Sterol cyclase

Fig. 5.1.2 Cholesterol biosynthesis branch of the isoprenoid biosynthetic pathway. Enzymes are numbered as follows 1 squalene synthase 2 squalene epoxidase 3 2,3-oxidosqua-lene sterol cyclase 4 sterol A24-reductase (desmosterolosis) 5 sterol C-14 demethylase 6 sterol A14-reductase (hydrops-ectopic calcification-moth-eaten, HEM, dysplasia) 7 sterol C-4 demethylase complex (including a 3/ -hydroxysteroid dehydrogenase defective in congenital hemidyspla-sia with ichthyosiform nevus and limb defects, CHILD, syndrome) 8 sterol A8-A7 isomerase (Conradi-Hunermann syndrome CDPX2) 9 sterol A5-desaturase (lathosterolosis) 10 sterol A7-reductase (Smith-Lemli-Opitz syndrome). Enzyme deficiencies are indicated by solid bars across the arrows...

Cyclization of Squalene-like Substrates. Ultrasonically stimulated BY is a source of sterol cyclase, which catalyzes the cyclization of squalene oxide and squalenoid compounds to lanos-terol derivatives (eq 13). ... 

In contrast to the above results the substrates (23) and (25) were transformed enzymically by 2,3-oxidosqualene sterol cyclase to the corresponding lanosterol derivatives (27) and (28). In addition, 6-demethyl-2,3-oxidosqualene underwent enzymic cyclization to 19-norlanosterol (29). Van Tamelen and Freed ... 

Biocatalytic C-C-formatiou BY and other yeasts, AcCoA AcCoA C-acetyltrans-ferase, tryptophan synthetase, prenyltransferase, oxynitrilases, aldolases, transketolases, sterol cyclase... 

Miscellaneous Reactions of Oxirans.—The first successful enzymatic cyclization of a non-natural squalene has been disclosed. (18Z)-Oxidosqualene (188), which does not possess the naturally occurring a -trans stereochemistry, was caused to cyclize, in the presence of 2,3-epoxysqualene sterol cyclase, to (205)-epinorlanosterol (189). The polyene oxide (190) underwent an uncommon tricyclization in CH2CI2 containing Bp3-OEt2 to form the cw-fused A/B-ring 18-nor-steroid (191) (25%) this compound was found to be identical with a material derived by treatment of a naturally occurring steroid with BF3. 

Kyler and co-workers have examined the effects of ultrasound on a suspension of baker s yeast Saccharomyces cerevisiae) as an inexpensive, convenient and direct source of sterol cyclase [174] (Scheme 78). This enabled them to produce sterols from squalene oxide and related substrates on a multigram scale. Previous experiments had relied on the use of microsomal cyclase. However, this process can only be used to convert extremely small quantities of substrate to the desired sterol (i.e. < 1-3 mg) and is obviously unsuitable for preparative purposes. In contrast, ultrasonically stimulated yeast cells could be used to convert 2,3-oxidosqualene to lanosterol in 42%... 

Corey, E. J., and H. Yamamoto Correlation of a Protosterol from 20,21-Dehydro-2,3-Oxidosqualene and 2,3-Oxidosqualene-Sterol Cyclase with Dihydrolanosterol. Tetrahedron Letters 1970, 2385. 

Fig. 5.1 Cyclization of 2,3-oxidosqualene to sterols and triterpenoids. The 2,3-oxidosqualene cyclase enzymes that catalyse the formation of the different products are indicated LS, lanosterol synthase CS, cycloartenol synthase LuS, lupeol synthase PAS, P-amyrin synthase aAS, a-amyrin synthase.

CATTEL, L., CERUTI, M., 2,3-Oxidosqualene cyclase and squalene epoxidase Enzymology, mechanism and inhibitors. In Physiology and Biochemistry of Sterols (G.W. Patterson and W.D. Nes, eds,), American Oil Chemists Society, Champaign. 1992, pp. 50-82. 

Keywords. Saponins, Triterpenoids, Sterols, 2,3-Oxidosqualene cyclases, Glycosyltransferases... 

Resolution of Cyclase Activities Required for Sterol and Triterpenoid Biosynthesis... 

Fig. 14.12. Enzymatic transformation of acyclic squalene oxide (A) into tetracyclic lano-sterol (G). The oxidosqualene-lanosterol cyclase controls the conformation of the substrate so effectively that only one out of 64 possible diastereomers is formed.

Head-to-head condensation of two farnesylpyrophosphate (C]3—PP) molecules yields a G13-cyclopropane (C3)-CH intermediate which is then reduced to yield squalene H(CH2-C(CH3)=CH-CH2)3-(CH2-CH=C(CH3)CH2)3 (C30), that is, if one represents the isoprene polarities as IP and PI, one could represent squalene as (IP)3—(PI)3. Squalene is subsequently oxidized [via a squalene monooxygenase] to yield squalene 2,3-epoxide which is cyclized to the tetracyclic sterol terpene lanosterol (C30) [via squalene cyclase]. 

Figure 1.7 illustrates the synthesis of sterols in yeasts. Basically, sterols are synthesised by the mevalonate pathway. The key stage in this pathway is, without any doubt, the reaction catalysed by squalene monooxygenase. This reaction, which uses oxygen as substrate, transforms squalene into squalene 2,3, epoxide. Later, squalene epoxide lanosterol cyclase catalyses the synthesis of the first sterol of the pathway. 

Squalene has been shown to assume the folding pattern of Woodward and Bloch in the cyclization process that forms sterols (Fig. 17). This was demonstrated by the labehng patterns of sterols derived from acetate and mevalonate [90,91]. There are several ways by which squalene can cyclize, consequently it is the precursor of several polycyclic terpenoids (Chapter 7). The product depends on the conformation squalene assumes in binding to the cyclase and the nature and position of the nucleophiles and bases on the enzyme. Mechanistically, squalene requires an electrophilic attack at C-3 for cyclization to occur. This can be accomplished by direct attack of a as in the cycUzation that produces tetrahymanol and femene or by... 

When multiplying, intracellular parasites do not synthesise their own membrane sterol, but must derive it from the host cell. It is interesting that the changes observed in erythrocytes infected with malaria merozoites are very similar to those brought about by depleting plasma membranes of cholesterol increased permeability, changes in Na and concentrations, increased acetylcholinesterase and adenylate cyclase activities [188-191]. 

Squalene is converted into the first sterol, lanosterol, by the action of squalene epoxidase and oxidosqualene lanosterol cyclase. The catalytic mechanism for the cyclase s four cyclization reactions was revealed when the crystal stmcture of the human enzyme was obtained (R. Thoma, 2004). Oxidosqualene lanosterol cyclase is considered an attractive target for developing inhibitors of the cholesterol biosynthetic pathway because its inhibition leads to the production of 24,25-epoxycholesterol (M.W. Huff, 2005). This oxysterol is a potent ligand activator of the liver X receptor (LXR) and leads to expression of several genes that promote cellular cholesterol efflux, such as ABCAl, ABCG5, and ABCG8 (Section 4.1). Thus, inhibitors of oxidosqualene lanosterol cyclase could be therapeutically advantageous because they would reduce cholesterol synthesis and promote cholesterol efflux (M.W. Huff, 2005). 

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