Squalene oxide cyclase

For the cyclization to occur, the a-region is essential for the enzyme cyclase. A second enzymatic control is involved in the /S-region for the double bond to orient properly on the incoming carbonium ion. The reaction is therefore believed to proceed nonstop until a tetracyclic system is obtained. The role of the squalene oxide cyclase is to maintain the carbon skeleton in place to maximize orbital overlap which allows generation of the ff-bonds in the sterol molecule. This is represented below ... 

Recent mechanism studies involving incubations with stable isotopes (66,69,70) and studies by us on conformiational analysis (38-42), distribution (7), structure-function/metabolism relationships (54, 55) and mechanistic enzymology of sterol transformation (12,56), negate the otherwise attractive explanation hypothesized by Ourisson et al, (9,10) for evolution of the sterol pathway beginning with the cycloartenol-based pathway. The new data indicate that the lanosterol-based pathway may have evolved before cycloartenol-based pathway, the squalene-oxide cyclase and... 

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.

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). ... 

The cyclisation is mediated by squalene-hopene cyclase from prokaryotic species, and is analogous in certain aspects to the squalene oxide - lanosterol cyclase from eukaryotic sources. [257]... 

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%... 

The sterol pathway is thought to originate with bacterial heterotrophs that developed enzymes that epoxidize squalene to squalene oxide (56-5 ). In keeping with the idea that ancestral enzymes lack a high degree of mechanistic specificity, the ancestral epoxidase probably produced a mixture of 3(S)- and 3(R)- squalene oxide. The squalene oxide diastereoisomers were then presented to the ancestral cyclase, which cyclized both substrates anaerobically to tetracyclic and pentacyclic products. Ttiey are not aerobic cyclizations, nor was the environment at this time likely aerobic, since photosynthesis came later. Thus the first sterols were not fiirther transformed and were... 

In addition to the squalene oxide to cycloartenol cyclase, the set of phytosterol enzymes- the S-adenosyl-L-methionine C-24 methyl transferases (SMT) and the 9,19-cyclopropyl to 8- isomerase (COI) are considered as phylogenetically significant to plant evolution. The plant SMT is assumed to catalyze Re-face methylation of bent... 

The properties of a soluble enzyme system from plants which catalyses cyclization of squalene 2(3),22(23)-diepoxide into oc-onocerin (28) have been reported. The enzyme requires both substrate epioxide groups for recognition and cyclization of the substrate. Additional inhibitors of squalene 2,3-oxide cyclase have been described, and a comparison of the effects of numerous hypocholesterolaemic agents on squalene metabolism in rat liver and the protozoan Tetrahymena pyriformis has been reported. ... 

Irrespective of whether the oxidative cyclization of pCA is a concerted reaction or involves two (or more) steps, the reaction requires a single enzyme molecule. This conversion, therefore, differs from squalene oxidative cyclization, which requires an enzyme for the oxidative step and another enzyme (2,3-oxidosqualene lanosterol cyclase) for the cyclization (Singer et aL, 1956). The possibility that the oxidative cyclization of pCA may be a true concerted (one step) process cannot be ruled out at this stage. It may explain the specificity (Steenkamp et aL, 1974) of the enzyme for pCA as substrate and the observation that in all reaction mixtures aCA was formed at approximately the same rate as the rate of dehydrogenation of the electron acceptor. 

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]. 

The enzyme involved is squalene 2,3-oxide cycloartenol cyclase and the substrate is the S enantiomer. The reaction is initiated by H" " attack on the oxygen of the epoxy group of the substrate held in the chair, boat, chair, boat unfolded conforma-... 

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. 

Oxidosqualene cyclase TS electron deficient C-2 squalene 2-amino, 2N-oxide(22) and 2,3-lmlno(30) squalene... 

Caras, I.W. and Bloch, K., Effects of a supernatant protein activator on microsomal squalene-2,3-oxide-lanosterol cyclase, J. Biol. Chem. 254 (23), 11816-11821, 1979. 

---