Squalene structure

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-... 

This synthetic allylamine derivative inhibits the enzyme squalene epoxidase at an early stage in fungal sterol biosynthesis. Acting as a structural analogue of squalene, naffidine causes the accumulation of this unsaturated hydrocarbon, and a decrease in ergosterol in the fungal cell membrane. 

Interest in presqualene pyrophosphate continues and it is claimed that the structure (88) assigned to a squalene precursor is incorrect. Presqualene pyrophosphate has been shown to contain a cyclopropyl ring (89), and both (89) and its parent alcohol have been synthesised. -Mechanisms for the conversion of (89) into squalene have been pub-lished. -... 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Squalene is a unique natural product of a C30H50 structure with 6 non-conjugated double bonds. Hence, its MS shows a fragmentation pattern typical of non-conjugated... 

The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. 

The application of this procedure to the fused polycyclic compound E, which already has a linear dual and only the last two steps (iii-iv) apply to it, leads to a linear acyclic structure F which may be traced back to the biogenetic cyclisation of squalene to lanosterol via cationic intermediates, as well as to the stereospecific cationic cyclisation of polyolefins studied by Johnson [18]. 

In 1952, Bloch and Woodward suggested a mechanism for the cycliza-tion of squalene to cholesterol. In 1962, Francis Crick and James Watson described the double helix structure of proteins. Hodgkin determined the structure of vitamin B12 and of penicillin through collaboration between Woodward and Eschenmoser, involving postdoctoral fellows. In 1877, Alexander Fleming discovered penicillin which was active against tuberculosis. 

A general type of chemical reaction between two compounds, A and B, such that there is a net reduction in bond multiplicity (e.g., addition of a compound across a carbon-carbon double bond such that the product has lost this 77-bond). An example is the hydration of a double bond, such as that observed in the conversion of fumarate to malate by fumarase. Addition reactions can also occur with strained ring structures that, in some respects, resemble double bonds (e.g., cyclopropyl derivatives or certain epoxides). A special case of a hydro-alkenyl addition is the conversion of 2,3-oxidosqualene to dammara-dienol or in the conversion of squalene to lanosterol. Reactions in which new moieties are linked to adjacent atoms (as is the case in the hydration of fumarate) are often referred to as 1,2-addition reactions. If the atoms that contain newly linked moieties are not adjacent (as is often the case with conjugated reactants), then the reaction is often referred to as a l,n-addition reaction in which n is the numbered atom distant from 1 (e.g., 1,4-addition reaction). In general, addition reactions can take place via electrophilic addition, nucleophilic addition, free-radical addition, or via simultaneous or pericycUc addition. 

Both the heat-stable SCP protein of Ritter and Dempsey (R2) and the heat-labile SCP protein of Scallen et al. (S2) bind other lipids (e.g., phospholipids and fatty acids) in addition to water-insoluble cholesterol and its precursors (R2, R3, R5, S2). In view of this apparent lack of specificity, Ritter and Dempsey (R5) have suggested that the carrier protein may be more generally called lipid carrier protein (LCP), although its binding to squalene and sterol carrier protein may more directly refiect its functional role in cholesterol biosynthesis. Obviously, more work is needed to clearly define both structural role and functional properties of this protein or proteins. 

R4. Ritter, M. C., and Dempsey, M. E., Structural characterization of the squalene and sterol carrier protein (8CP) of human liver. Circulation 46, Suppl. II, 245 (1972). 

The methylene chloride soluble portion of a methanol extract from the wood of Eury-coma longifolia shows strong cytotoxic properties. One of the active constituents, longi-lene peroxide (77) (P2i, 0—0 = 1.472 A, Figure 31), was isolated in a 0.0003% yield. The characteristic horse-shoe-like arrangement, which is observed in the crystal structure of squalene derivative 77, has been associated with its biological activity ... 

The isoprenoids contribute most to the list of structural similarities in the sea and on land. They range from common classes in both ecosystems, such as drimane sesquiterpenes, to rare classes in the sea, such as the trichothecenes (Chart 8.3.11). The similarity in marine and terrestrial polyether triterpenes (Chart 8.3.12) may be seen as convergence toward chemically favored structures, starting from squalene as a biosynthetic precursor. Similar conclusions may apply to polycyclic triterpenes. 

Currently there is no experimentally determined three-dimensional structural information available for OSCs, although studies with a related enzyme, squa-lene-hopene cyclase (SC EC 5.4.99.7) have proved informative. SCs are involved in the direct cyclisation of squalene to pentacyclic triterpenoids known as hopanoids, which play an integral role in membrane structure in prokaryotes [ 51 ]. A number of SC genes have been cloned from bacteria [52 - 54]. The SC and OSC enzymes have related predicted amino acid sequences, and so should have similar spatial structures [55]. The crystal structure of recombinant SC from the Gram-positive bacterium Alicyclobacillus acidocaldarius has established that the enzyme is dimeric [55]. Each subunit consists of two a-a barrel domains that assemble to form a central hydrophobic cavity [55,56]. 

More recently it has been shown (6, 7) that zinc dialkyl dithiophosphates also act as chain-breaking inhibitors. Colclough and Cunneen (7) reported that zinc isopropyl xanthate, zinc dibutyl dithiocarbamate, and zinc diisopropyl dithiophosphate all substantially lowered the rate of azobisisobutyronitrile-initiated oxidation of squalene at 60°C. Under these conditions, hydroperoxide chain initiation is negligible, and it was therefore concluded that inhibition resulted from removal of chain-propagating peroxy radicals. Also, consideration of the structure of these zinc dithioates led to the conclusion that no suitably activated hydrogen atom was available, and it was suggested that inhibition could be accounted for by an electron-transfer process as follows ... 

Steroids are important lipids whose structures are based on a tetracyclic system. Most steroids function as hormone chemical messengers, and thus these molecules have been discussed in detail in chapter 5. Structurally, steroids are heavily modified triterpenes that are biosynthesized starting from the acyclic hydrocarbon squalene and progressing through cholesterol to the final steroid product Bloch and Cornforth, who were awarded Nobel Prizes in medicine (1964), contributed greatly to the elucidation of this remarkable biosynthetic transformation. 

While squalene, the parent of all triterpenoids, is a linear acyclic compound, the majority of triterpeneoids exist in cyclic forms, penta- and tetracyclic triterpenes being the major types. Within these cyclic triterpenoids distinct structural variations lead to several structural classes of triterpenoids. Some of the major structures types of triterpenoids are shown helow. 

Butenafine hydrochloride (Mentax) is a benzylamine that is structurally related to the allylamines. As with the allylamines, butenafine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes. Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis. 

Squalene is also an intermediate in the synthesis of cholesterol. Structurally, chemically, and biogenetically, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that trans-squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instability however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of lipid-soluble drugs. 

Squalene takes part in metabolism as precursor for synthesis of steroids and structurally quite similar to (3-carotene, coenzyme qlO, vitamins Ki, E, and D. The squalene in skin and fat tissue comes from endogenous cholesterol synthesis as well as dietary resources in people who consume high amounts of olive and fish oil especially shark liver (Gershbein and Singh, 1969). Squalene is synthesized by squalene synthase which converts two units of farnesyl pyrophosphate, direct precursor for terpenes and steroids, into squalene. As a secosteroid, vitamin D biosynthesis is also regulated by squalene. Moreover, being precursor for each steroid family makes squalene a crucial component of the body. 

Squalene is suggested to enhance elimination of lipophilic xenobiotics by several experimental evidences. Its nonpolar structure promotes a promising affinity for unionized drugs. Richter and Schafer (1982) studied squalene for elimination of [14C]hexachlorobenzene (HCB) as an alternative method to paraffin treatment. Animal models have been fed by squalene and paraffin as 8% of the diet. Results indicated that squalene supplementation was as effective as paraffin on fecal excretion of HCB. 

Stage (4) Conversion of Squalene to the Four-Ring Steroid Nucleus When the squalene molecule is represented as in Figure 21-37, the relationship of its linear structure to the cyclic structure of the sterols becomes apparent. All... 

Squalene is converted to the sterol lanosterol by a sequence of reactions that use molecular oxygen and NADPH. The hydroxy-lation of squalene triggers the cyclization of the structure to lanosterol. 

IPP react with each other, releasing pyrophosphate to form another allyl pyrophosphate containing 10 carbon atoms. The chain can successively build up by five-carbon units to yield polyisoprenes by head-to-tail condensations alternatively, tail-to-tail condensations of two C15 units can yield squalene, a precursor of sterols. Similar condensation of two C2q units yields phytoene, a precursor of carotenoids. This information is expected to help in the development of genetic methods to control the hydrocarbon structures and yields. 

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. 

SAMPLE SOLUTION (a) As the structural formula in step 5 of Figure 26.10 indicates, the double bond of cholesterol unites C-5 and C-6 (steroid numbering). The corresponding carbons in the cyclization reaction of step 1 in the figure may be identified as C-7 and C-8 of squalene 2,3-epoxide (systematic IUPAC numbering). 

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