Formation of cholesterol

Step 5—Formation of Cholesterol The formation of cholesterol from lanosterol takes place in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain (Figure 26-3). The methyl groups on C,4 and C4 are removed to form 14-desmethyl lanosterol and then zymosterol. The double bond at 03—C9 is subsequently moved to Cj-Cg in two steps, forming desmosterol. Finally, the double bond of the side chain is reduced, producing cholesterol. The exact order in which the steps described actually take place is not known with certainty. 

Chloramines change LDL charge characteristics, inducing uncontrolled uptake of modified LDL by macrophages and the formation of cholesterol-engorged foam cells [160]. The ability of HOC1 to modify LDL was confirmed in a model system [161]. 

Helical ribbons were found to be metastable intermediates in the process of cholesterol crystallization from bile in the gallbladder.160 Since gallstones result from the formation of cholesterol monohydrate crystals in supersaturated... 

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 formation of cholesterol chlorohydrins has been a subject of intense research [99-102]. The role of these compounds is not yet fully understood, but in addition to cytotoxicity and a possible action on atherosclerosis [100], they have been suggested to be biomarkers of myeloperoxidase-derived HOC1 [103]. Moreover, chlorohydrins and other halohydrins are useful intermediates for the synthesis of a vast range of biologically active natural and synthetic products [104, 105], In fact, considering the importance of these compounds, their preparation is of major interest. 

In the bile cholesterol is kept soluble by fats, phospholipids like lecithin and by bile acids. The important bile acids in human bile are cholic acid, chen-odeoxycholic acid or chenodiol and ursodeoxycholic acid or ursodiol. Bile acids increase bile production. Dehydrocholic acid, a semisynthetic cholate is especially active in this respect. It stimulates the production of bile of low specific gravity and is therefore called a hydrocholeretic drug. Chenodiol and ursodiol but not cholic acid decrease the cholesterol content of bile by reducing cholesterol production and cholesterol secretion. Ursodiol also decreases cholesterol reabsorption. By these actions chenodiol and ursodiol are able to decrease the formation of cholesterolic gallstones and they can promote their dissolution. 

Inhibitors of HMG-CoA reductase activity (for example compac-tin240), or compounds that lower the levels of the enzyme (including a number of oxygenated cholesterol derivatives,241- 24 la such as 25-liy-droxycholesterol), not only decrease the formation of polyprenyl diphosphate, but also affect the formation of cholesterol and the polyprenyl side-chains of coenzyme Q. Consequently, prolonged treatment with such compounds may cause side effects, for example, changes in membrane fluidity (see also, Section III,5), decreased activity of membrane enzymes,1214,2,3 and inactivation of membrane transport systems,246 and, therefore, indirectly prevent glvcosvlation of proteins. 

Formation of cholesterol and some of its derivatives. All of the carbon atoms of cholesterol are derived from acetyl-CoA by way of mevalonate in a pathway with 33 reaction steps. From cholesterol a wide variety of steroids and bile acids and bile salts are formed. Many of the reactions leading to cholesterol derivatives are organ-... 

Third, acyl-CoA cholesterol acyltransferase (ACAT) [EC 2.3.1.26], an enzyme that works after the formation of cholesterol, was considered a unique target of inhibition [32], ACAT catalyzes the synthesis of cholesteiyl esters from cholesterol and long-chain fatty acyl-CoA. ACAT plays important roles in the body, for example, in the absorption of dietary cholesterol from the intestines, production of lipoprotein in liver and formation of foam cells from macrophages in arterial walls. Therefore, ACAT inhibition is expected not only to lower plasma cholesterol levels but also to have a direct effect at the arterial wall. A number of synthetic ACAT inhibitors such as ureas, imidazoles, and acyl amides have been developed [33], Several groups have searched for novel ACAT inhibitors... 

Figure 18.3. Scheme for the formation of cholesterol epoxides. Compounds are as follows (1) CHOL (2) a-epoxide (3) ft-epoxide (4) triol. For abbreviations, see Table 18.1. 

Ahn, D.U., Nam, K.C., Du, M., Jo, C. 2001. Effect of irradiation and packaging conditions after cooking on the formation of cholesterol and lipid oxidation products in meats during storage. Meat Sci. 57, 413-418. 

Lai, S.-M., Gray, J.I., Buckley, D.J., Kelly, P.M. 1995. Influence of free radicals and other factors on formation of cholesterol oxidation products in spray-dried whole egg. J. Agric. Food Chem. 43, 1127-1131. 

HMG-CoA reductase, the enzyme that catalyses the formation of mevalonate [MVA, (2)] from HMG by an irreversible reaction that is considered rate-limiting with respect to the formation of cholesterol, has received much attention. Details of the purification of the enzyme from chicken liver and baker s yeast are available,15 and the solubilized enzyme from rat liver microsomes is readily and reversibly inactivated at temperatures below 19°C.16 Cold-inactivation is an uncommon phenomenon, and all the enzymes that have been found to exhibit this behaviour have been soluble proteins. Native HMG-CoA reductase is a particulate enzyme that is probably bound to protein or lipid of the microsomal membrane, although it is not known whether the solubilized enzyme contains a lipid component. Microsomal reductase is not cold-sensitive, and the cold-inactivation of the solubilized enzyme can be completely prevented by addition to the preparation of NADP+ or (more effectively) of NAD PH.17... 

Epand RM. Do proteins facilitate the formation of cholesterol-rich domains Biochim. Biophys. Acta 2004 1666 227-238. 

The common immediate precursor for the biosynthetic formation of cholesterol and triterpenes is squalene (76) which is derived from the head-to-head condensation of two molecules of farnesyl pyrophosphate (73) (equation 11) . This is a complex reaction... 

For these and other (practical and academic) reasons the behaviour ol cholesterol in monolayers and bilayers, both being effective model systems. Is oltcn studied. Here, we discuss some results regarding the fluidity of cholesterol mono-layers and the formation of cholesterol exudates upon monolayer collapse. 

Terpenic compounds are resorbed from the digestive tract and sue situated in the hepatie tissues. Thanks to their ability to dissolve fats, they prevent the formation of cholesterol gathering inside the liver and they also recover proper colloidal state to the bile. Terpenes also enhance the bile content in the hepatic cells and in the liver tracts. Terpenic hydrocarbons dilating the smooth muscles [78, 79] make the hepatic tracts more distended both inside and outside. It has been pointed out that the terpenes contained in Rowachol dissolve bile stones [87-89]. The meehanism of terpenes activity has not as yet been completely explained. It was explained that menthol and other monoterpenes inhibit the activity of the lecithin-cholesterol acyltransferase in the human serum [90]. They also lower the activity of the hepatic S-3-hydroxy-3-methylglutaryl-CoA reductase, which is responsible for the physiological inhibition of cholesterol synthesis in the liver [82, 91, 92]. 

MVA is now known to be metabolized by routes other than those which give rise to terpenoids and steroids. The breakdown occurs predominantly in the kidneys to give C2 units that can be utilized in fatty-acid synthesis. The sterol and the shunt pathways have been evaluated in nine different tissues of rat previous conclusions that the kidneys are the predominant site of both types of metabolism have been confirmed. MVA is known to accumulate, at a low level, in the blood, and these results suggest that impairment of renal clearance of serum MVA by either route may account for the hypercholesterolaemia associated with some kidney disorders. A study of the effects of possible antimetabolites of MVA (for example the 2,3-anhydro-compound) on the formation of cholesterol in cell-free systems from liver has been reported. ... 

Cholesterol is synthesized mainly in the liver by a three-stage process. All 27 carbon atoms in the cholesterol molecule are derived from acetyl-CoA. The first stage is the synthesis of the activated five-carbon isoprene unit, isopentenyl pyrophosphate. Six molecules of isopentenyl pyrophosphate then condense to form squalene in a sequence of reactions that also synthesize isoprenoid intermediates that are important in protein isoprenylation modifications. The characteristic four-ring structure of cholesterol is then formed by cycUzing of the linear squalene molecule. Several demethylations, the reduction of a double bond, and the migration of another double bond result in the formation of cholesterol. Figure 34-1 provides an overview of cholesterol biosynthesis. 

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