Squalene formation

Anderson, D. G., Gorgosterol biosynthesis localisation of squalene formation in the zooxanthellar component of various gorgonians, Comp. Biochem. Physiol., 81B, 423, 1985. 

In similarity to the biosynthesis of other cyclopropane-containing molecules, most mechanistic studies of squalene formation have been confined to chemical model systems and virtually no definitive experiments with the enzyme itself have been reported. 

The increased accumulation of anthocyanins in hypocotyls of mevinolin-treated radish seedlings ( 9) certainly does not simply reflect the routing away of acetate units from sterois (cf. Figure 1) but also reflects a more general response of plants upon treatment with chemicals (95). Inhibitors (see also below) affecting later steps in phytosterol synthesis seem to affect various other products of the isoprenoid pathway before and after squalene formation (95). Secondary effects of such growth... 

Ci5 units (Scheme 4.12). Formation and collapse of 4.48) and 4.120) appear to be similar, the only apparent difference being in the last step the carbonium ion 4.121) is quenched by proton loss to give phytoene 4.122), whereas in squalene formation the corresponding ion is neutralized by hydride donation from NADPH [60]. 

Fio. 2. Simplified scheme of cholesterol biosynthesis up to squalene formation. Dotted arrow refers to the site of feedback, control of cholesterogenesis. 

SuGA, T., T. Shishibori, and S. Kimoto Biosynthesis of Triterpenoids. The Stereochemistry of the Squalene Formation and its Cyclization to p-Amyrin, Chemistry Letters 1972, 129. 

Guided by the desire to preserve the squalene chain for as long as possible, Heathcock s strategy for the synthesis of methyl homosecodaphniphyllate (1) defers the formation of a carbon-carbon bond between positions 2 and 3 to a late stage in the synthesis... 

Step 4—Formation of Lanosterol Squalene can fold into a structure that closely resembles the steroid nucleus (Figure 26-3). Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by a mixed-... 

In a variation of these reactions, Grieco and Masaki used p-toluenesulfonyl groups to direct alkylation reactions in the formation of carbon chains and then cleaved the sulphones with lithium in ethylamine. This type of synthetic construction involving the use of sulphur-containing molecules has become a typical sequence in organic syntheses. In this case, the reactions formed part of successful syntheses of squalene and sesquifenchene and were carried out without any migration or loss of stereochemical integrity of the double bonds. Similar sequences have been reported by Trost (prenylation reactions) and Marshall (synthesis of a cembranoid precursor). 

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. 

One could plunge into the steric problems posed by the mechanism of protein synthesis on the ribosome 25 26)> or consider the steric fit of the hormone insulin to its acceptor in the cell membrane 27>. Or one could delve into the beautiful intricacy of terpenoid, squalene and steroid metabolism, or get lost in double bond formation, or in the steric problems posed by the branched chain fatty acids and their derivatives 28-34). 

There is evidence that organotellurium compounds react with vicinal cysteine sulph-hydryl groups on squalene monooxygenase, plausibly because of the formation of unstable intermediates in which the tellurium atom is bonded to sulphhydryl groups in squalene... 

Perhaps the most spectacular of the natural carbocation rearrangements is the concerted sequence of 1,2-methyl and 1,2-hydride Wagner-Meerwein shifts that occurs during the formation oflanosterol from squalene. Lanosterol is then the precursor of the steroid cholesterol in animals. 

Carbocation formation is initiated by epoxide ring opening in squalene oxide, giving a tertiary carbocation, and this is transformed into the four-ring system of the protosteryl cation by a series of electrophilic addition reactions (see Box 8.3). 

Formation of squalene. Isopentenyl diphosphate undergoes isomerization to form dimethylallyl diphosphate. The two C5 molecules condense to yield geranyl diphosphate, and the addition of another isopentenyl diphosphate produces farnesyl diphosphate. This can then undergo dimerization, in a head-to-head reaction, to yield squalene. Farnesyl diphosphate is also the starting-point for other polyisoprenoids, such as doli-chol (see p. 230) and ubiquinone (see p. 52). 

Formation of cholesterol. Squalene, a linear isoprenoid, is cyclized, with O2 being consumed, to form lanosterol, a C30 sterol. Three methyl groups are cleaved from this in the subsequent reaction steps, to yield the end product cholesterol. Some of these reactions are catalyzed by cytochrome P450 systems (see p. 318). 

The endergonic biosynthetic pathway described above is located entirely in the smooth endoplasmic reticulum. The energy needed comes from the CoA derivatives used and from ATP. The reducing agent in the formation of mevalonate and squalene, as well as in the final steps of cholesterol biosynthesis, is NADPH+H ... 

Further detailed study of the substrate specificity of yeast squalene synthetase has been reported (see Vol. 7, p. 130). The enzyme is very sensitive to changes in substrate. For example, 10,11-dihydrofarnesyl pyrophosphate was converted into 2,3,22,23-tetrahydrosqualene with only 60% of the efficiency of farnesyl pyrophosphate whereas 6,7-dihydro- and 6,7,10,11-tetrahydro-farnesyl pyrophosphates were not metabolized. The first of the two binding sites has a greater preference for farnesyl pyrophosphate and this accounts for the formation of the unsymmetrical squalene product when mixtures of farnesyl pyrophosphate and a modified substrate are used. The importance of the methyl groups, especially that at C-3, for binding is emphasized by the low efficiency of conversion of 3-desmethylfarnesyl, , -3-methylundeca-2,6-dien-l-yl (1), and E,E-7-desmethylfarnesyl pyrophosphates. The prenylated cyclobutanones (2) and (3)... 

Toward the synthesis of zaragozic acids, a novel family of fungal metabolites that has been shown to be picomolar competitive inhibitors of squalene synthease, Hodgson s group and Hashimoto s group have used cyclic carbonyl ylide formation/[3 + 2]-cycloaddition approach. " In Hashimoto s synthesis, the 2,8-dioxabicyclo[3,2,l]octane core... 

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