthesize sterol from [ C]acetate has also been demonstrated [88]. Sterol biosynthesis by a holothuroid was first investigated by Numura [89], and sterol biosynthesis from [ C]acetate in sea cucumbers has also been reported [90]. 

The conversion of oxidosqualene 50 to lanosterol 52, the so-called squalene folding in the biosynthesis of steroids has initiated much research efforts (Scheme 10) [23]. This process is catalyzed by the enzyme lanosterol synthase, which controls precisely the formation of four rings and six new stereocenters. According to the pioneering work by Eschen-moser and Stork the cyclization proceeds in a concerted fashion due to favorable orbital overlap [24, 25]. In contrast Nishizawa et al. were able to trap several cationic intermediates 55-57 from a related model system 54... 

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