Biosynthesis of cholesterol

Cholesterol is a major constituent of the cell membranes of animal cells (see p. 216). It would be possible for the body to provide its full daily cholesterol requirement (ca. 1 g) by synthesizing it itself However, with a mixed diet, only about half of the cholesterol is derived from endogenous biosynthesis, which takes place in the intestine and skin, and mainly in the liver (about 50%). The rest is taken up from food. Most of the cholesterol is incorporated into the lipid layer of plasma membranes, or converted into bile acids (see p. 314). A very small amount of cholesterol is used for biosynthesis of the steroid hormones (see p. 376). In addition, up to 1 g cholesterol per day is released into the bile and thus excreted. 

Cholesterol is one of the isoprenoids, synthesis of which starts from acetyl CoA (see p. 52). In a long and complex reaction chain, the C27 sterol is built up from C2 components. The biosynthesis of cholesterol can be divided into four sections. In the first (1), mevalonate, a Ce compound, arises from three molecules of acetyl CoA. In the second part (2), mevalonate is converted into isopen-tenyl diphosphate, the active isoprene. In the third part (3), six of these C5 molecules are linked to produce squalene, a C30 compound. Finally, squalene undergoes cycliza-tion, with three C atoms being removed, to yield cholesterol (4). The illustration only shows the most important intermediates in biosynthesis. 

The endergonic biosynthetic pathway described above is located entirely in the smooth endoplasmic reticulum. The energy needed comes from the CoA derivatives used and from ATP. The reducing agent in the formation of mevalonate and squalene, as well as in the final steps of cholesterol biosynthesis, is NADPH+H  

The division of the intermediates of the reaction pathway into three groups is characteristic CoA compounds, diphosphates, and highly lipophilic, poorly soluble compounds (squalene to cholesterol), which are bound to sterol carriers in the cell. 

Koolman, Color Atlas of Biochemistry, 2nd edition 2005 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Early in the 1930s the structure of cholesterol was determined, an achievement that concluded a brilliant chapter in structural organic chemistry. At that time it was not clear how such a complex structure could be assembled from small molecules. 

Work on the biosynthesis of cholesterol began in earnest after Rudolf Schoenheimer and David Rittenberg, at Columbia University, developed isotopic tracer techniques for the analysis of biochemical pathways. In 1941, Rittenberg and Konrad Bloch were able to show that deuterium-labeled acetate (C2H, COO ) was a precursor of cholesterol in rats and mice. In 1949, James Bonner and Barbarin Arreguin postulated that three acetates could combine to form a single five-carbon unit called isoprene. 

This proposal supported, with an earlier prediction of Sir Robert Robinson, that cholesterol was a cyclization product of squalene, a 30-carbon polymer of isoprene units. In 1953, Robert Bums Woodward and Bloch postulated a cyclization scheme for squalene (fig. 20.2) that was later shown to be correct. In 1956, the unknown isoprenoid precursor was identified as mevalonic acid by Karl Folkers and others at Merck, Sharpe, and Dohme Laboratories. The discovery of mevalonate provided the missing link in the basic outline of cholesterol biosynthesis. Since that time, the sequence and the stereochemical course for the biosynthesis of cholesterol have been defined in detail. 

In the experiments with acetic acid labelled radioisotopically and fed to ani-mals, it has been established that the cholesterol carbon framework is made up entirely of the acetic acid carbon. 

Biosynthesis of cholesterol from acetyl-CoA proceeds, assisted by the enzymes of endoplasmic reticulum and hyaloplasm, in many tissues and organs. This pro-cess is especially active in the liver of adult humans. 

Cholesterol biosynthesis is a multistage process in general, it may be divided into three steps  

The initial reactions in the first step, prior to the formation of P-hydroxy-p-methylglutaryl-CoA from acetyl-CoA, resemble those involved in ketogenesis with the only distinction that ketogenesis occurs in the mitochondria, while cho-lesterol biosynthesis is carried out extramitochondrially  

Further, p-hydroxy-(3-methylglutaryl-CoA is converted with hydroxymethylgluta-ryl-CoA reductase to mevalonic acid  

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The biosynthesis of cholesterol as outlined in Figure 26 10 is admittedly quite complicated It will aid your understanding of the process if you consider the following questions... 

Squalene epoxidase, a key enzyme in the biosynthesis of cholesterol (9), epoxidizes one face of one of the three different olefins in squalene (7) to give squalene epoxide (8), which then cyclizes eventually to give cholesterol (9) (Scheme 1). The AD of squalene (7)... 

The biosynthesis of cholesterol may be divided into five steps (l) Synthesis of mevalonate occurs from acetyl-CoA (Figure 26-1). (2) Isoprenoid units are formed... 

Figure 26-3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks Refer to labeling of squalene in Figure 26-2.

Fiandanese and coworkers [103] described a new approach for the synthesis of the butenolides xerulin (6/1-207) and dihydroxerulin (6/1-208), which are of interest as potent noncytotoxic inhibitors of the biosynthesis of cholesterol (Scheme 6/1.53). The key transformation is a Pd°-catalyzed Sonogashira/addition process of 6/1-204 or 6/1-206 with (Z)-3-iodo-2-propenoic acid 6/1-205, which is followed by the formation of a lactone to give 6/1-207 and 6/1-208, respectively. 

The primary defect in familial hypercholesterolemia is the inability to bind LDL to the LDL receptor (LDL-R) or, rarely, a defect of internalizing the LDL-R complex into the cell after normal binding. This leads to lack of LDL degradation by cells and unregulated biosynthesis of cholesterol, with total cholesterol and LDL cholesterol (LDL-C) being inversely proportional to the deficit in LDL-Rs. 

Popjak, G. (1958). Biosynthesis of cholesterol and related substances. Annu. Rev. 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Competitive blocker of a-adrenergic receptors in heart and blood vessels Inhibits the enzyme HMG-CoA reductase and reduces the biosynthesis of cholesterol Acts as an angiotensin II receptor antagonist Inhibits the synthesis of prostaglandins via the selective inhibition of the enzyme cyclooxygenase-2... 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

The statins are considered as a major breakthrough in the development of hypolipaemic drugs. These agents inhibit the biosynthesis of cholesterol (Fig. 8) and also increase the density of LDL-receptors. They induce a potent lowering of total cholesterol, LDL, and a weak lowering effect on the triglycerides. The plasma HDL-cholesterol level is moderately enhanced. 

Fig. 8. Most important steps in the biosynthesis of cholesterol. The reduction of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to yield mevalonic acid is an important rate-limiting step and also the site of attack of the HMG-CoA-reductase inhibitors (statins).

Figure 7.66 Trifluoromethyl alcohols and ketones as inhibitors of the biosynthesis of cholesterol.

Trifluoromethyl ketones and alcohol derivatives of squalene have been prepared in order to inhibit squalene epoxycyclase. This important enzyme regulates the biosynthesis of cholesterol. It bears a cysteine in its active site. Although these compounds have been shown to be good inhibitors, the involved mechanism is different from what was expected. Indeed, they do not inhibit squalene epoxycyclase, but they are substrates of this enzyme and are transformed into fluorohydroxysterols. The repression of the expression of HMG-CoA reductase is responsible for the observed inhibition of cholesterol biosynthesis. This repression comes from the back-regulation that is exerted by fluorohydroxysterols. Indeed, these compounds induce an important diminution of the cell activity of HMG-CoA reductase (Figure 7.66). °... 

Varma, R., Nene, S. (2003). Biosynthesis of cholesterol oxidase by Streptomyces lavendulae NCIM 2421. Enz. Microb. Technol, 33, 286-291. 

AcetylCoA carboxylase Glycogen synthase HMGCoA reductase NO synthase Biosynthesis of fatty adds Glycogen synthesis Biosynthesis of cholesterol Biosynthesis of NO ... 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Less frequently NADPH is used to reduce an isolated double bond. An example is the hydrogenation of desmosterol by NADPH (Eq. 15-11), the final step in one of the pathways of biosynthesis of cholesterol (Fig. 22-7). In this and in other reactions of the same... 

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