Acetylation of cholesterol

Calculate the thermodynamics of acetylation of cholesterol (to cholesterol acetate) using both acetic anhydride and ethyl acetate. Data for acetic acid and ethanol are available. Which reaction is more favorable ... 

Anhydrides and esters are routinely used as acylating agents. Anhydrides, however, are the reagents of choice for acylating alcohols. For example, acetylation of cholesterol is carried out using acetic anhydride (Z = 0C(=0)CH3), and not ethyl acetate (Z = OCH2CH3). 

HPLC on an octadecyl column can be applied to the analysis of caffeine from tea or cola syrup (Chapter 8—use 20% methanol, 0.8% acetic acid, and 79.2% water as eluant), the acetylation of cholesterol (Chapter 10) pulegone and citronellal from citronellol (Chapter 25), cholesterol from gallstones (Chapter 22), the isolation of eugenol from cloves (Chapter 28— use 10% methanol, 5.4% acetic acid, and 84.6% water as eluant), isolation of lycopene and /3-carotene (Chapter 9), and the product obtained from enzymatic reduction of ethyl acetoacetate (Chapter 59). 

In the following year, Fernholz and Chakravorty succeeded in oxidizing the acetate of cholestanol (prepared by acetylation of cholesterol in which the carbon-... 

Write a balanced, stoichiometric reaction for the synthesis of cholesterol from acetyl-CoA. 

The organism would probably grow quite well. The structure shown is simply analogous to the acetyl ester of cholesterol except that the side chain has been removed. The organism would, presumeably, degrade the sterol nucleus by its normal route. 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

The enzymes in peroxisomes do not attack shorter-chain fatty acids the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both further oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2). 

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.

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. 

About 1 g of cholesterol is ingested by adults each day in developed countries. A similar amount enters the lumen via the bile, synthesised from acetyl-CoA in the liver, is also released from sloughed epithelial cells. Absorption of cholesterol also occurs from the mixed micelles. Within the enterocyte, it is esterified and the cholesterol ester is incorporated into the chylomicrons. 

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 biosynthesis of steroids is complex, as one wonld expect since all the compounds in this group must be derived from a single precnrsor (cholesterol (5.4)). The primary sonrce of all the compounds involved in steroid synthesis is acetate, in the form of acetyl-coenzyme A. Cholesterol, besides being ingested in food, is synthesized in large amounts, and an adnlt human contains about 250 g of cholesterol. In contrast, the steroid hormones are produced at the milligram level or lower. 

Scheme 7.6 Stereoselective acetylation of the hydroxyl diethyl ester (9) to the (S)-acetate as an intermediate for the synthesis of a squalene synthase inhibitor ( ) of cholesterol synthesis.

ALTERNATE PROTOCOL 2 ENZYMATIC MEASUREMENT OF CHOLESTEROL Test combination kits for enzymatic determination of cholesterol in food are now commercially available. For the determination of total cholesterol, esterified cholesterol is hydrolyzed to free cholesterol and fatty acid under mild alkaline conditions. Cholesterol oxidase oxidizes free cholesterol to cholest-4-en-3-one to generate hydrogen peroxide, which further oxidizes methanol to formaldehyde. Formaldehyde then reacts with acetyl acetone in the presence of NH4+ ions to form yellow lutidine dye, which is subsequently determined spectrophotometric al 1 y. 

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-... 

The sequence of cholesterol biosynthesis begins with a condensation in the cytosol of two molecules of acetyl-CoA in a reaction catalyzed by thiolase (fig. 20.3). The next step requires the enzyme /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) synthase. This enzyme catalyzes the condensation of a third acetyl-CoA with /3-ketobutyryl-CoA to yield HMG-CoA. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. The activity of this reductase is primarily responsible for control of the rate of cholesterol biosynthesis. 

Sterol carrier protein 2 has also been shown to be involved in the intracellular transport and metabolism of cholesterol. Hirai et al. (1994) suggested that sterol carrier protein 2 plays an important role during foam cell formation induced by acetylated LDL and may be an important step in atherosclerosis [142], Lipoproteins can bind lipopolysaccharide and decrease the lipopoly-saccharide-stimulated production of proinflammatory cytokines [142, 143], In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, or myeloperoxidase [144, 145],... 

Elevated levels of cholesterol in the blood, or hypercholesterolemia, have been linked to heart disease. Cholesterol, a necessary component of all cell membranes, is available to the body by two routes through the diet and through synthesis by the body itself. When changes to one s diet fail to reduce cholesterol levels, medication that inhibits cholesterol biosynthesis may be necessary. The biosynthetic pathway for cholesterol synthesis starts with acetyl-CoA (2.15) (Scheme 2.3). Through a series of steps, three... 

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