Squalene monooxygenase

Squalene monooxygenase, an enzyme bound to the endoplasmic reticulum, converts squalene to squalene-2,3-epoxide (Figure 25.35). This reaction employs FAD and NADPH as coenzymes and requires Og as well as a cytosolic protein called soluble protein activator. A second ER membrane enzyme, 2,3-oxidosqualene lanosterol cyclase, catalyzes the second reaction, which involves a succession of 1,2 shifts of hydride ions and methyl groups. 

Scheme 10.17 Reaction cycle of the flavin-dependent squalene monooxygenase. Dashed arrows indicate electron transport.

Organotellurium compounds such as dimethyltellurium dichloride and dimethyltelluride have been reported as potential inhibitors of squalene monooxygenase, causing a dramatic reduction in the rate of cholesterol biosynthesis and leading to degradation of the myelin sheath. 

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... 

Dimethyltelluride, dimethyltellurium dichloride and trimethyltelluronium chloride inhibit squalene monooxygenase in Schwann cells in culture. 

Tellurium-induced demyelination seems to be a result of squalene monooxygenase inhibition, and dimethyl tellurium dichloride may be the neurotoxic species presented to Schwann cells in vivo. 

The transformation of squalene into lanosterol. The squalene monooxygenase reaction requires 02, NADPH, FAD, phospholipid, and a cytosolic protein. The cyclase reaction has no known cofactor requirements. The reaction proceeds 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. 

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 synthase, 3 = Squalene monooxygenase, 4 = 2,3-Oxidosqualene lanosterol cyclase, 5 = Enzymes catalyzing 20 separate reactions. Note that squalene and lanosterol are acted upon by ER membrane enzymes while they are bound to carrier proteins in the cytoplasm. 

The enzyme squalene monooxygenase adds a single oxygen atom from O2 to the end of the squalene molecule, forming an epoxide. NADPH then reduces the other oxygen atom of O2 to H2O. The unsaturated carbons of the squalene 2, 3- epoxide are aligned in a way that allows conversion of the linear squalene epoxide into a cyclic sfructure. The cyclization leads to the formation of lanosterol, a sterol with the four-ring structure characteristic of the steroid nucleus. A series of complex... 

B) The action of squalene monooxygenase oxidizes carbon 14 of the squalene chain, forming an epoxide. 

C) Squalene monooxygenase is considered a mixed function oxidase because it catalyzes a reaction in which only one of the oxygen atoms of O2 is incorporated into the organic substrate. 

D) Squalene monooxygenase uses reduced flavin nucleotides (e.g., FAD(2H)) as the cosubstrate in the reaction. 

Figure 21.29 shows the conversion of squalene to cholesterol. The details of this conversion are far from simple. Squalene is converted to squalene epoxide in a reaction that requires both NADPH and molecular oxygen (O2). This reaction is catalyzed by squalene monooxygenase. Squalene epoxide then undergoes a complex cyclization reaction to form lanosterol. This remarkable reaction is catalyzed by squalene epoxide cyclase. The mechanism of the reaction is a concerted reaction—that is, one in which each part is essential for any other part to take place. No portion of a concerted reaction can be left out or changed because it all takes place simultaneously rather than in a sequence of steps. The conversion of lanosterol to cholesterol is a complex process. It is known that 20 steps are required to remove three methyl groups and to move a double bond, but we shall not discuss the details of the process. 

Gupta N, Porter TD. Garlic and garhe-derived compounds inhibit human squalene monooxygenase. J Nutr 2001 131 1662-1667. 

Gupta, N., and T. D. Porter. 2002. Inhibition of human squalene monooxygenase by selenium compounds. J. Biochem. Mol Toxicol. 76(1) ... 

Squalene is a naturally occurring triterpene and the precursor of steroids [66]. Oxidation (via squalene monooxygenase) of one of the terminal double bonds of squalene yields 2,3-squalene oxide, which undergoes enzyme-catalyzed cyclization to afford lanosterol, which is then elaborated into cholesterol and other steroids. Humans cannot live without squalene, because squalene is regarded as an essential building block for the production of hormones and other important substances in the human body. Squalene in olive oil may contribute to the low cholesterol levels of individuals consuming Mediterranean-style diets [67]. 

Squalene monooxygenase Ergl squalene-epoxidase oxidosqualene synthase Target of G4 inhibitors such as allylamines side target of some amines (G2)... 

Squalene (1) is converted to (35)-squalene 2,3-epoxide (2) by the action of microsomal squalene epoxidase in the presence of O2 and NADPH (EC 1.14.99.7) (Goad, 1991b Goodwin, 1985). Epoxidation can occur at either end of the squalene molecule, suggesting that an intermediate form is released from the synthetase enzyme complex prior to epoxidation and cyclization. Squalene epoxidase (squalene monooxygenase EC 1.14.99.7) is a two-component system. The nature of the terminal oxidase has not been examined in detail. The second component, a flavoprotein, has now been fully characterized as an NADPH-cytochrome c reductase. The monooxygenase from rat liver has a molecular weight of 47,000, and the protein requires NADPH, cyto-... 

---