Cholesterol formation

This cholesterol formation reaction is catalyzed by the enzyme HMG-CoA reductase. One means to stop or reduce the production of cholesterol is to interfere with the supply of mevalonate. This is the function of Lipitor, which acts as an inhibitor of HMG-CoA reductase. 

Two conditions in which the rate of ketone body formation is increased are hypoglycaemia and prolonged starvation in adults or short-term starvation in children. What is the mechanism for increasing the rate Although there are several fates for fatty acids in the liver, triacylglycerol, phospholipid and cholesterol formation and oxidation via the Krebs cycle, the dominant pathway is ketone body formation (Figure 7.20). Three factor regulate the rate of ketone body formation (i) hormone sensitive lipase activ-... 

Figure 12 Amyloid cascade hypothesis (modified after Hardy and Selkoe, 2002. Reprinted with permission. American Association for the Advancement of Science) Cholesterol is thouc it to be involved in the formation of f-amyloid (AP) in the brain. Inhibitors of cholesterol formation could then prevent the formation of (neurotoxic) amyloid.

FIGURE 21-44 Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase insulin promotes dephosphorylation (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase. 

Plant waxes are concentrated on leaves and leaf sheaths and on fruit skins, or in some exceptional cases in the seeds of plants. Most vegetable waxes contain predominantly wax esters plus a variety of other lipid materials, which affect the degree of saturation and other properties of the wax derived from different sources. Most use has been made of plant waxes in the cosmetic sector, but there is increasing interest in the use of plant-derived sterols as dietary supplements to reduce cholesterol formation. 

The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis, as will be discussed shortly. 

Figure 26.13. Cholesterol Formation. Lanosterol is converted into cholesterol in a complex process.

Following up this phenomenon of catalysis by an electric charge, Llopis and Davies have recently shown (50a) that the hydrolysis of mono-layers of cholesterol formate (to cholesterol and formic acid) on 0.1 N... 

Fig. 21. (a) Rate constant for the hydrolysis on 0.1 N HCl of a cholesterol formate monolayer (50a). The incorporation into the film of a little long-chain sulfate (C22H46-SOi ) greatly accelerates the reaction. The calculated increases in reaction rate according to the Gouy (33) and Donnan equations are shown (b) For hydrolysis on 0.66 N HCl incorporation of CisH37N(CH3)+ into the film retards reaction because hydrogen ions are repelled from the surface (50a). 

This method of finding the concentration of ions near the surface was applied by Davies (49,21) to the hydrolysis of ionized films of the ester monocetyl succinate. Table IX shows that the rate constant for this hydrolysis, which increased 300% if calculated using bulk concentrations of the catalytic hydroxyl ion, varied by not more than 36% when evaluated using the surface concentrations deduced from (xxv) and (xxvi). Figure 19 shows a similar effect for the addition of neutral salt, the marked catalysis by which is thus demonstrated to be due entirely to electrostatic effects. The acceleration in the rate of hydrolysis of a film cholesterol formate if the surface bears a negative charge can be predicted on the basis of the Donnan equations (xxv) and (xxvi). Values of 5 of 6 A. and 8 A. have been used, the results being compared with experiment in Fig. 21a. The calculated retardation is shown in Fig. 21b. 

Detailed studies of the kinetics of cholesterol formation from MVA in man have been made and it has been discovered that sub-lines of Ehrlich ascites tumours that did not produce glycogen had a very low rate of steroidogenesis. 

Metabolic inhibitors may fail even where no species selectivity is required. The antimetabolite A4)5-cholestenone, designed to inhibit cholesterol synthesis, illustrates this it blocks the conversion of desmosterol to cholesterol, the final step in this pathway (Fig. 4). The blockade of cholesterol formation, however,... 

The discovery of ezetimibe, cholesterol-formation inhibitor, substituted azetidi-none 04JMC1. 

Cholesterol can be obtained from the diet or it can be synthesized de novo. An adult on a low-cholesterol diet typically synthesizes about 800 mg of cholesterol per day. The liver is the major site of cholesterol synthesis in mammals, although the intestine also forms significant amounts. The rale of cholesterol formation by these organs is highly responsive to the cellular level of cholesterol. This feedback regulation is mediated primarily by changes in the amount and activity of 3-hydroxy 3 methylglutaryl CoA reductase. As described earlier (p. 739), this enzyme catalyzes the formation of meval-onate, the committed step in cholesterol biosynthesis. HMG CoA reductase is controlled in multiple ways ... 

The answer is d. (Murray, pp 505-626. Scrivei, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) In the first stage ol cholesterol formation, acetyl coenzyme A condenses to form mevalonate, which is then phosphorylated and decarboxylated to form isopentenyl pyrophosphate. Half of the isopentenyl pyrophosphate isomerizes to form dimethylallyl pyrophosphate. These two isomeric C5 pyrophosphate units (isopentenyl pyrophosphate and dimethylallyl pyrophosphate) condense to form a CIO compound called geranyl pyrophosphate. Isopentenyl pyrophosphate then condenses with geranyl pyrophosphate to form the C15 compound farne-syl pyrophosphate. Finally, two farnesyl pyrophosphates condense in the presence of NADPH to form the C30 compound squalene. Squalene is ultimately cyclized through a series of steps to form cholesterol. Thus, the correct sequence of events leading from C5 units to C30 squalene is sequential condensation of 5-carbon units until a 15-carbon unit is formed, then condensation of two 15-carbon units to form squalene. 

A similar kinetic approach has been used to measure the specific activity of rat liver cytosol or of protein fractions obtained during the purification of SCP2 [21]. As with purified SCP2, the velocity of cholesterol formed is a hyperbolic function of the amount of cytosol protein present. As before, a straight line is obtained when the velocity of cholesterol formation is plotted as a function of cholesterol formed per mg of rat liver cytosol [21]. The purification factor for SCP2 can be calculated from X intercept for rat liver cytosol/2f intercept for purified SCP2. Using this approach [21], a purification factor of 1300-1400-fold was obtained. 

Another series of inhibitors of sterol metaboUsm in insects were synthesized by our group. These are 24,28-iminofucosterol (104) [176], stigmasta-5,24(28),28-trien-3)8-ol (105) [177], and cholesta-5,23,24-trien-3(j8-ol (106) [177] (Fig. 19). When the imine (104) or the allene (105) was administered in the silkworm diet in combination with sitosterol or cholesterol, the growth and development of B. mori were markedly retarded. The imine was expected to inhibit the conversion of fucosterol epoxide to desmosterol, and this was verified by in vitro experiments where the imine, at the same level as the substrate [ H]fucosterol epoxide (92), completely blocked the transformation into desmosterol. However, the imine may not exert its effect solely by limitation of desmosterol or cholesterol formation because cholesterol as the sole dietary sterol was unable to prevent the inhibitory effect. In contrast, the allene (106) seemed to exert little effect on sitosterol dealkylation because the sterols in silkworms fed on the allene (106) in combination with sitosterol were essentially the same as in controls. 

The first recognized human metabolic defect in the biosynthesis of cholesterol and isoprenoids was mevalonic aciduria [10]. Mevalonic aciduria is an autosomal recessive disorder that is quite rare, with only 30 known patients (D. Haas, 2006). In normal individuals, a small amount of mevalonic acid diffuses from cells into the plasma at levels proportional to the rate of cellular cholesterol formation. Patients with the severe, classical form of mevalonic aciduria excrete 10,000-200,000 times the normal amount of mevalonic acid because they have severely reduced amounts of mevalonate kinase activity. Their clinical features include failure to thrive, anemia, gastroenteropathy, hepatosplenomegaly, psychomotor retardation, hypotonia, ataxia, cataracts, and dysmorphic features [10]. Surprisingly, patients with severe deficiencies in mevalonate kinase show normal plasma cholesterol levels and cultured mevalonic aciduria fibroblasts have a rate of cholesterol synthesis that is half that of normal cells. Close examination of cholesterogenic enzymes in mevalonic aciduria fibroblasts has revealed a 6-fold increase in HMG-CoA reductase activity, which is postulated to compensate for the low mevalonate kinase activity. Thus, mevalonate is overproduced. 

Bile contains cholesterol and bile salts, the latter being important in keeping cholesterol in solution. An increase in cholesterol concenira-Hon ora decrease in bile salts may result in the formation of cholesterol. stones, if they give rise to symptoms, laparoscopic cholecystectomy i.s the treatment of choice. However, smalt non-calcified stones may be dissolved by prolonged oral adniinislration of the bile acid ursodeoxycholic acid, which decreases the cholesterol content of bile by inhibiting an enzyme involved in cholesterol formation. 

Formation of Cholesterol Formation of Other Plant Sterols Biological Activity of Plants Sterols Progestans in Plants and from Animals Progestagens from Insects Ecdysteroids Phytoecdysteroids Chemotaxis in Fungi Cucurbitacins... 

Condensation of mevalolactone with 8-alanine furnished the amide CXXIV, which has been reported to inhibit cholesterol formation in vivo [311]. A derivative of the thiol analog of mevalonic acid (CXXV) has been found to reduce serum cholesterol levels in the hypercholesterolemic rat at high doses [312]. Cysteine bearing a 5-carbon residue, (CXXVI) has been isolated from cat urine and named fehnine [313]. It has been speculated that felinine may be a normal product of mammalian metabolism and participates in the transfer of Cg isoprene units in the biosynthesis of sterols [313]. Felinine has been synthesized by Trippett [314], Eggerer [315], and more recently by Schoeberl et al. [316]. 

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