The Synthesis of Cholesterol

Cholesterol, which is essential for the synthesis of adrenal, ovarian, and testicular steroid hormones, originates from two sources. The body synthesizes approximately 2 g of cholesterol per day, according to the following pathway  

In addition, between 300 and 800 mg of cholesterol is ingested per day, depending on a person s diet. On average, between 300 and 1500 mg of cholesterol is excreted per day. 

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Squalene is also an intermediate in the synthesis of cholesterol. StmcturaHy, chemically, and biogeneticaHy, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instabiUty however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of Hpid-soluble dmgs. 

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

Trace each of the carbon atoms of mevalonate through the synthesis of cholesterol, and determine the source (i.e., the position in the mevalonate structure) of each carbon in the final structure. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Which of the following drugs recommended for the lowering of blood cholesterol inhibits the synthesis of cholesterol by blocking 3-hydroxy-3-me thy 1 glutary 1-coenzyme A (HMG-CoA) reductase ... 

Warfarin CoA to mevalonic acid for the synthesis of cholesterol Anticoagulant Inhibits synthesis of clotting factors II (prothrombin), VII, IX,... 

On the other hand, in the synthesis of cholesterol (30) by Woodward and CO workers [10] the less stable fran -configuration between rings C and D is attained through a homosteroid (29). i.e. a steroid analogue in which the C/D indane system is substituted by a decalin in which the rran -configuration is the thermodynamically favoured (Scheme 8.7). The conversion of the six-membered ring into one of five members is carried out at a later stage, under conditions that do not affect the preformed tran -junction. 

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

Receptors can mediate the action of endogenous signalling compounds and may therefore be viewed as regulatory proteins. Such receptors are the physiological targets for neurotransmitters and hormones. Other types of receptors include enzyme proteins, transport proteins and structural proteins. For example, statins inhibit an enzyme catalysing the synthesis of cholesterol and loop diuretics inhibit an enzyme that facilitates the re-uptake of salt in primary urine. 

Also known as statins. HMG CoA reductase (Hydroxymethyl-Glutaryl Coenzyme A Reductase) inhibitors block the synthesis of cholesterol in liver by competitively inhibiting HMG CoA reductase activity, also cause depletion of critical intracellular pools of sterols and increased transcription of LDL receptors leading to enhanced removal from plasma of LDL cholesterol and LDL precursors. They also reduce hepatic synthesis of VLDL, increase plasma HDL. Reduction of LDL occurs over 4-6 weeks. 

Vitamin E is a family of eight compounds, four tocopherols and four tocotrienols. Tocotrienols appear to affect a key enzyme in the liver (HMG CoA reductase), which plays a key role in the synthesis of cholesterol. As such tocotrienols help maintain good cardiovascular health. Vitamin E is an antioxidant and prevents the oxidation of LDL (the bad cholesterol). Vitamin E functions as anticoagulant, which means it delays the clotting of the blood. It can help prevent thrombosis, the formation of blood clots in the arteries. 

Inhibition of HMG-CoA reductase. Top The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas). 

The remaining six disorders are due to defects of enzymes involved specifically in the synthesis of cholesterol (Fig. 5.1.2). The detection of specific intermediate sterol species in cells, tissues, and/or body fluids of patients suspected to suffer from a defect in cholesterol biosynthesis based on their clinical presentation is often the first line of diagnosis, which can then be followed by enzyme and/or molecular diagnostic testing [9]. 

A simple transposition of a C=C bond occurs during metabolism of the common fatty acid oleic acid (see Fig. 17-9), and you will encounter some spectacular examples of double-bond repositioning in the synthesis of cholesterol (see Fig. 21-35). 

We first describe the biosynthesis of fatty acids, the primary components of both triacylglycerols and phospholipids, then examine the assembly of fatty acids into triacylglycerols and the simpler membrane phospholipids. Finally, we consider the synthesis of cholesterol, a component of some membranes and the precursor of steroids such as the bile acids, sex hormones, and adrenocortical hormones. 

The reactions and enzymes involved in the synthesis of cholesterol from mevalonate are illustrated in Figure 18.5. [Note The numbers shown in brackets below correspond to numbered reactions shown in this figure.]... 

One of the best therapeutic approaches may be to prevent absorption of cholesterol from the intestines by inclusion of a higher fiber content in the diet.66 Supplementation with a cholesterol-binding resin may provide additional protection. Plant sterols also interfere with cholesterol absorption. Incorporation of esters of sitostanol into margarine provides an easy method of administration. Supplemental vitamin E may also be of value.q Another effective approach is to decrease the rate of cholesterol synthesis by administration of drugs that inhibit the synthesis of cholesterol. Inhibitors of HMG-CoA reductase,s hh (e.g., vaLostatin) iso-pentenyl-PP isomerase, squalene synthase (e.g.,... 

The final chapter in part 5, chapter 20, Metabolism of Cholesterol, deals with the synthesis of cholesterol and some of its derivatives, the steroid hormones and the bile acids. This chapter considers the structure, function and metabolism of these molecules. Also, the health-related concerns associated with cholesterol excess are addressed. 

On the other hand, fermented dairy products such as yoghurt have been hypothesized to reduce LDL-cholesterol due to their effects on encouraging a gut microbial environment to facilitate the production of short chain fatty acids and thus reduce the synthesis of cholesterol (Nestel, 2008). Fermented dairy has in fact been proposed as a nutraceuti-cal with cholesterol-lowering potential (Chen et al., 2008). 

DHEA may affect the synthesis of cholesterol and other lipids involved in atherogenesis. Many studies have assessed the relationship between endogenous DHEA levels and the risk for developing cardiovascular disease. Both high and low DHEA levels have been associated with increased risk of cardiovascular morbidity in men. In postmenopausal women, cardiovascular morbidity was greater in women with high DHEAS levels. 

The first stage in the synthesis of cholesterol is the formation of isopentenyl pyrophosphate Fig. 1). Acetyl CoA and acetoacetyl CoA combine to form 3-hydroxy-3-methylglutaryl CoA (HMG CoA). This process takes place in the liver, where the HMG CoA in the mitochondria is used to form ketone bodies during starvation (see Topic K2), whereas that in the cytosol is used to synthesize cholesterol in the fed state (under the influence of cholesterol). HMG CoA is then reduced to mevalonate by HMG CoA reductase Fig. 1). This is the committed step in cholesterol biosynthesis and is a key control point. Mevalonate is converted into 3-isopentenyl pyrophosphate by three consecutive reactions each involving ATP, with C02 being released in the last reaction Fig. 1). 

LCAT), which catalyzes the synthesis of cholesterol esters (F14, S46, S59) apoA-II, which activates hepatic triglyceride lipase (J2) and apoC-II, which activates lipoprotein lipase, responsible for the hydrolysis of triglycerides in chylomicrons and VLDL (H20, L5). Their mode of action is considered in Section 4 when the individual apolipoproteins are discussed. 

Examples of HMG-CoA reductase inhibitors include lovastatin, simvastatin, and pravastatin the so-called statins. These drugs inhibit the rate-limiting enzyme in the synthesis of cholesterol in the liver. In addition, the reduction in the formation of hepatic cholesterol leads to a compensatory increase in the hepatic synthesis of LDL receptors on the surface of hepatocytes. These receptors bind plasma LDL leading to a reduction in plasma LDL—the bad cholesterol. 

In summary, cholesterol appears to play an important role in modifying membranes, at least the plasma membranes of animal cells, in temperature-compensatory manners. The significance of cholesterol in adaptation to temperature by animals raises several interesting evolutionary questions. Do the many taxa that lack cholesterol employ other types of molecules to achieve the sorts of adaptations effected by cholesterol in animal cells In view of the requirement for molecular oxygen for the synthesis of cholesterol, did the earliest cells, which evolved in the near absence of molecular oxygen, develop oxygen-independent synthetic pathways for producing lipids with cholesterol-like effects ... 

A few words about HDL these lipoproteins are synthesized largely by the liver. They act as ApoE, ApoC, and ApoA traffickers, but in addition, they also serve as a factory for the synthesis of cholesterol esters. HDL may absorb free cholesterol from various peripheral tissues, including arteries. Cholesterol is then converted to a large extent to fatty acyl esters by the action of the enzyme lecithin-cholesterol acyltransferase [LCAT see Equation 19.2)]. LCAT is activated by ApoA-I. Inactive LCAT is a plasma component. 

Insulin also exerts a stimulatory effect on the synthesis of cholesterol in the liver. In this tissue, HMG-CoA reductase is activated. HMG-CoA reductase, like hormone-sensitive lipase, can exist in two forms one is phosphorylated (inactive) and the other is dephosphorylated (active). Phosphorylation of the enzyme depends on an increase in the cellular concentration of cAMP and activation of protein kinase. The dephosphorylation (activation) is catalyzed by a phosphatase. In fat cells, a similar phosphatase dephosphorylates (inactivates) hormone-sensitive lipase. Insulin stimulates the activity of the phosphatase in both liver and fat cells. In this way, active HMG-CoA reductase predominates in the liver cell and directs HMG-CoA into cholesterol synthesis, and in the fat cell hormone-sensitive lipase is inactivated. 

What is the mechanism of the stimulation, by triglyceride in the diet, of the synthesis of cholesterol ... 

The subjects in our study also developed hypocholesterolemia. The decline in total plasma cholesterol during manganese depletion in both studies is presumably related to the need for manganese at several sites in the synthesis of cholesterol (5). 

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